Tweedelijnsbehandeling BRAF-V600E/K gemuteerd irresectabel of gemetastaseerd stadium III/IV

Publicatiedatum: 09-10-2025

Beoordeeld op geldigheid: 01-08-2025

Uitgangsvraag

Wat is de plaats van systemische therapie in de tweede lijns-behandeling van patiënten met een BRAF-V600E/K gemuteerd irresectabel of gemetastaseerd stadium III/IV melanoom?

Aanbeveling

Overweeg behandeling in studieverband.

Overweeg als tweedelijnsbehandeloptie voor patiënten met een BRAFV600-gemuteerd irresectabel of gemetastaseerd melanoom volgende behandelopties: TIL- behandeling of anti-PD-1 blokkade met ipilimumab (indien niet gebruikt in de eerstelijns setting) of doelgerichte behandeling in de vorm van BRAF + MEK-inhibitie (indien niet gebruikt in de eerstelijns setting).

Individualiseer deze behandelbeslissing rekening houdend met het behandeldoel (kortetermijnvoordeel versus langetermijnvoordeel) en klinische kenmerken [lactaatdehydrogenase (LDH), betrokken organen, prestatiestatus (PS), tumorlast, snelheid van ziekteprogressie], comorbiditeiten, bijwerkingen van de verschillende therapieën en patiëntvoorkeuren.

Overwegingen

De cruciale uitkomstmaat overall survival in de context van patiënten met irresectabel of gemetastaseerd stadium III/IV melanoom met een BRAF-V600E/K mutatie werd gerapporteerd door 8 RCTs die verschillende systemische behandelingen in de tweede lijn onderzochten.

MDX010-20 rapporteerde het effect van ipilimumab met een gp100 peptide vaccin en ipilimumab zonder een gp100 peptide vaccin in vergelijking met alleen gp100 op overall survival bij patiënten met niet-receerbaar of gemetastaseerd stadium III/IV melanoom (Revicki, 2012; Hodi, 2010). Er werd daarbij een klinisch relevant voordeel gevonden voor het gebruik van ipilimumab met een gp100 peptide vaccine en voor ipilimumab zonder een gp100 peptide vaccine in vergelijking met gp100 alleen. Het absolute verschil in mediane overall survival tussen behandeling met ipilimumab met een gp100 peptide vaccine versus behandeling met alleen gp100 was 3.6 maanden met een hazard ratio van 0.68 (95% CI 0.55–0.85). Het absolute verschil in mediane overall survival tussen behandeling met ipilimumab zonder een gp100 peptide vaccine versus behandeling met alleen gp100 was 3.7 maanden met een hazard ratio van 0.66 (0.51–0.87). De bewijskracht van deze studie is laag. Dit heeft te maken met het risico op bias (de rol van de sponsor in deze studie) en door imprecisie omdat de confidence interval de grens voor klinische besluitvorming omvat.

De studie rapporteerde ook het effect op progression free survival, adverse events en kwaliteit van leven. Er werd geen klinisch relevant verschil gevonden tussen de studiegroepen voor de uitkomsten progression free survival, adverse events en kwaliteit van leven.

KEYNOTE-006 rapporteerde het effect van pembrolizumab (iedere 2 of 3 weken) in vergelijking met ipilimumab (iedere 3 weken) op overall survival bij patiënten met unresectable of gemetastaseerd stadium III/IV melanoom (Robert, 2019; Carlino, 2018; Schachter, 2017; Robert, 2015). Er werd daarbij geen klinisch relevant voordeel gevonden voor het gebruik van pembrolizumab. Het absolute verschil in mediane overall survival tussen behandeling met pembrolizumab versus behandeling met ipilimumab was 16.8 maanden met een hazard ratio van 0.73 (95% CI 0.61–0.88). De bewijskracht van deze studie is zeer laag. Dit heeft te maken met het risico op bias (open-label studie design; meer patiënten stopten in de controle groep; de rol van de sponsor) en door imprecisie, omdat de confidence interval de grens voor klinische besluitvorming omvat.

De studie rapporteerde ook het effect op progression free survival en adverse events. Voor de uitkomst progression free survival werd een klinisch relevant voordeel gevonden voor behandeling met pembrolizumab. Het absolute verschil in mediane progressievrije overleving was 5.0 maanden (HR 0.57; 95% CI 0.48–0.67). Er werd geen klinisch relevant verschil gevonden tussen de studiegroepen voor de uitkomst adverse events.

MASTERKEY-265 rapporteerde het effect van T-VEC plus pembrolizumab in vergelijking met placebo plus pembrolizumab op overall survival bij patiënten met unresectable of gemetastaseerd stadium III/IV melanoom (Chesney, 2023). Er werd daarbij geen klinisch relevant voordeel gevonden voor het gebruik van T-VEC plus pembrolizumab (HR 0.96; 95% CI 0.76 to 1.22). De bewijskracht van deze studie is zeer laag. Dit heeft te maken met het risico op bias (meer patiënten stopten in de controle groep; studie werd vroegtijdig gestopt) en door imprecisie.

De studie rapporteerde ook het effect op progression free survival en adverse events. Er werd geen klinisch relevant verschil gevonden tussen de studiegroepen voor de uitkomsten progression free survival en adverse events.

OPTiM rapporteerde het effect van T-VEC in vergelijking met GM-CSF op overall survival bij patiënten met niet-receerbaar of gemetastaseerd stadium III/IV melanoom (Andtbacka, 2019; Andtbacka, 2015). Er werd daarbij geen klinisch relevant voordeel gevonden voor het gebruik van T-VEC. Het absolute verschil in mediane overall survival tussen behandeling met T-VEC versus behandeling met GM-CSF was 4.4 maanden met een hazard ratio 0.79 (95% CI 0.62–1.00). De bewijskracht van deze studie is zeer laag. Dit heeft te maken met het risico op bias (open-label studie design; meer patiënten stopten in de interventie groep; de rol van de sponsor) en door imprecisie, omdat het betrouwbaarheidsinterval de grens voor klinische besluitvorming omvat.

De studie rapporteerde ook het effect op adverse events. Er werd geen klinisch relevant verschil gevonden tussen de studiegroepen voor de uitkomst adverse events.

COMBI-v rapporteerde niet het effect van dabrafenib en trametinib versus vemurafenib op de mediane OS. Echter, het absolute verschil in mediane 3-jaarsoverleving tussen dabrafenib en trametinib (45%) en vemurafenib (32%) was 13%, met een hogere 3-jaarsoverleving in de dabrafenib en trametinib groep. Dit verschil werd volgens de PASKWIL-criteria als klinisch relevant beschouwd. De bewijskracht hiervan is redelijk, dit heeft te maken met het risico op bias.

De studie rapporteerde ook het effect op progression free survival en adverse events. Voor de uitkomst progression free survival werd een klinisch relevant voordeel gevonden voor behandeling met cobimetinib gecombineerd met vemurafenib. Het absolute verschil in mediane progressievrije overleving was 5.4 maanden (HR 0.51; 95% CI 0.39–0.67). Er werd geen klinisch relevant verschil gevonden tussen de studiegroepen voor de uitkomst adverse events.

COLUMBUS rapporteerde het effect van encorafenib en binimetinib versus encorafenib versus vemurafenib op de mediane OS. Behandeling met encorafenib en binimetinib resulteerde in de langste mediane OS. Het absolute verschil tussen encorafenib en binimetinib (33,6 maanden) en encorafenib (23,5 maanden) was 10,1 maanden met een HR van 0,81 (95% BI: 0,61 tot 1,06). Dit verschil werd volgens de PASKWIL-criteria niet als klinisch relevant beschouwd. Het absolute verschil tussen encorafenib en binimetinib (33,6 maanden) en vemurafenib (16,9 maanden) was 16,7 maanden met een HR van 0,61 (95% BI: 0,47 tot 0,79). Dit verschil werd volgens de PASKWIL-criteria als klinisch relevant beschouwd. Het absolute verschil tussen encorafenib (23,5 maanden) en vemurafenib (16,9 maanden) was 6,6 maanden met een HR van 0,76 (95% BI: 0,58 tot 0,98). Dit verschil werd volgens de PASKWIL-criteria niet als klinisch relevant beschouwd. De bewijskracht hiervan is redelijk, dit heeft te maken met de imprecisie, omdat de confidence interval de grens voor klinische besluitvorming omvat.

De studie rapporteerde ook het effect op progression free survival en adverse events. Voor de uitkomst progression free survival werd een klinisch relevant voordeel gevonden voor behandeling met encorafenib end binimetinib vergeleken met vemurafenib. Het absolute verschil in mediane progressievrije overleving was 7.6 maanden (HR en CI niet gegeven). Er werd geen klinisch relevant verschil gevonden tussen de studiegroepen voor de uitkomst adverse events.

NCT02278887 rapporteerde het effect van tumor-infiltrating lymphocytes (TILs) versus ipilimumab op overall survival bij patiënten met unresectable of gemetastaseerd stadium III/IV melanoom (Rohaan, 2022). Er werd daarbij geen klinisch relevant voordeel gevonden voor het gebruik van TILs. Het absolute verschil in mediane overall survival was 6.9 maanden met een hazard ratio van 0.83 (95% CI, 0.54 to 1.27). De bewijskracht van deze studie is zeer laag. Dit heeft te maken met het risico op bias (onduidelijke randomisatie, open-label studie design, en doordat meer patiënten in de controle groep de behandeling stopten in vergelijking met de interventie groep) en imprecisie.

De studie rapporteerde ook het effect op progression free survival, adverse events en kwaliteit van leven. Een langere mediane progression free survival werd gevonden voor patiënten in de TILs groep, met een absoluut verschil van 4.1 maanden met patiënten in de ipilimumab groep (HR 0.50; 95% CI 0.35 to 0.72). Behandeling met TILs resulteerde in een hoger percentage patiënten met adverse events (risk difference: 0.43; 95% CI 0.32, 0.54; NNH=2). Er werd geen klinisch relevant verschil gevonden tussen de studiegroepen voor de uitkomst kwaliteit van leven.

Checkmate-037 rapporteerde het effect van nivolumab versus investigator’s choice chemotherapy (ICC; dacarbazine or carboplatin plus paclitaxel) op overall survival bij patiënten met unresectable of gemetastaseerd stadium III/IV melanoom (Weber 2015, Larkin 2018). Er werd daarbij geen klinisch relevant voordeel gevonden voor het gebruik van nivolumab. Het absolute verschil in mediane overall survival was 1.3 maanden met een hazard ratio van 0.95 (95.54% CI 0.73 to 1.24). De bewijskracht van deze studie is zeer laag. Dit heeft te maken met het risico op bias (open-label studie design; doordat meer patiënten in de interventie groep de behandeling stopten in vergelijking met de controle groep; de rol van de sponsor in deze studie) en imprecisie.

Kwaliteit van bewijs

Ipilimumab with or without a gp100 peptide vaccine compared to gp100 alone
De overall kwaliteit van bewijs is zeer laag. Dit betekent dat we zeer onzeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaat overall survival.

Pembrolizumab every 2 weeks or every 3 weeks compared to ipilimumab

De overall kwaliteit van bewijs is zeer laag. Dit betekent dat we zeer onzeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaat overall survival.

T-VEC plus pembrolizumab versus placebo plus pembrolizumab

De overall kwaliteit van bewijs is zeer laag. Dit betekent dat we zeer onzeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaat overall survival.

T-VEC versus GM-CSF

De overall kwaliteit van bewijs is zeer laag. Dit betekent dat we zeer onzeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaat overall survival.

Dabrafenib and trametinib versus vemurafenib
De overall kwaliteit van bewijs is redelijk. Dit betekent dat we redelijk zeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaat overall survival.

Encorafenib and binimetinib versus encorafenib versus vemurafenib

Encorafenib and binimetinib versus encorafenib

De overall kwaliteit van bewijs is laag. Dit betekent dat we onzeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaat overall survival.

Encorafenib en binimetinib versus vemurafenib
De overall kwaliteit van bewijs is laag. Dit betekent dat we onzeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaat overall survival.

Encorafenib versus vemurafenib

De overall kwaliteit van bewijs is laag. Dit betekent dat we onzeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaat overall survival.

Tumor-infiltrating lymphocytes (TILs) versus ipilimumab

De overall kwaliteit van bewijs is zeer laag. Dit betekent dat we zeer onzeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaat overall survival.

Nivolumab versus investigator’s choice chemotherapy

(ICC; dacarbazine or carboplatin plus paclitaxel)

De overall kwaliteit van bewijs is zeer laag. Dit betekent dat we zeer onzeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaat overall survival.

Ondanks de vooruitgang in de behandeling van irresectabel of gemetastaseerd melanoom, blijven veel vragen onbeantwoord en voor een belangrijke deel van de patiënten blijft de prognose slecht. Inclusie van irresectabel of gemetastaseerd melanoom patienten in klinische studies blijft daarom de hoogste prioriteit in alle settings.

Waarden en voorkeuren van patiënten (en eventueel hun naasten/verzorgers)
Bij de behandeling van patiënten met een irresectabel of gemetastaseerd stadium III/IV melanoom dient zorgvuldig rekening te worden gehouden met de waarden en voorkeuren van de patiënt. De keuze voor deelname aan klinische studies of voor tweedelijnsbehandelopties – zoals TIL-therapie, anti-PD-1-blokkade met ipilimumab, of doelgerichte therapie in de vorm van BRAF + MEK-inhibitie bij patiënten met een BRAFV600-mutatie – wordt bij voorkeur afgestemd op individuele patiëntkenmerken en specifieke behandeldoelen.

Professioneel perspectief
Factoren zoals het gewenste behandeldoel (kortetermijn- of langetermijnvoordeel), klinische kenmerken (bijvoorbeeld lactaatdehydrogenase-niveaus, betrokken organen, prestatiestatus, tumorlast en progressiesnelheid), evenals comorbiditeiten spelen een cruciale rol bij deze behandelbeslissing. Door deze aspecten zorgvuldig af te wegen in lijn met de voorkeuren van de patiënt kan een optimaal behandeltraject worden gekozen dat zowel klinische effectiviteit waarborgt als aansluit bij de persoonlijke waarden van de patiënt.

TIL-therapie is een intensieve behandeloptie voor geselecteerde patiënten (<76 jaar, PS 0-1, LDH <2 ULN en 1 eerdere anti-PD-1 bevattende behandeling) die de bijwerkingen ervan kunnen verdragen. Er is (nog) geen EMA goedkeuring voor deze behandeling.

Als de eerstelijnsbehandeling anti-PD-1-monotherapie was of als patiënten een primaire refractaire ziekte hadden na anti-PD-1-therapie, is ipilimumab en nivolumab een optie op basis van de resultaten van de fase II SWOG S1616-studie. In deze studie werd behandeling met ipilimumab en nivolumab geassocieerd met een statistisch significante verbetering van de PFS vergeleken met ipilimumab alleen (HR 0,63; 90% BI 0,41-0,97; p = 0,04).

Kostenaspecten
Vanwege geheime prijsafspraken, kan de exacte impact op het geneesmiddelenbudget niet worden vastgesteld, maar het staat vast dat deze impact hoog is. Het huidig prijsniveau wordt echter acceptabel geacht in verhouding tot de effectiviteit van de behandeling. Een lagere prijs van de behandelingen zou desondanks in alle opzichten zeer wenselijk en naar mening van de werkgroep zelfs noodzakelijk zijn, mede met het oog op de komende ontwikkelingen en het betaalbaar houden en borgen van een goede kwaliteit van de zorg in de nabije toekomst.

Haalbaarheid/aanvaardbaarheid
Bij de behandeling van patiënten met een irresectabel of gemetastaseerd stadium III/IV melanoom is het van belang niet alleen te kijken naar klinische effectiviteit en patiëntvoorkeuren, maar ook naar de haalbaarheid en aanvaardbaarheid van de aanbevolen behandelopties. Deelname aan klinische studies kan voor sommige patiënten een haalbare optie zijn, mits er toegang is tot geschikte onderzoeksfaciliteiten en de patiënt bereid is de mogelijk intensieve studieverplichtingen te dragen. Voor patiënten met een BRAFV600-mutatie kunnen tweedelijnsopties zoals TIL-therapie, anti-PD-1-blokkade met ipilimumab, of BRAF + MEK-inhibitie passend zijn, maar de haalbaarheid van deze therapieën wordt mede bepaald door de beschikbaarheid en toegankelijkheid van specialistische zorg en middelen. De aanvaardbaarheid van deze behandelopties hangt bovendien sterk samen met het behandeldoel en de verwachte belasting voor de patiënt: sommige patiënten kunnen de voorkeur geven aan behandelingen met een potentieel kortetermijnvoordeel en lagere bijwerkingenlast, terwijl anderen bereid zijn intensievere therapieën te overwegen in ruil voor een mogelijke langere overlevingswinst. Zo kunnen haalbaarheid en aanvaardbaarheid per patiënt variëren, wat zorgvuldige overweging van hun persoonlijke en klinische omstandigheden vereist om een passend behandeltraject te waarborgen.

Rationale van de aanbevelingen

De werkgroep is van mening dat deelname aan klinische studies in de behandeling van irresectabel of gemetastaseerd stadium III/IV melanoom de hoogste prioriteit heeft, gezien de sombere prognose voor een groot deel van de patiënten en de noodzaak om effectiviteit en aanvaardbaarheid van behandelingen verder te optimaliseren. Hierbij is het essentieel om patiëntwaarden en individuele klinische kenmerken leidend te laten zijn, zodat behandelbeslissingen aansluiten bij zowel haalbaarheid als de persoonlijke voorkeuren van de patiënt.

Onderbouwing

Conclusies / Summary of Findings

Ipilimumab with or without a gp100 peptide vaccine compared to gp100 alone

Overall survival

Very low GRADE

The evidence is very uncertain about the effect of ipilimumab with or without a gp100 peptide vaccine on overall survival when compared with treatment with gp100 alone in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Hodi, 2010

Very low GRADE

The evidence is very uncertain about the effect of ipilimumab with or without a gp100 peptide vaccine on overall survival when compared with treatment Ipilimumab alone in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Hodi, 2010

Progression free survival

Very low GRADE

The evidence is very uncertain about the effect of ipilimumab with or without a gp100 peptide vaccine on progression free survival when compared with treatment with gp100 alone in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Hodi, 2010

Adverse events

Very low GRADE

The evidence is very uncertain about the effect of ipilimumab with or without a gp100 peptide vaccine on adverse events when compared with treatment with gp100 alone in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Hodi, 2010

Quality of Life

Very low GRADE

The evidence is very uncertain about the effect of ipilimumab with or without a gp100 peptide vaccine on quality of life when compared with treatment with gp100 alone in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Revicki, 2012

Pembrolizumab every 2 weeks or every 3 weeks compared to ipilimumab

Overall survival

Very low GRADE

The evidence is very uncertain about the effect of pembrolizumab every 2 weeks or every 3 on overall survival when compared with treatment with ipilimumab in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Robert, 2019; Carlino, 2018; Schachter, 2017; Robert, 2015

Progression free survival

Very low GRADE

The evidence is very uncertain about the effect of pembrolizumab every 2 weeks or every 3 on adverse events when compared with treatment with ipilimumab in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Robert, 2019; Carlino, 2018; Schachter, 2017; Robert, 2015

Adverse events

Very low GRADE

Sources: Robert, 2019; Carlino, 2018; Schachter, 2017; Robert, 2015

T-VEC plus pembrolizumab versus placebo plus pembrolizumab

Overall survival

Very low GRADE

The evidence is very uncertain about the effect of treatment with T-VEC plus pembrolizumab on overall survival when compared with placebo plus pembrolizumab in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Chesney, 2023

Progression free survival

Very low GRADE

The evidence is very uncertain about the effect of treatment with T-VEC plus pembrolizumab on progression free survival when compared with placebo plus pembrolizumab in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Chesney, 2023

Adverse events

Very low GRADE

The evidence is very uncertain about the effect of treatment with T-VEC plus pembrolizumab on adverse events when compared with placebo plus pembrolizumab in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Chesney, 2023

T-VEC versus GM-CSF

Overall survival

Very low GRADE

The evidence is very uncertain about the effect of treatment with T-VEC on overall survival when compared with GM-CSF in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Andtbacka, 2019; Andtbacka, 2015

Adverse events

Very low GRADE

The evidence is very uncertain about the effect of treatment with T-VEC on adverse events when compared with GM-CSF in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Andtbacka, 2019; Andtbacka, 2015

Dabrafenib plus trametinib versus vemurafenib

Overall survival

Moderate GRADE

Dabrafenib plus trametinib likely result in an increase in overall survival when compared with vemurafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Robert, 2015; Robert, 2016

Progression free survival

Moderate GRADE

Dabrafenib plus trametinib likely result in an increase in progression free survival when compared with vemurafenib and placebo in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Robert, 2015; Robert, 2016

Adverse events

Moderate GRADE

Dabrafenib plus trametinib likely result in little to no difference in adverse events when compared with vemurafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Robert, 2015; Robert, 2016

Encorafenib and binimetinib versus encorafenib versus vemurafenib

Encorafenib plus binimetinib versus encorafenib

Overall survival

Moderate GRADE

Encorafenib plus binimetinib likely result in little to no difference in overall survival when compared with encorafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Dummer, 2018; Dummer, 2018-2; Ascierto, 2020

Progression free survival

Low GRADE

Encorafenib plus binimetinib may result in little to no difference in progression free survival when compared with encorafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Dummer, 2018; Dummer, 2018-2; Ascierto, 2020

Adverse events

Low GRADE

Encorafenib plus binimetinib may result in little to no difference in adverse events when compared with encorafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Dummer, 2018; Dummer, 2018-2; Ascierto, 2020

Encorafenib plus binimetinib versus vemurafenib

Overall survival

Moderate GRADE

Encorafenib plus binimetinib likely result in an increase in overall survival when compared with vemurafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Dummer, 2018; Dummer, 2018-2; Ascierto, 2020

Progression free survival

Moderate GRADE

Encorafenib plus binimetinib likely result in an increase in progression free survival when compared with vemurafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Dummer, 2018; Dummer, 2018-2; Ascierto, 2020

Adverse events

Low GRADE

Encorafenib plus binimetinib may result in little to no difference in adverse events when compared with vemurafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Dummer, 201; Dummer, 2018-2; Ascierto, 2020

Encorafenib versus vemurafenib

Overall survival

Moderate GRADE

Encorafenib likely result in little to no difference in overall survival when compared with vemurafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving first line systemic therapy.

Source: Dummer, 2018; Dummer, 2018-2; Ascierto, 2020

Progression free survival

Low GRADE

Encorafenib may result in little to no difference in overall survival when compared with vemurafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving first line systemic therapy.

Source: Dummer, 2018; Dummer, 2018-2; Ascierto, 2020

Adverse events

Low GRADE

Encorafenib may result in little to no difference in adverse events when compared with vemurafenib in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving first line systemic therapy.

Source: Dummer, 2018; Dummer, 2018-2; Ascierto, 2020

Tumor-infiltrating lymphocytes (TILs) versus ipilimumab

Overall survival

Very low GRADE

The evidence is very uncertain about the effect of treatment with tumor-infiltrating lymphocytes (TILs) on overall survival when compared with ipilimumab in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Rohaan, 2022

Progression free survival

Very low GRADE

Source: Rohaan, 2022

Adverse events

Low GRADE

Treatment with tumor-infiltrating lymphocytes (TILs) may increase adverse events compared to ipilimumab in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Rohaan, 2022

Quality of life

Low GRADE

Treatment with tumor-infiltrating lymphocytes (TILs) may result in little to no difference in quality of life compared to ipilimumab in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Source: Rohaan, 2022

Nivolumab versus investigator’s choice chemotherapy

(ICC; dacarbazine or carboplatin plus paclitaxel)

Overall survival

Very low GRADE

The evidence is very uncertain about the effect of treatment with nivolumab on overall survival when compared with investigator’s choice chemotherapy in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Weber 2015; Larkin 2018

Progression free survival

Very low GRADE

The evidence is very uncertain about the effect of treatment with nivolumab on progression free survival when compared with investigator’s choice chemotherapy in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Weber 2015; Larkin 2018

Adverse events

Very low GRADE

The evidence is very uncertain about the effect of treatment with nivolumab on adverse events when compared with investigator’s choice chemotherapy in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Weber 2015; Larkin 2018

Quality of life

Very low GRADE

The evidence is very uncertain about the effect of treatment with nivolumab on quality of life when compared with investigator’s choice chemotherapy in patients with BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma receiving second line systemic therapy.

Sources: Weber 2015; Larkin 2018

Samenvatting literatuur

Eight randomized controlled trials that studied clinical outcomes of second line systemic therapy in patients with unresectable or metastatic stadium III/IV melanoma with a BRAF-V600E/K mutation were included in the literature analysis.

Description of studies

The study characteristics of the included trials are summarized in Table 1 in the main module Systematische therapie.

Revicki (2012), Hodi (2010) - MDX010-20 is a randomized, double-blind phase 3 study that enrolled patients at 125 centres in 13 countries in North America, South America, Europe, and Africa. This trial evaluated the effect of ipilimumab with or without a gp100 peptide vaccine on overall survival compared to gp100 alone in patients with unresectable stage III or IV melanoma who received a previous therapeutic regimen. Patients were randomized to ipilimumab, at a dose of 3 mg/kg of body weight, plus a gp100 peptide vaccine (n=403); ipilimumab (n=137); or gp100 (n=136). The mean age was 55.6 years in the ipilimumab plus gp100 peptide vaccine group, 56.8 years in the ipilimumab group and 57.4 years in the gp100 group. The percentage of males was 61.3 %, 59.1%, and 53.7% for the three groups, respectively. No information was available on the BRAF mutation status of the patients. Hodi (2010) reported on overall survival (OS), progression free survival (PFS), and adverse events (AEs) after a follow up time of 55 months. Revicki (2012) reported health related QoL outcomes during the 12 week treatment induction period. In this literature analysis the median outcomes for OS and PFS are analysed and the last endpoint for OS (2-year OS rates) are described.

Robert (2019), Carlino (2018), Schachter (2017), Robert (2015) - KEYNOTE-006 is an international, randomized, open-label phase 3 study performed in 16 countries. In this trial treatment with pembrolizumab versus ipilimumab was studied, to compare PD-1 inhibition with CTLA-4 blockade in patients with unresectable stage III/IV melanoma. Patients were randomized to pembrolizumab at a dose of 10 mg/kg of body weight every 2 weeks (n= 279); pembrolizumab at a dose of 10 mg/kg every 3 weeks (n=277); or ipilimumab at a dose of 3 mg/kg every 3 weeks (n=278). The mean age was 61 years in the pembrolizumab every 2 weeks group, 63 years in the pembrolizumab every 3 weeks group and 62 years in the ipilimumab group. The percentage of males was 57.7 %, 62.8%, and 58.3% for the three groups, respectively. Robert (2015) reported on OS, PFS, and AEs after a median follow-up of 7.9 months. Schachter (2017) reported updated results after a median follow-up of 22.9 months. Carlino (2018) reported updated outcomes by line of therapy and programmed death ligand 1 expression after a median follow-up of 33.9 months. Robert (2019) reported updated results of OS, PFS, and AEs after a median follow-up of 57.7 months. In this literature analysis the median outcomes for OS and PFS are analysed and the last endpoints for OS and PFS (2-year OS rates and 2-year PFS rates) are described.

Chesney (2023) - MASTERKEY-265 is a multicenter, double-blind, placebo controlled, randomized phase 3 study in 21 countries. This trial evaluated the efficacy and safety of T-VEC plus pembrolizumab versus placebo plus pembrolizumab in patients with stage IIIB-IV M1c unresectable melanoma. Patients were randomized to a combination of T-VEC plus pembrolizumab 200 mg once every 3 weeks (n=346) or placebo plus pembrolizumab 200 mg once every 3 weeks (n=346). The median age was 64 years in both study groups. The percentage of males was 57.5% in the T-VEC-pembrolizumab group and 63.3% placebo-pembrolizumab group. Chesney (2023) reported OS, PFS, and AES, after a median follow-up of 25.6 months for the primary PFS analysis, 31.0 months for the second OS interim analysis, and 35.6 months for the final analysis. In this literature analysis the median outcomes for OS and PFS are analysed.

Andtbacka (2019), Andtbacka (2015) - OPTiMis a randomized open-label phase 3 trial at 64 sites in the United States, the United Kingdom, Canada, and South Africa. This trial evaluated outcomes with talimogene laherparepvec (T-VEC) compared with granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with unresectable, stage IIIB/C/IV melanoma with ≥1 lesion that was suitable for direct or ultrasound-guided injection. Patients were randomized in 2:1 ratio to T-VEC (at the approved dose) (n=295 (68%)) of subcutaneous recombinant GM-CSF (n=141 (32%)). The median age was 63 years in the T-VEC group and 64 years in the GM-CSF group. The percentage of males was 59% in the T-VEC group and 55% in the GM-CSF group. Of 204 of the 295 (69%) in the T-VEC group, and 95 of the 141 (67%) in the GM-CSF group, the BRAF mutation status was unknown. For 157 of the 295 (53%) patients in the T-VEC group, and 76 of the 141 (54%) in the GM-CSF group, this was a second line therapy or later. OS and AEs were reported after a median follow-up of 49 months in the final analysis of OS. In this literature analysis the median OS is analysed.

Robert (2015), Robert (2016) - COMBI-v described an open-label, randomized, phase 3 study performed at 193 centres worldwide, where they evaluated the efficacy and safety of using combination therapy with dabrafenib plus trametinib versus vemurafenib monotherapy in patients with previously untreated patients with unresectable stage IIIC or IV melanoma with BRAF V600E or V600K mutations. A total of 704 patients were randomized in a 1:1 ratio to receive either a combination of dabrafenib (150 mg orally twice daily) plus trametinib (2 mg orally once daily) or vemurafenib (960 mg orally twice daily). The median age was 55 (18–91) years in the combination group and 54 (18–88) years in the control group. In the combination group 59% was male, compared to 51% in the control group. The following relevant outcomes were reported, OS, PFS and number of patients with serious AEs. In this literature analysis the median outcomes for OS and PFS are analysed and the last endpoints (3-year OS and 3-year PFS) of the outcomes are described.

Dummer (2018), Dummer (2018-2), Ascierto (2020) - COLUMBUS described a two-part, randomised, open-label, phase 3 study, performed at 162 sites in 28 countries. They evaluated the efficacy and safety of encorafenib plus binimetinib versus encorafenib alone and versus vemurafenib alone in patients with histologically confirmed, locally advanced, unresectable, or metastatic BRAF-V600 mutated cutaneous melanoma, or unknown primary melanoma. In part 1 of the study, 577 patients were randomly assigned (1:1:1) to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The median age was 57 (20–89; 48–66) years in the combination group, 54 (23–88; 46–63) years in the encorafenib control group and 56 (21–82; 45–65) years in the vemurafenib control group. In the combination group 60% was male, compared to 60% and 56% in the two control groups, respectively. The following relevant outcomes were reported, OS, PFS and number of patients with serious AEs. In this literature analysis the median outcomes for OS and PFS are analysed and the last endpoint (3-year OS) for the outcome OS is described.

Rohaan (2022) - NCT02278887 is a multicenter, open-label, phase 3, randomized trial with two participating clinical sites. In trial, tumor-infiltrating lymphocytes (TILs) were compared with ipilimumab in patients with unresectable or metastatic stage IIIC or IV cutaneous melanoma, with ≥1 lesions that could be surgically removed for generation of TILs. Patients were randomized to adoptive cell therapy with TILs (n=84) or ipilimumab at a dose of 3 mg/kg every 3 weeks (n=84). The median age was 59 years in both study groups. The percentage of males was 56% in the TILS group and 63% in the ipilimumab group. OS, PFS, AEs, and QoL were reported after a median follow-up of 33 months. In this literature analysis the median outcomes for OS and PFS are analysed and the last endpoints for OS and PFS (2-year OS rates and 6-month PFS rates) are described.

Weber (2015), Larkin (2018) - CHECKMATE-037 described a randomized, controlled, open-label, phase III study, which was conducted in 90 sites in 14 countries with a median follow-up of approximately 2 years. They evaluated the efficacy and safety of second-line nivolumab versus investigator’s choice chemotherapy (ICC) in patients with metastatic melanoma who experienced progression after treatment with first-line ipilimumab (plus a BRAF inhibitor, if BRAF-mutation positive). A total of 405 patients were randomized 2:1 to receive nivolumab (n= 272, 3 mg/kg every two weeks) or ICC (n = 133, dacarbazine 1,000 mg/m2 every 3 weeks or carboplatin area under the curve 6 plus paclitaxel 175 mg/m2 every 3 weeks). Of the 272 patients that received nivolumab, 60 (22%) had a BRAF mutation. Of the 133 patients that received ICC, 29 (22%) had a BRAF mutation. The median age was 59 (23-88) years in the nivolumab group and 62 (29-85) years in the ICC group. In the nivolumab group 65% was male, compared to 64% in the ICC group. The following relevant outcomes were reported, OS, PFS, number of patients with serious AEs and quality of life.

Results

Overall survival (OS) - Critical outcome

All eight included studies reported on OS.

MDX010-20 reported the effect of ipilimumab with a gp100 peptide vaccine plus ipilimumab without a gp100 peptide vaccine compared to gp100 alone on OS. The 2-year OS rates were 21.6% in the ipilimumab with a gp100 peptide vaccine group, 23.5% in the ipilimumab group, and 13.7% in the gp100 alone group. Treatment with ipilimumab with or without a gp100 peptide vaccine resulted in a longer median OS compared to treatment with gp100 alone. The absolute difference between treatment with ipilimumab with a gp100 peptide vaccine (10.0 months) and treatment with gp100 alone (6.2 months) was 3.8 months with a HR of 0.68 (95% CI 0.55–0.85). This difference was considered clinically relevant according to the PASKWIL criteria. The absolute difference between treatment with ipilimumab without gp100 (10.1 months) compared to treatment with gp100 peptide vaccine alone was 3.7 months with a HR of 0.66 (0.51–0.87). This difference was considered clinically relevant according to the PASKWIL criteria. Treatment with ipilimumab with a gp100 peptide vaccine resulted in a similar median OS compared to treatment with ipilimumab, with an absolute difference of 0.1 months and HR of 1.04 (95% CI 0.83–1.30). This difference was not considered clinically relevant according to the PASKWIL criteria.

KEYNOTE-006 reported the effect of pembrolizumab every 2 weeks or pembrolizumab every 3 weeks compared to ipilimumab every 3 weeks on OS. The 2-year OS rates were 55% in the pembrolizumab-every-2-weeks group, 55% in the pembrolizumab-every-3-weeks group, and 43% in the ipilimumab-every-3-weeks group. Treatment with pembrolizumab resulted in a longer median OS than treatment with ipilimumab. In patients receiving second-line therapy the absolute difference between the combined pembrolizumab groups (23.5 months) and the ipilimumab group (13.6 months) was 9.9 months with a HR of 0.75 (95% CI 0.55–1.03). This difference was not considered clinically relevant according to the PASKWIL criteria.

MASTERKEY-265 reported the effect of a combination of T-VEC plus pembrolizumab versus placebo plus pembrolizumab on OS. Treatment with T-VEC-pembrolizumab did not result in a longer OS compared with treatment with placebo-pembrolizumab. The median OS was not estimable in the T-VEC plus pembrolizumab group and 49.2 months (40.57 to not estimable) in the pembrolizumab group with a HR of 0.96 (95% CI 0.76 to 1.22; P =0 .74).

OPTiM reported the effect of T-VEC versus GM-CSF on OS in first line treatment, without subgroup analyses on BRAF mutation. Treatment with T-VEC resulted in a longer median OS than treatment with GM-CSF. The median follow-up in the final OS analysis was 49 months. Median OS weas 23.3 months (CI, 19.5-29.6) and 18.9 months (95% CI, 16.0-23.7) in the TVEC and GM-CSF arm, respectively (HR, 0.79; 95% CI, 0.62-1.00). This difference was not considered clinically relevant according to the PASKWIL criteria.

COLUMBUS reported the effect of encorafenib plus binimetinib versus encorafenib versus vemurafenib on median OS. Treatment with encorafenib and binimetinib resulted in the longest median OS. The absolute difference between encorafenib and binimetinib (33.6 months) and encorafenib (23.5 months) was 10.1 months with a HR of 0.81 (95% 0.61 to 1.06). This difference was not considered clinically relevant according to the PASKWIL criteria. The absolute difference between encorafenib and binimetinib (33.6 months) and vemurafenib (16.9 months) was 16.7 months with a HR of 0.61 (95% 0.47 to 0.79). This difference was considered clinically relevant according to the PASKWIL criteria. The absolute difference between encorafenib (23.5 months) and vemurafenib (16.9 months) was 6.6 months with a HR of 0.76 (95% 0.58 to 0.98). This difference was not considered clinically relevant according to the PASKWIL criteria.

COMBI-v did not reported the effect of dabrafenib plus trametinib versus vemurafenib on median OS. However, the absolute difference in median 3-year survival between dabrafenib and trametinib (45%) versus vemurafenib (32%) was 13%, with a higher 3-year survival in the dabrafenib and trametinib group. This difference was considered clinically relevant according to the PASKWIL criteria.

NCT02278887 reported the effect of tumor-infiltrating lymphocytes (TILs) versus ipilimumab on OS. The 2-year OS rates were 54.3% in the TILs group and 44.1% in the ipilimumab group. Treatment with TILs resulted in a longer median OS compared to treatment with ipilimumab. The absolute difference between the TILs group (25.8 months) and the ipilimumab group (18.9 months) was 6.9 months with a HR of 0.83 (95% CI, 0.54 to 1.27). This difference was not considered clinically relevant according to the PASKWIL criteria.

Checkmate-037 reported the effect of nivolumab versus investigator’s choice chemotherapy (ICC; dacarbazine or carboplatin plus paclitaxel) on OS in patients with a BRAF mutation. The absolute difference in median OS in patients in the nivolumab group (9.07 months) compared to patients in the ICC group (17 months) was 7.93 months with a HR of 1.32 (0.75 to 2.32). This difference was not considered clinically relevant according to the PASKWIL criteria.

Figure 1. Forest plot of median overall survival for second line systemic therapy versus placebo, other systemic therapy, or best supportive care in patients with a BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma

_{^a For MDX010-20 the HR for ipilumab without gp100 versus gp100 vacine is shown.}

_{^b For KEYNOTE-066 the HR for combined pembrolizumab versus ipilimumab is shown.}

_{^c For COLOMBUS the HR for encorafenib and binimetinib versus vemurafenib is shown.
^d COMBI-v did not report the HR for median OS and is therefore not shown in this figure.}

Progression free survival – important outcome measure

Seven of the eight included studies reported on PFS.

MDX010-20 reported the effect of ipilimumab with a gp100 peptide vaccine and ipilimumab without a gp100 peptide vaccine compared to gp100 alone on PFS. Median PFS was comparable between the three study groups. After the first assessment of progression at week 12 there was a separation between the curves. There was a 19% reduction in the risk of progression in the ipilimumab plus gp100 group, as compared with gp100 alone with a HR of 0.81. There was a 36% reduction in risk of progression in the ipilimumab alone group as compared with the gp100 alone group with a HR of 0.64. According to the PASKWIL criteria we could not assess clinical relevance (median OS in the control group was < 12 months).

KEYNOTE-006 reported the effect of pembrolizumab every 2 weeks or pembrolizumab every 3 weeks compared to ipilimumab every 3 weeks on PFS. The 2-year PFS rates were 31% in the pembrolizumab-every-2-weeks group, 28% in the pembrolizumab-every-3-weeks group, and 14% in the ipilimumab-every-3-weeks group. Treatment with pembrolizumab resulted in a longer median PFS than treatment with ipilimumab. The absolute difference between the combined pembrolizumab groups and the ipilimumab group was 5.0 months with a HR of 0.57 (95% CI 0.48–0.67). This difference was considered clinically relevant according to the PASKWIL criteria.

MASTERKEY-265 reported the effect of a combination of T-VEC plus pembrolizumab versus placebo plus pembrolizumab on PFS. Treatment with T-VEC-pembrolizumab resulted in a longer PFS compared with treatment with placebo-pembrolizumab. The absolute difference between the combined pembrolizumab groups and the ipilimumab group was 5.8 months with a HR of 0.86 (95% CI, 0.71 to 1.04). This difference was not considered clinically relevant according to the PASKWIL criteria.

COLUMBUS reported the effect of encorafenib plus binimetinib versus encorafenib versus vemurafenib on PFS. Treatment with encorafenib and binimetinib resulted in the longest PFS. The absolute difference between encorafenib and binimetinib (14.9 months) and encorafenib (9.6 months) was 5.3 months. According to the PASKWIL criteria we could not assess clinical relevance (HR and 95% CI not provided). The absolute difference between encorafenib and binimetinib (14.9 months) and vemurafenib (7.3 month) was 7.6 months with a HR of 0.51 (95% 0.39 to 0.67). This difference was considered clinically relevant according to the PASKWIL criteria. The absolute difference between encorafenib (9.6 months) and vemurafenib (7.3 months) was 2.3 months. According to the PASKWIL criteria we could not assess clinical relevance (HR and 95% CI not provided).

COMBI-v reported the effect of dabrafenib plus trametinib versus vemurafenib on PFS. Treatment with dabrafenib and trametinib resulted in a longer PFS than treatment with vemurafenib. The absolute difference between the dabrafenib and trametinib group (11.4 months) and the vemurafenib group (7.3 months) was 4,1 months with a HR of 0.56 (95% 0.46 to 0.69). This difference was considered clinically relevant according to the PASKWIL criteria.

NCT02278887 reported the effect of tumor-infiltrating lymphocytes (TILs) versus ipilimumab on PFS. The 6-month PFS rates were 52.7% in the TILs group and 21.4% in the ipilimumab group. Treatment with TILs resulted in a longer median PFS compared to treatment with ipilimumab. The absolute difference between the TILs group and the ipilimumab group was 4.1 months with a HR of 0.50 (95% CI, 0.35 to 0.72). This difference was considered clinically relevant according to the PASKWIL criteria.

Checkmate-037 reported the effect of nivolumab versus investigator’s choice chemotherapy (ICC; dacarbazine or carboplatin plus paclitaxel) on PFS in their total patient population (both BRAF mutant and BRAF wild-type). Treatment with nivolumab resulted in a shorter median PFS compared to treatment with ICC. The absolute difference was 0.6 months with a HR of 1.0 (95.1% CI, 0.78 to 1.44). This difference was not considered clinically relevant according to the PASKWIL criteria.

Figure 2. Forest plot of median progression free survival for second line systemic therapy versus placebo, other systemic therapy, or best supportive care in patients with a BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma

_{^a For KEYNOTE-066 the HR for combined pembrolizumab versus ipilimumab is shown.}

_{^b For COLOMBUS the HR for encorafenib and binimetinib versus vemurafenib is shown.}

_{^c MDX010-20 did not report the 95% CI of the HR for median PFS and is therefore not shown in this figure.}

Treatment related adverse events (AEs) grade ≥ 3 - Important outcome

Eight of the eight studies reported AE.

MDX010-20 reported the effect of ipilimumab with a gp100 peptide vaccine plus ipilimumab without a gp100 peptide vaccine compared to gp100 alone on AEs. Treatment with ipilimumab with a gp100 peptide vaccine resulted in a higher percentage of treatment related AEs grade ≥3 compared to treatment with gp100 alone. The risk difference between ipilimumab with a gp100 peptide vaccine and gp100 alone is 0.05 (95% CI -0.03, 0.13; NNH= 20) favoring treatment with gp100 alone. This difference is not considered clinically relevant according to the PASKWIL criteria. The risk difference between ipilimumab without a gp100 peptide vaccine and gp100 alone is 0.14 (95% CI 0.03, 0.25; NNH= 7) favoring treatment with gp100 alone. This difference is not considered clinically relevant according to the PASKWIL criteria.

KEYNOTE-006 reported the effect of pembrolizumab every 2 weeks or pembrolizumab every 3 weeks compared to ipilimumab every 3 weeks on AEs. Treatment with pembrolizumab (pooled groups) resulted in a lower percentage of treatment related AEs grade ≥3 compared to treatment with ipilimumab. The risk difference between pembrolizumab (pooled groups) and ipilimumab is -0.01 (95% CI -0.06, 0.05; NNH=100) favoring treatment with pembrolizumab. This difference is not considered clinically relevant according to the PASKWIL criteria.

MASTERKEY-265 reported the effect of a combination of T-VEC plus pembrolizumab versus placebo plus pembrolizumab on AEs. Treatment with T-VEC-pembrolizumab resulted in a higher percentage of treatment related AEs grade ≥3 compared to treatment with placebo-pembrolizumab. The risk difference between T-VEC plus pembrolizumab and placebo-pembrolizumab is 0.05 (95% CI -0.01, 0.10; NNH=20) favoring treatment with placebo plus pembrolizumab. This difference is not considered clinically relevant according to the PASKWIL criteria.

OPTiM reported the effect of T-VEC versus GM-CSF on AEs. Treatment with T-VEC resulted in a higher percentage of treatment related AEs grade ≥3 compared to treatment with GM-CSF. The risk difference between T-VEC and GM-CSF is 0.07 (95% CI 0.02, 0.12; NNH=14) favoring treatment with GM-CSF. This difference is not considered clinically relevant according to the PASKWIL criteria.

COLUMBUS reported the effect of encorafenib and binimetinib versus encorafenib versus vemurafenib on AEs. There was no risk difference in the percentage of AEs between encorafenib and binimetinib (68%) and encorafenib (68%). The risk difference in AEs between encorafenib and binimetinib (68%) and vemurafenib (66%) was 2%. This difference was not considered clinically relevant according to the PASKWIL criteria. The risk difference between encorafenib (68%) and vemurafenib (66%) was also 2%. This difference was not considered clinically relevant according to the PASKWIL criteria.

COMBI-v reported the effect of dabrafenib and trametinib versus vemurafenib on AEs. Treatment with dabrafenib and trametinib resulted in less AEs than treatment with vemurafenib. The risk difference between the dabrafenib and trametinib group (48%) and the vemurafenib group (57%) was 9%. This difference was not considered clinically relevant according to the PASKWIL criteria.

NCT02278887 reported the effect of tumor-infiltrating lymphocytes (TILs) versus ipilimumab on AEs. Treatment with TILs resulted in a higher percentage of treatment related AEs grade ≥3 compared to treatment with ipilimumab. The risk difference between TILs and ipilimumab is 0.43 (95% CI 0.32, 0.54; NNH=2) favoring treatment with ipilimumab. This difference is considered clinically relevant according to the PASKWIL criteria.

Checkmate-037 reported the effect of nivolumab versus investigator’s choice chemotherapy (ICC; dacarbazine or carboplatin plus paclitaxel) on AES. Treatment with nivolumab resulted in a higher percentage of treatment related AEs grade ≥3 compared to treatment with ICC. The risk difference between nivolumab and ICC is 0.17 (95% CI 0.09, 0.25; NNH=6) favoring treatment with ICC. This difference is not considered clinically relevant according to the PASKWIL criteria.

Figure 3. Forest plot of Adverse Events for second line systemic therapy versus placebo, other systemic therapy, or best supportive care in patients with a BRAF-V600E/K mutation with unresectable or metastatic stadium III/IV melanoma

_{^a For MDX010-20 the risk difference for ipilumab without gp100 versus gp100 vacine is shown.}

_{^b For KEYNOTE-066 the risk difference for combined pembrolizumab versus ipilimumab is shown.}

_{^c For COLOMBUS the risk difference for encorafenib and binimetinib versus vemurafenib is shown.}

Quality of life (QoL) - Important outcome

Three of the eight studies reported the effect of second line systemic therapy on QoL.

MDX010-20 analysed the effect of ipilimumab with or without a gp100 peptide vaccine compared to gp100 alone on health related quality of life (HRQL) with the EORTC QLQ-C30. Mean changes of baseline to week 12 scores for function, global health status, and symptoms were analysed. These were categorized as “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20). In general, the authors observed “no change” or “a little” impairment in the ipilimumab plus gp100 and ipilimumab alone groups. The study showed significant differences in constipation, favouring ipilimumab (p<0.05). This difference is not considered clinically relevant (difference less than 10 points). In the gp100 alone group, moderate to large changes for global health, role function, fatigue, and pain were observed. These differences between the treatment arms are not considered clinically relevant (difference less than 10 points). The authors conclude that ipilimumab with or without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients.

NCT02278887 of tumor-infiltrating lymphocytes (TILs) versus ipilimumab on QoL. In this study, Health-related quality of life (HRQL) was measured with the EORTC Quality-of- Life Questionnaire Core 15 palliative care. In this questionnaire, higher scores on the global quality-of-life and functioning scales indicate better functioning and higher scores on the symptom scales indicate higher levels of symptom burden. Higher mean scores were observed after treatment among patients in the TIL group on the global health-related quality-of life (difference 7.7), physical functioning (difference 2.9), and emotional functioning (difference 9.7) domains compared to patients in the ipilimumab group. These differences are not considered clinically relevant (differences less than 10 points). Lower symptoms scores were observed after treatment among patients in the TIL group for fatigue, pain, and insomnia compared to patients in the ipilimumab group, with differences still observed at week 60. These differences are not considered clinically relevant (differences less than 10 points). Higher symptom scores of nausea and vomiting were observed among patients in the TIL group compared to patients in the ipilimumab group. This difference was not considered clinically relevant (difference less than 10 points).

Checkmate-037 analysed the effect of nivolumab versus investigator’s choice chemotherapy (ICC; dacarbazine or carboplatin plus paclitaxel) on QoL. HRQL was assessed using the EORTC QLQ-C30 version 3 and EuroQoL EQ-5D summary index and visual analog scale. The study showed that quality of life in patients on nivolumab remained stable for all EORTC QLQ-C30 individual scales during the treatment course. No scores reached the minimal important difference of ≥10 points. The authors stated that no clinically significant improvement was observed for either the EuroQoL EQ-5D utility index or the EuroQoL EQ-5D visual analog scale for nivolumab. In the article the authors mention that at 12 weeks, the ICC group demonstrated a clinically significant decrease in the EuroQoL EQ-5D utility index. These data are not shown in the article or supplementary material.

Level of evidence of the literature

There are four levels of evidence: high, moderate, low, and very low. RCTs start at a high level of evidence.

Ipilimumab with or without a gp100 peptide vaccine compared to gp100 alone

The level of evidence regarding the outcome measure overall survival was downgraded by three levels because of study limitations (risk of bias), the confidence interval encloses the threshold for a clinically relevant effect and no clinically relevant effect (imprecision), and the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure progression free survival was downgraded by three levels because of study limitations (risk of bias), because we could not asses clinical relevance according to the PASKWIL criteria (imprecision), and the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure adverse events was downgraded by three levels because of study limitations (risk of bias), was downgraded by one level because the optimal information size is not met (imprecision) and the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure quality of life was downgraded by three levels because of study limitations (risk of bias), was downgraded by one level because the optimal information size is not met (imprecision), and the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

Pembrolizumab every 2 weeks or every 3 weeks compared to ipilimumab

The level of evidence regarding the outcome measure overall survival was downgraded by four levels because of study limitations (risk of bias -2); the confidence interval encloses the threshold for a clinically relevant effect and no clinically relevant effect (imprecision), and the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure progression free survival was downgraded by three levels because of study limitations (risk of bias -2) and the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure adverse events was downgraded by four levels because of study limitations (risk of bias -2), because the optimal information size is not met (imprecision), and because of a lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

T-VEC plus pembrolizumab versus placebo plus pembrolizumab

The level of evidence regarding the outcome measure overall survival was downgraded by four levels because of study limitations (risk of bias -2), the optimal information size is not met (imprecision), and the lack of a subgroup analysis (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure progression free survival was downgraded by four levels because of study limitations (risk of bias -2), the optimal information size is not met (imprecision), and the lack of a subgroup analysis (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure adverse events was downgraded by four levels because of study limitations (risk of bias -2), the optimal information size is not met (imprecision), and the lack of a subgroup analysis (indirectness). Therefore, the level of evidence was graded as very low.

T-VEC versus GM-CSF

The level of evidence regarding the outcome measure adverse events was downgraded by four levels because of study limitations (risk of bias -2), was downgraded by one level because the optimal information size is not met (imprecision), and the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

Dabrafenib and trametinib versus vemurafenib

The level of evidence regarding the outcome measure overall survival was downgraded by one level because of study limitations (risk of bias -1). Therefore, the level of evidence was graded as moderate.

The level of evidence regarding the outcome measure progression free survival was downgraded by one level because of study limitations (risk of bias -1). Therefore, the level of evidence was graded as moderate.

The level of evidence regarding the outcome measure adverse events was downgraded by two level because of study limitations (risk of bias -2). Therefore, the level of evidence was graded as low.

Encorafenib and binimetinib versus encorafenib versus vemurafenib

Encorafenib and binimetinib versus encorafenib

The level of evidence regarding the outcome measure overall survival was downgraded by two levels because of study limitations (risk of bias -1) and because the confidence interval encloses the threshold for a clinically relevant effect (imprecision -1). Therefore, the level of evidence was graded as low.

The level of evidence regarding the outcome measure progression free survival was downgraded by two level because of study limitations (risk of bias -1), and no clinically relevant effect could be established (imprecision -1). Therefore, the level of evidence was graded as low.

The level of evidence regarding the outcome measure adverse events was downgraded by two level because of study limitations (risk of bias -2). Therefore, the level of evidence was graded as low.

Encorafenib and binimetinib versus vemurafenib

The level of evidence regarding the outcome measure adverse events was downgraded by two level because of study limitations (risk of bias -2). Therefore, the level of evidence was graded as low.

Encorafenib versus vemurafenib

The level of evidence regarding the outcome measure adverse events was downgraded by two level because of study limitations (risk of bias -2). Therefore, the level of evidence was graded as low.

Tumor-infiltrating lymphocytes (TILs) versus ipilimumab

The level of evidence regarding the outcome measure overall survival was downgraded by three levels because of study limitations (risk of bias), the confidence interval encloses the threshold for a clinically relevant effect and no clinically relevant effect (imprecision), and because of the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure progression free survival was downgraded by three levels because of study limitations (risk of bias) the confidence interval encloses the threshold for a clinically relevant effect and no clinically relevant effect (imprecision), and because of the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure adverse events was downgraded by two levels because of study limitations (risk of bias), and because of the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as low

The level of evidence regarding the outcome measure quality of life was downgraded by two levels because of study limitations (risk of bias), and because of the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as low.

Nivolumab versus investigator’s choice chemotherapy

(ICC; dacarbazine or carboplatin plus paclitaxel)

The level of evidence regarding the outcome measure overall survival was downgraded by three levels because of study limitations (risk of bias -2); was downgraded by one level because the optimal information size is not met (imprecision). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure progression free survival was downgraded by four levels because of study limitations (risk of bias -2), the optimal information size is not met (imprecision), and the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure adverse events was downgraded by four levels because of study limitations (risk of bias -2), the confidence interval encloses the threshold for a clinically relevant effect and no clinically relevant effect (imprecision) , and the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

The level of evidence regarding the outcome measure quality of life was downgraded by three levels because of study limitations (risk of bias -2), and the lack of subgroup analyses (indirectness). Therefore, the level of evidence was graded as very low.

Zoeken en selecteren

The search and selection methods can be found in the main module Systematische therapie.

Referenties

1 - Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. doi: 10.1200/JCO.2014.58.3377. Epub 2015 May 26. PMID: 26014293.
2 - Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. doi: 10.1186/s40425-019-0623-z. PMID: 31171039; PMCID: PMC6554874.
3 - Ascierto PA, Dummer R, Gogas HJ, Flaherty KT, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, de Groot JWB, Loquai C, Gollerkeri A, Pickard MD, Robert C. Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Eur J Cancer. 2020 Feb;126:33-44. doi: 10.1016/j.ejca.2019.11.016. Epub 2020 Jan 2. PMID: 31901705.
4 - Carlino MS, Long GV, Schadendorf D, Robert C, Ribas A, Richtig E, Nyakas M, Caglevic C, Tarhini A, Blank C, Hoeller C, Bar-Sela G, Barrow C, Wolter P, Zhou H, Emancipator K, Jensen EH, Ebbinghaus S, Ibrahim N, Daud A. Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial. Eur J Cancer. 2018 Sep;101:236-243. doi: 10.1016/j.ejca.2018.06.034. Epub 2018 Aug 7. PMID: 30096704.
5 - Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, Hoeller C, Gajewski TF, Gutzmer R, Rutkowski P, Demidov L, Arenberger P, Shin SJ, Ferrucci PF, Haydon A, Hyngstrom J, van Thienen JV, Haferkamp S, Guilera JM, Rapoport BL, VanderWalde A, Diede SJ, Anderson JR, Treichel S, Chan EL, Bhatta S, Gansert J, Hodi FS, Gogas H. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. J Clin Oncol. 2023 Jan 20;41(3):528-540. doi: 10.1200/JCO.22.00343. Epub 2022 Aug 23. PMID: 35998300; PMCID: PMC9870217.
6 - Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018 Oct;19(10):1315-1327. doi: 10.1016/S1470-2045(18)30497-2. Epub 2018 Sep 12. Erratum in: Lancet Oncol. 2018 Oct;19(10):e509. doi: 10.1016/S1470-2045(18)30705-8. PMID: 30219628.
7 - Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. doi: 10.1016/S1470-2045(18)30142-6. Epub 2018 Mar 21. PMID: 29573941.
8 - Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. PMID: 20525992; PMCID: PMC3549297.
9 - Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator's Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. doi: 10.1200/JCO.2016.71.8023. Epub 2017 Jul 3. PMID: 28671856; PMCID: PMC6804912.
10 - Revicki DA, van den Eertwegh AJ, Lorigan P, Lebbe C, Linette G, Ottensmeier CH, Safikhani S, Messina M, Hoos A, Wagner S, Kotapati S. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual Life Outcomes. 2012 Jun 13;10:66. doi: 10.1186/1477-7525-10-66. PMID: 22694829; PMCID: PMC3426458.
11 - Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. doi: 10.1056/NEJMoa1412690. Epub 2014 Nov 16. PMID: 25399551.
12 - Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. doi: 10.1016/S1470-2045(19)30388-2. Epub 2019 Jul 22. PMID: 31345627.
13 - Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. doi: 10.1056/NEJMoa1503093. Epub 2015 Apr 19. PMID: 25891173.
14 - Rohaan MW, Borch TH, van den Berg JH, Met Ö, Kessels R, Geukes Foppen MH, Stoltenborg Granhøj J, Nuijen B, Nijenhuis C, Jedema I, van Zon M, Scheij S, Beijnen JH, Hansen M, Voermans C, Noringriis IM, Monberg TJ, Holmstroem RB, Wever LDV, van Dijk M, Grijpink-Ongering LG, Valkenet LHM, Torres Acosta A, Karger M, Borgers JSW, Ten Ham RMT, Retèl VP, van Harten WH, Lalezari F, van Tinteren H, van der Veldt AAM, Hospers GAP, Stevense-den Boer MAM, Suijkerbuijk KPM, Aarts MJB, Piersma D, van den Eertwegh AJM, de Groot JB, Vreugdenhil G, Kapiteijn E, Boers-Sonderen MJ, Fiets WE, van den Berkmortel FWPJ, Ellebaek E, Hölmich LR, van Akkooi ACJ, van Houdt WJ, Wouters MWJM, van Thienen JV, Blank CU, Meerveld-Eggink A, Klobuch S, Wilgenhof S, Schumacher TN, Donia M, Svane IM, Haanen JBAG. Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. N Engl J Med. 2022 Dec 8;387(23):2113-2125. doi: 10.1056/NEJMoa2210233. PMID: 36477031.
15 - Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. doi: 10.1016/S0140-6736(17)31601-X. Epub 2017 Aug 16. PMID: 28822576.
16 - Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. doi: 10.1016/S1470-2045(15)70076-8. Epub 2015 Mar 18. PMID: 25795410.

Evidence tabellen

Revicki, 2012

Hodi, 2010

MDX010-20

NCT00094653

Randomized, double-blind, phase 3 study.

Patients at 125 centers in 13 countries in North America, South America, Europe, and Africa.

Patient enrolment between: September 2004 and August 2008.

Funding and conflicts of interest:

The sponsors, Medarex and

Bristol-Myers Squibb

contributed to:

- - Trial design
  - Data collection
  - Initial draft of the manuscript
All authors signed a confidentiality disclosure agreement with the sponsor.

Disclosure forms provided by the authors are available with the full text of this article.

Inclusion criteria:

Diagnosis of unresectable stage III or IV melanoma who received a previous therapeutic regimen containing one or more of the following: dacarbazine, temozolomide, fotemustine, carboplatin, or interleukin-2.;
Age ≥ 18 years;
Life expectancy ≥ 4 months;
ECOG PS 0 or 1;
Positive status for HLA-A⋆0201;
Normal hematologic, hepatic, and renal function;
No systemic treatment in the previous 28 days.

Exclusion criteria:

Any other cancer from which the patient had been disease-free for < 5 years (except treated and cured basal-cell or squamous-cell skin cancer, superficial bladder cancer, or treated carcinoma in situ of the cervix, breast, or bladder);
primary ocular melanoma;
Previous receipt of anti–CTLA-4 antibody or cancer vaccine;
Autoimmune disease;
Active, untreated metastases in the central nervous system;
Pregnancy or lactation;
Concomitant treatment with any nonstudy anticancer therapy or immunosuppressive agent;
Long-term use of systemic corticosteroids.

Mean age, years

I: 55.6

C1: 56.8

C2: 57.4

Male, n (%)

I: 247 (61.3%)

C1: 81 (59.1%)

C2: 73 (53.7%)

ECOG PS:

0 – I: 232 (57.6%)

0 – C1: 72 (52.6%)

0 – C2: 70 (51.5%)

1 – I: 166 (41.2%)

1 – C1: 64 (46.7%)

1 – C2: 61 (44.9%)

2 – I: 4 (1%)

2 – C1: 1 (0.7%)

2 – C2: 4 (2.9%)

3 – I: 1 (0.2%)

3 – C1: 0

3 – C2: 0

Unknown:

I: 0

C1: 0

C2: 1 (0.7%)

Groups were comparable at baseline.

Ipilimumab, at a dose of 3 mg per kilogram of body weight, plus a gp100 peptide vaccine

n= 403

C1:
Ipilimumab plus gp100 placebo

n=137

C2:
gp100 plus ipilimumab placebo.

n=136

Patients were followed for up to 55 months.

Median follow-up time for survival:

I: 21.0 months

C1: 27.8 months

C2: 17.2 months

Median OS, months (95% CI)

I: 10.0 (8.5 to 11.5)

C1: 10.1 (8.0 to 13.8)

C2: 6.4 (5.5 to 8.7)

I vs C2: HR for death: 0.68 (0.55–0.85); P<0.001

C1 vs C2: HR for death: 0.66 (0.51–0.87); P=0.003

I vs C1: HR for death: 1.04 (0.83–1.30). P=0.76

1-Year OS:

I: 43.6%

C1: 45.6%

C2: 25.3%

18-month OS:

I: 30.0%
C1: 33.2%
C2: 16.3%

2-Year OS:

I: 21.6%

C1: 23.5%

C2: 13.7%

Median PFS, months (95% CI):

I: 2.76 (2.73 to 2.79)

C1: 2.86 (2.76 to 3.02)

C2: 2.76 (2.73 to 2.83)

AEs grade 3 or 4:

I: 173/374

C1: 60/127

C2: 62/128

Drug-related AEs,

Grade 3 or 4/total:

I: 66/338

C1: 30/105

C2: 15/104

Immune-related AEs,

Grade 3 or 4/total:

I: 39/221

C1: 19/80

C2: 4/42

Drug-related deaths, n:

I: 8

C1: 4

C2: 2

For more information on AEs see results section of the article.

EORTC QLQ-C30 symptom scores (improvements are indicated by negative scores):

Difference in constipation scores:

I: 5.2

C1:1.9

C2:11.8

I vs C2: p<0.05

C1 vs C2: p<0.05

Favouring ipilimumab.

None of the other

differences in HRQL scores between the three treatments were statistically significant.

The original primary end point was best overall response rate. The primary end point was amended to overall survival (amendment approved on January 15, 2009) in the ongoing blinded study.
Efficacy analyses were performed on the intention-to-treat population, which included all patients who had undergone randomization (676 patients).
The safety population included all patients who had undergone randomization and who had received any amount of study drug (643 patients).
In the vaccine groups, patients received two modified HLA-A⋆0201–restricted peptides, injected subcutaneously as an emulsion with incomplete Freund’s adjuvant (Montanide ISA-51): a gp100:209-217(210M) peptide, 1 mg injected in the right anterior thigh, and a gp100:280-288(288V) peptide, 1 mg injected in the left anterior thigh.

Authors conclusions:

Hodi, 2010:

Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.

Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment.

Revicki, 2012:

Ipilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during

the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients.

Robert, 2019

Carlino, 2018
Schachter, 2017

Robert, 2015

KEYNOTE-006

NCT01866319

International, randomized,

open-label phase 3 study.

In 16 countries.

Patient enrolment: From September 18, 2013, to March 3, 2014.

Funding and conflicts of interest:

The sponsors, Merck Sharp & Dohme,

contributed to:

Trial design
Statisticians and a science writer were employed by the sponsor.

Disclosure forms provided by the authors are available with the full text of this article.

Inclusion criteria:

Age ≥ 18 years
Histologically confirmed, unresectable stage III or IV melanoma who received no more than one previous systemic therapy for advanced disease
Known BRAF V600 mutational status was required;
previous BRAF inhibitor therapy was not required for patients with normal lactate dehydrogenase levels
no clinically significant tumor-related symptoms or evidence of rapidly progressive disease.
ECOG PS of 0 or 1
Provision of a tumor sample adequate for assessing PD-L1 expression.

Exclusion criteria:

Patients who had received previous therapy with CTLA-4, PD-1, or PD-L1 inhibitors
Ocular melanoma
Active brain metastases
History of serious autoimmune disease.

Mean age, years

Ia: 61 (18–89)

Ib: 63 (22–89)

C: 62 (18–88)

Male, n (%)

Ia: 161 (57.7)

Ic: 174 (62.8)

C: 162 (58.3)

ECOG PS:

0 – Ia: 196 (70.3)

0 – Ib: 189 (68.2)

0 – C: 188 (67.6)

1 – Ia: 83 (29.7)

1 – Ib: 88 (31.8)

1 – C: 90 (32.4)

PD-L1-positive tumours:

80.6%

Groups were comparable at baseline.

Ia:

pembrolizumab at a dose of 10 mg per kilogram of body weight every 2 weeks

n= 279

Ib:
pembrolizumab at a dose of 10 mg per kilogram of body weight either every 3 weeks

n=277

C:
Four cycles of ipilimumab at a

dose of 3 mg per kilogram every 3 weeks

n=278

Robert, 2019:

Median follow-up for survival: 57.7 months (IQR 56.7–59.2).

Carlino, 2018:

Median follow-up: 33.9 months.

Schachter, 2017:

Median follow-up:

22.9 months

Discontinued treatment:

Ia: 147 progressive disease

29 adverse events

2 deaths

2 complete responses

21 other

Ib: 139 progressive disease

45 adverse events

1 death

5 complete responses

23 other

C: 46 progressive disease

35 adverse events

5 deaths

24 other

Withdrew consent and did not receive

treatment:

Ia: n=1

C: n=22

Robert, 2015:

Median follow-up at data cutoff (with 502 events reported), months: 7.9 (range: 6.1 to 11.5)

March 3, 2015:

Follow-up for OS:

Minimum follow-up: 12 months with 289 deaths occurred

Mean duration of exposure, days:

Ia: 164

Ib: 151

C: 50

Rate discontinuation of a study drug because of treatment related

AEs:

Ia: 4.0%,

Ib: 6.9%,

C: 9.4%,

Robert, 2019:

Median OS:
I (pooled groups): 32.7 months (95% CI 24·5–41·6)

C: 15.9 months (13.3–22.0)

HR: 0.73 (95% CI 0.61–0.88, p=0·00049).

Median PFS:
I (pooled groups): 8.4 months (95% CI 6.6–11.3)

C: 3.4 months (2.9–4.2)

HR 0.57, 95% CI 0.48–0.67,

p<0.0001.

Grade 3–4 treatment-related AEs:
I (pooled groups): 96 (17%)

C: 50 (20%)

Treatment-related sepsis.

C: n=1

Schachter, 2017:

Death: n=383

Median OS:
Ia: not reached (range 22.1 months–not reached)

Ib: not reached (23.5 months–not reached)

C: 16.0 months (range 13.5–22.0)

HR pembro every 2 weeks vs ipi: 0.68, 95% CI 0·53–0·87; p=0·0009

HR pembro every 3 weeks vs ipi: 0.68, 0·53–0·86; p=0·0008.

2 year OS rate:

Ia: 55% (95% CI 49–61)

Ib: 55% (95% CI 49–61)

C: 43% (95% CI 37–49)

PFS events: n= 566

I (pooled groups): 364 (65%)

C: 202 (35%)

Median PFS, months:

Ia: 5.6 months (range 3.4–8.2)

Ib: 4.1 months (range 2.9–7.2)

C: 2.8 months (range 2.8–2.9)

HR for both Pembro schedules vs ipi: 0.61; 95% CI 0·50–0·75; p<0·0001

HR for Ia vs Ib: 0.95; 95% CI

0·77–1·17; p=0·62).

2-year PFS rate:

Ia: 31%

Ib: 28%

C: 14%

Treatment related AEs grade 3 to 5:

Ia: 47 (17%) of 278

Ib: 46 (17%) of 277

C: 50 (20%) of 256

Robert, 2015:

Median overall survival was not reached in any study group.

1-Year OS:

Ia: 74.1%

Ib: 68.4%

C: 58.2%

HR for death for pembrolizumab every 2 weeks versus ipilimumab: 0.63; 95% CI, 0.47 to 0.83; P<0.0005
HR for death for pembrolizumab every 3 weeks versus ipilimumab: 0.69; 95% CI, 0.52 to 0.90; P = 0.0036

Median PFS, months (95% CI):

Ia: 5.5 (95% CI, 3.4 to 6.9)

Ib: 4.1 (95% CI, 2.9 to 6.9)

C: 2.8 (95% CI, 2.8 to 2.9)

HR for progression for pembrolizumab every 2 weeks versus ipilimumab: 0.58 (95% CI, 0.46 to 0.72; P<0.001)
HR for pembrolizumab every 3 weeks versus ipilimumab: 0.58 (95% CI, 0.47 to 0.72; P<0.001).

6-month PFS, months:

Ia: 47.3%

Ib: 46.4%

C: 26.5%

Treatment related AEs grade 3 to 5:

Ia: 13.3%

Ib: 10.1%

C: 19.9%

Drug-related deaths, n:

Ia: 0

Ib: 0

C: 1

For more information on AEs see results section of the article.

Co-primary endpoints were OS and PFS.

Robert, 2019:

Data cutoff: Dec 3, 2018.

Carlino, 2018:

Data cutoff: 03 Nov 2016.
Reported outcomes by line of therapy and PD-L1 expression

Schachter, 2017:

Data cutoff: Dec 3, 2015.

Robert, 2015:

Data cutoff 1st interim analysis: Sep 3, 2014 (PFS and AEs)
Data cutoff 2nd interim analysis: Mar 3, 2015 (OS).
OS results for the pembrolizumab groups were superior to those for the ipilimumab group. The independent data and safety monitoring committee recommended stopping the study early.

Authors conclusions:

Robert, 2019:

Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up.

These results provide further support for use of pembrolizumab in patients with advanced melanoma.

Carlino, 2018:
Findings support pembrolizumab monotherapy as standard of care in patients

with advanced melanoma, regardless of first- or second-line therapy or PD-L1 status.

Schachter, 2017:

Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma.

Robert, 2015:

The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma.

Chesney, 2023

MASTERKEY-265

NCT02263508

A multicenter, double-blind, placebo controlled,

randomized phase III study in 21 countries.

Patient enrolment between: March 17, 2016, through April 26, 2018.

Funding and conflicts of interest:

- Supported by Amgen Inc and Merck Sharp & Dohme LLC, a subsidiary of

Merck & Co, Inc, Rahway, NJ.

The sponsors contributed to:

Medical writing support

- Authors’ disclosures of potential conflict of interest is provided at the end of the full text article.

Main Inclusion criteria:

Histologically confirmed stage IIIB-IV M1c unresectable melanoma
Age ≥ 18 years
ECOG PS 0 or 1
At least one visceral or nodal/soft tissue melanoma lesion for which the longest diameter was ≥ 10 mm
In/exclusion criteria with regard to prior therapy for patients with BRAF-mutated melanoma is specified in the article.

Exclusion criteria:

Active untreated brain metastases
Primary uveal or mucosal melanoma
Prior therapy with T-VEC or any other oncolytic viruses
Prior therapy with anti–PD-1/PD-L1/PD-L2 agents
Prior therapy with tumor vaccine in the nonadjuvant setting
History of autoimmune diseases
Evidence of immunosuppression therapy for > 2 weeks or < 7 days prior to the first dose of study
Active herpetic skin lesions
Current treatment with antiherpetic drug.

For more information on in-/exclusion see the article.

Median age, years (range)

I: 64 (26-92)

C: 64 (19-94)

Male, n (%)

I: 199 (57.5)

C: 219 (63.3)

ECOG PS:

0 – I: 259 (74.9)

0 – C: 249 (72.0)

1 – I: 87 (25.1)

1 – C: 97 (28.0)

Groups were comparable at baseline.

I: A combination of T-VEC plus pembrolizumab (T-VEC-pembrolizumab)

n=346

T-VEC was administered at

≤ 4 x 106 plaque-forming unit followed by ≤ 4 x 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter.

Pembrolizumab was administered intravenously 200 mg once every 3 weeks.

C: Placebo plus pembrolizumab (placebo-pembrolizumab

n=346

Pembrolizumab was administered intravenously 200 mg once every 3 weeks.

Median follow-up in months:

25.58 (range, 0.3-45.8) for the PFS primary analysis.
31.0 (range, 0.3-53.0) for the second OS interim analysis.
35.56 (range, 0.3-58.4) for the final analysis

Discontinued study:

I: n = 152

Death n = 131

Withdrawal of consent n = 15

Lost to follow-up n=6

C: n = 170

Death n = 142

Withdrawal of consent n = 22

Lost to follow-up n = 6

April 2020, all patients discontinued study treatments.

The final analysis was performed early given the futility noted in the second interim analysis and included an additional follow-up of 6 months.

Deaths at planned second interim OS analysis:

I: 136 (39.3%)

C: 146 (42.2%)

Median OS, months (95% CI):

I: Not estimable

C: 49.2 (40.57 to not estimable)

HR of 0.96 (95% CI, 0.76 to 1.22; P = .74)

The primary analysis of PFS was to be performed after 407 PFS events occurred.

Median PFS (95% CI) (months):

I: 14.3 (10.25 to 22.11)

C: 8.5 (5.72 to 13.54)

Stratified log-rank: HR, 0.86 (95% CI, 0.71 to 1.04), P=.13

Treatment related AEs grade 3 or 4:

I: 70 (20.3%)

C: 54 (15.7%)

Fatal AEs:

I: 45 (13.1%)

C: 42 (12.2%)

Treatment related fatal AEs, n:

I: 4 (1.2%)

C: 1 (0.3%)

Immune-related AEs:

I: 27.5%

C: 24.8%

For more information on AEs see results section of the article

At final analysis:

PFS overall stratified HR, 0.87; 95% CI, 0.72 to 1.06
OS: overall stratified HR, 0.97; 95% CI, 0.77 to 1.21)

No new safety signals were observed.

The dual primary end points were PFS and OS.
Data cutoff dates:
Mar 2, 2020, for the PFS primary analysis;

Sep 29, 2020, for the second interim OS analysis;

Mar 26, 2021, the final analysis.

On June 12, 2020, the DMC met to review data from the PFS primary analysis and recommended that the study continues as planned.
On December 22, 2020, the DMC reviewed the efficacy and safety data from the second OS interim analysis. The DMC indicated that the futility boundary for OS was crossed and recommended that no further study-related procedures are conducted.
On January 8, 2021, the study was unblinded and proceeded directly to a final analysis conducted in an unblinded manner.
All patients were off study treatment as of April 2020. The last visit date for the final analysis was March 11, 2021.
No improvement in OS was observed in any of the predefined subgroups.
Sensitivity analysis were performed:
- which censored patients at the time of

subsequent anticancer therapy

excluding patients with stage IVM1c disease
second-line therapies were generally balanced between the arms, and the crossover rate from the placebo arm to receive subsequent T-VEC treatment was<5%

Authors conclusions:

This randomized, double-blinded, placebo-controlled, multicenter, international phase III trial did not show improved PFS or OS for the combination of T-VEC plus pembrolizumab

compared with placebo plus pembrolizumab for immunotherapy- naïve patients with advanced melanoma in the frontline setting. There were no new safety concerns with the addition of T-VEC to pembrolizumab, and the safety profile of the combination was consistent with the known safety profile

of each drug.

Robert 2015,

Robert 2016,

COMBI-v

Type of study:

open-label, randomized, phase 3 study

Setting and country: Multicentre, 193 centries.

Funding and conflicts of interest:

The study was funded by the sponsor, GlaxoSmithKline, and also provided editorial assistance.

Detailed declarations of interests are provided in the article.

Inclusion criteria:
->= 18 years

-the presence of BRAF V600E or V600K mutations

was centrally determined with the investigational

use of the THxID BRAF assay (bioMérieux)

-measureable disease, according to the Response Evaluation Criteria

in Solid Tumors (RECIST), version 1.1,15

-An Eastern Cooperative Oncology Group (ECOG)

performance status of 0 or 1

-Patients who

had undergone treatment for brain metastases with

no increase in lesion size for at least 12 weeks were

eligible

Exclusion criteria:

-See supplement.

N total at baseline: 703

I: 352

C: 352

Important prognostic factors²:

Median age (IQR)

I: 55 (18–91)

C: 54 (18–88)

Sex:

I: 208 (59)

C: 180 (51)

ECOG performance status:

I: 248 (71)

C: 248 (70)

BRAF mutation V600E:

I: 312(90)

C: 317 (90)

Groups comparable at baseline?

Yes.

Describe intervention (treatment/procedure/test):

A combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily)

Describe control (treatment/procedure/test):

Vemurafenib (960 mg orally

twice daily).

Robert 2015

Clinical data cutoff

April 17, 2014

Median follow-up

11 (I), 10 (C) months

Loss-to-follow-up:

I: 16

4 lost to follow-up

2 investigator discretion

10 withdrew consent

C: 28

9 lost to follow-up

1 investigator discretion

18 withdrew consent

Robert 2016

Clinical data cutoff

July 2016

Median follow-up

27 (I), 26 (C) months

Loss-to-follow-up:

Robert 2015

Median overall survival:

I: not reached

C: 17.2 months

Median 1 year survival:

I: 72% (95% CI, 67 to 77)

C: 65% (95% CI, 59 to 70)

Median progression-free survival:

I: 11.4 months

C: 7.3 months

HR, 0.56; 95% CI, 0.46 to 0.69

Adverse events:

I: 343 (98)

C: 345 (99)

Grade 3-4:

I: 167 (48)

C: 198 (57)

Quality of life:

Not reported.

Robert 2016

Median overall survival:

Median 3 year survival:

I: 45% [95% CI, 39-50]

C: 32% [95% CI, 27-37]

Median 3 year progression-free survival:

I: 25% [95% CI, 20-30]

C: 11% [95% CI, 7-16]

Adverse events:

Similar to Robert 2015

Quality of life:

Not reported.

Author’s conclusion:

In conclusion, the combination of dabrafenib plus trametinib was superior to vemurafenib monotherapy with regard to all efficacy end points, including overall survival, with no additional overall toxicity.

Robert 2016 is only a published conference abstract, limited information available.

Andtbacka, 2019; Andtbacka, 2015

OPTiM

NCT00769704

A randomized open-label phase III trial at 64 sites in the United States, the United

Kingdom, Canada, and South Africa.

Patient enrolment between: 2009 and 2011

Funding and conflicts of interest:

- Funded by BioVex, who were subsequently acquired by Amgen Inc. during the OPTiM trial.

The sponsor contributed to:

Design of the trial
Data collection
Data analysis
Interpretation of data
Development of the manuscript.

- A competing interests statement is provided at the end of the full text article.

Main inclusion criteria:

≥ 18 years
Histologically confirmed, unresectable, bidimensionally measurable stage IIIB/C/IV melanoma with ≥1 cutaneous, subcutaneous or nodal lesions that was suitable for direct or ultrasound-guided injection;
ECOG PS ≤1
Serum lactate dehydrogenase ≤1.5 × upper limit of normal;
≤3 visceral lesions (excl. lung or nodal lesions associated with visceral organs) with none > 3 cm;
Adequate organ function.
Patients with history of autoimmune disease, but not use of high-dose steroids.

Exclusion criteria:

Requiring intermittent or chronic treatment with an antiviral agent (eg, acyclovir) or high-dose steroids
Primary ocular or mucosal melanoma
Bone metastases
Active cerebral metastases
> 3 visceral metastases
Any visceral metastasis >3 cm
Liver metastases had to be stable for 1 month before random assignment.

For more information on in-/exclusion see the article.

Median age, years (range)

I: 63 (22 to 94)

C: 64 (26 to 91)

Male, n (%)

I: 173 (59%)

C: 77 (55%)

ECOG PS:

0 – I: 209 (71%)

0 – C: 97 (69%)

1 – I: 82 (28%)

1 – C: 32 (23%)

Unknown:

I: 4 (1%)

C: 12 (9%)

Groups were comparable at baseline.

I: intratumoral Talimogene laherparepvec (T-VEC) (at the approved dose)

n= 295 (68%)

C: subcutaneous

recombinant granulocyte-macrophage colony-stimulating

factor (GM-CSF)

n= 141 (32%)

Median follow-up in the final analysis of OS: 49 months.

Median duration of treatment in weeks (range):

I: 23.1 (0.1–176.7)

C: 10.0 (0.6–120.0)

Andtbacka, 2015:

Discontinued T-VEC: n=291

Disease progression:

n=191

PR or CR for ≥ 6 continuous months:

n=42

Maximum allowed dose without

PR/CR: n=26

Adverse event: n=11

Consent withdrawn: n=10

Physician decision: n=6

Death: n=5

Discontinued GM-CSF: n=127

Disease progression: n=95

PR or CR for ≥ 6 continuous months: n=0

Maximum allowed dose without

PR/CR: n=9

Adverse event: n=3

Consent withdrawn: n=12

Physician decision: n=5

Death: n=3

Intent-to treat population (stage IIIB–IVM1c melanoma):

Median OS, months (95% CI):

I: 23.3 (19.5–29.6)

C: 18.9 (16.0–23.7)

unstratified HR for death, 0.79 (95% CI,0.62–1.00); P = 0.0494).

Estimated 5-year survival

I: 33.4%

C: Not estimable

Stage IIIB–IVM1a disease

Effect of T-VEC on OS vs GM-CSF:

Stage IIIB/C: HR, 0.48, P < 0.05

Effect of T-VEC on OS vs ITT population including stage IVM1b/c disease:

Stage IIIB–IVM1a: HR, 0.56; 95% CI, 0.40–0.79; P < 0.001

Estimated 5-year

survival with T-VEC:

Stage IIIB–IVM1a melanoma: 48.9% (95% CI, 40.6–56.7)
Stage IVM1b/c disease: 15.1% (95% CI, 9.3–22.2).

Treatment related AEs grade 3/4:

I: 33 (11.3%)

C: 6 (4.7%)

Immune-related AEs:

I: 24/295

C: ?

Immune-related AEs grade 3: n=4

Immune-related AEs grade 4: None reported

Treatment-related deaths, n:

I: 0

C: 0

For more information on AEs see results section of the article

Primary end point: durable response rate (objective response lasting continuously ≥ 6 months) per independent

assessment. Key secondary end points: OS and overall response rate

Data cut-off for this final analysis of OPTiM was 5 September 2014.
4 patients in the T-VEC arm and 14 in the GM-CSF arm did not receive T-VEC or GM-CSF.
When the 18 patients who did not receive allocated treatment were excluded (T-VEC arm, n =4; GM-CSF arm, n = 14), median OS in the final analysis dataset was 24.5 versus 18.9 months for T-VEC versus GM-CSF (HR, 0.78; P = 0.0439).
Ad-hoc sensitivity analysis for OS accounting for subsequent systemic anti-cancer treatment, there was a 27% reduction in the risk of death for T-VEC versus GM-CSF (unadjusted HR, 0.73; 95% Cl, 0.59–0.92; P = 0.0069).

Authors conclusions:

Andtbacka, 2019:

In conclusion, as well as demonstrating a longer-term effect on survival, this analysis confirms that T-VEC resulted in high CR rates, most notably in patients with

early metastatic melanoma (stage IIIB–IVM1a). Once achieved, CRs were durable and associated with prolonged survival. The favorable clinical outcomes observed in some patients treated with T-VEC, along with

its good safety profile, support continued efforts to further define its future role in melanoma as a combination partner with immunotherapy.

Andtbacka, 2015:

T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma

in a phase III clinical trial. T-VEC was well tolerated and resulted in a higher DRR (P<0.001) and

longer median OS (P=0.051), particularly in untreated patients or those with stage IIIB, IIIC, or IVM1a disease. T-VEC represents a novel potential therapy for patients with metastatic melanoma.

Rohaan, 2022

NCT02278887

Multicenter, open-label, phase 3, randomized trial, two participating

clinical sites (the Netherlands Cancer Institute, Amsterdam and National Center

for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, Denmark).

Patient enrolment between: September 2014 and March 2022.

Funding and conflicts of interest:

- Supported by the Dutch Cancer Society, the Netherlands

Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, the Antoni van Leeuwenhoek

Foundation, Copenhagen University Hospital (Herlev), the Danish Cancer Society, and the Capital Region of Denmark Research Foundation.

- Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Inclusion criteria:

Age 18 to 75 years
Histologically confirmed, unresectable or metastatic stage IIIC or IV cutaneous melanoma
one or more lesions that could be surgically removed for generation of TILs.
Residual measurable disease after resection
WHO performance- status score of 0 or 1
A serum LDH level that was ≤ 2 times the upper limit of the normal range.
One previous line of systemic treatment for this disease stage, excluding ipilimumab, was allowed.
Patients with vitiligo

Exclusion criteria:

Life expectancy <3 mo
Metastatic ocular/ mucosal or other non-cutaneous melanoma
Adjuvant treatment with ipilimumab < 6 mo prior to randomization.
Requirement for immunosuppressive doses of systemic corticosteroids or immunosuppressive drugs < 3 weeks prior

to randomization.

>2 CNS metastases
Patients with a symptomatic CNS lesion > 1 cm or that shows significant surrounding edema on MRI scan were not eligible until they were treated and demonstrated no clinical or radiologic CNS progression for ≥ 2 mo.
Inability to receive high dose interleukin-2
Toxicities from prior non-systemic treatment that have not recovered to grade ≤1.
Pregnancy or breastfeeding women,
Active systemic infections, coagulation disorders or other active major medical illnesses.
Autoimmune disease

For more information on in-/exclusion see the appendix of the article.

Median age, years (range)

I: 59 (26–74)

C: 59 (30–77)
Two patients who were older than 75 years of age were included in the trial because these patients were deemed to be in excellent clinical condition by the principal investigator.

Male, n (%)

I: 47 (56)

C: 53 (63)

WHO PS:

0 – I: 69 (82)

0 – C: 70 (83)

1 – I: 15 (18)

1 – C: 14 (17)

Groups were comparable at baseline.

Adoptive cell therapy with tumor-infiltrating

lymphocytes (TILs).

Patients assigned to receive TILs underwent

a metastasectomy for retrieval and

expansion of TILs, followed by administration of nonmyeloablative,

lymphodepleting chemotherapy, single intravenous adoptive transfer of 5×109 to 2×1011 TILs, and subsequent high-dose interleukin-2 every 8 hours, for a maximum of 15 doses per protocol.

n=84

Ipilimumab:

3 mg/kg intravenously

every 3 weeks, for a maximum of 4 doses.

n=84

Median follow-up in months: 33

Median duration of hospital admission: 17 days (range, 12 to 38).

Median ipilimumab

Infusions: 3 (range, 1 to 4)

Treatment discontinuation because of AEs:

26/42 (62%)

TIL arm:

No patients were lost to follow-up

No patients discontinued treatment

Ipilimumab arm:

No patients were lost to follow-up

42 patients discontinued treatment:

26 due to adverse events
14 due to rapid disease progression
1 patient decision

1 death

Median OS, months (95% CI):

I: 25.8 (18.2 to not reached)

C: 18.9 (13.8 to 32.6)

HR for death 0.83 (95% CI, 0.54 to 1.27).

2-year OS (95% CI):

I: 54.3% (43.9 to 67.2)

C: 44.1% (33.6 to 57.8)

Median PFS, in months (95% CI):

I: 7.2 (4.2 to 13.1)

C: 3.1 (3.0 to 4.3)

HR for progression or death, 0.50; 95% CI, 0.35 to 0.72

6-month PFS:

I: 52.7% (95% CI, 42.9 to

64.7)

C: 21.4% (95% CI, 14.2

to 32.2)

Treatment related AEs grade 3 or 4:

I: 100%

C: 57%

In the TIL group, these events were mainly

chemotherapy-related myelosuppression.

For more information on AEs see results section of the article.

EORTC QLQ-C15 PAL quality-of-life and functioning scales. Mean HRQOL score at 6 months:

Global QoL:

I: 77.4

C:69.6

Difference: 7.7 (5.1 to 10.4)

Physical functioning

I: 82.0

C: 79.1

Difference: 2.9 (1.4 to 4.5)

Emotional functioning

I: 85.4

C: 75.7

Difference: 9.7 (7.5 to 11.9)

Scores on the EORTC

QLQ-C15 PAL symptom scales:

Fatigue:

I: 25.9

C: 33.8

Difference: −7.9 (−11.2 to −4.6)

Nausea and vomiting

I: 7.5

C: 5.9

Difference: 1.6 (0.7 to 2.5)

Pain

I: 14.3

C: 20.7

Difference: −6.4 (−9.3 to −3.5)

Dyspnea

I: 10.0

C: 12.4

Difference: −2.4 (−5.0 to 0.1)

Insomnia

I: 23.6

C: 28.1

Difference −4.5 (−7.2 to −1.9)

Appetite loss

I: 12.4

C: 13.5

Difference: −1.1 (−2.9 to 0.7)

Constipation

I: 6.7

C: 7.1

Difference: −0.4 (−1.3 to 0.5)

Data cutoff: June 9, 2022
At data cutoff 80 patients had received TILs and 82 patients had received at least one infusion of ipilimumab.
For 6-month PFS and ORR the results of assessments according to immune related response criteria are reported.

Authors conclusions:

In patients with advanced melanoma, progression-free survival was significantly longer

among those who received TIL therapy than among those who received ipilimumab.

Weber 2015,

Larkin 2018

Checkmate 037

Type of study: phase III, randomized, controlled, open-label study

Setting and country: Multicentre, 90 sites in 14 countries.

Funding and conflicts of interest:

The study was designed jointly by the funder of the study

and the senior investigators (JSW and JL). Data collected by the funder were analysed in collaboration with all

authors. The funder of the study funded writing and

editorial support.

Detailed declarations of interests are provided in the article.

Inclusion criteria:
- aged >= 18 years
-histologically confirmed, unresectable stage IIIC or IV metastatic melanoma and ECOG performance status 0 or 1.

-Patients with BRAF must have experienced progression after treatment with anti-CTLA-4 and BRAF inhibitor.

-patients with BRAFV600 mutation must have experienced progression after treatment with anti–CTLA-4 and a BRAF inhibitor.

Exclusion criteria:

-active brain metastases
-prior treatment with anti–PD-1, anti–programmed death ligand 1 (PD-L1), or anti–PD-L2
-grade 4 toxicity or use of infliximab during previous ipilimumab treatment
-primary ocular melanoma.

More detailed inclusion and exclusion criteria are described in the appendix of Weber et al, 2015.

N total at baseline: 405

Intervention: 272

Control: 133

Important prognostic factors²:

Median age (IQR)

I: 59 (23-88)

C: 62 (29-85)

Sex:

I: 65% M

C: 64% M

ECOG performance status:

I: 60% 0

C: 63% 0

BRAF mutant:

I: 60 (22%)

C: 29 (22%)

Treatment with PD-1/PD-L1:

I: 11%

C: 41%

Brain metastases:

I: 20%

C: 14%

Increased lactate dehydrogenase levels:

I: 52%

C: 38%

Groups comparable at baseline?

Yes, except for brain metastases and lactate dehydrogenase levels.

Describe intervention (treatment/procedure/test):

Nivolumab 3 mg/kg intravenously every 2 weeks.

Describe control (treatment/procedure/test):

Investigator’s choice chemotherapy (ICC), which consisted of dacarbazine 1,000 mg/m2 every 3 weeks or carboplatin area under the curve 6 plus paclitaxel 175 mg/m2 every 3 weeks intravenously.

Larkin 2018

Clinical data cutoff March 29, 2016

Length of follow-up median (IQR):

Approximately 2 years.

Length of duration therapy median:

I: 4.7 months (95% CI 3.3-6.0)

C: 2.0 months (95% CI 1.6-2.8)

Loss-to-follow-up:

Intervention: 233 (86%) discontinued treatment.

182 disease progression

15 study drug toxicity

6 adverse event

19 patient request

3 withdrew consent

1 maximum clinical benefit

1 poor/noncompliance

4 no longer met study criteria

2 other

Control: 102 (77%) discontinued treatment.

74 disease progression

11 study drug toxicity

3 adverse event

7 patient request

2 withdrew consent

3 maximum clinical benefit

2 other

Weber 2015

Clinical data cutoff not reported?

Range of follow-up:

5.2-16.7 months

Loss-to-follow-up:

Intervention: 111 (53%) discontinued treatment.

96 disease progression

5 study drug toxicity

0 death

2 AE unrelated to study drug

5 request to discontinue

2 withdrew consent

1 max clinical benefit

Control: 129 (92%) discontinued treatment.

175 disease progression

7 study drug toxicity

0 death

3 AE unrelated to study drug

2 request to continue

3 withdrew consent

1 max clinical benefit

1 other

Outcome measures and effect size (include 95%CI and p-value if available):

Larkin 2018

Median overall survival:
I: 15.7 months (95% CI, 12.9 to 19.9)

C: 14.4 months (95% CI, 11.7 to 18.2)

HR, 0.95; 95% CI, 0.73 to 1.24

Median progression-free survival:

I: 3.1 months

C: 3.7 months

HR, 1.0; 95.1% CI, 0.78 to 1.436

Adverse events:

I: 77%

C: 82%

Treatment related grade 3 and 4:

I: 31%

C: 14%

Further specified in table 3.

Quality of life:

I:
no change in EORTC QLQ-C30
no clinically significant improvement for EQ-5D/EQ-5D VAS.

C:
no change in EORTC QLQ-C30
A clinically significant decrease for EQ-5D at 12 weeks.

Weber 2015

Median overall survival:
Not reported.

Median progression-free survival:

I: 4.7 months (95% CI 2.3–6.5)

C: 4.2 months (2.1–6.3)

HR, 0.82; 99% CI 0.32–2.05

Adverse events:

I: 68%

C: 79%

Treatment related grade 3 and 4:

I: 9%

C: 31%

Quality of life:

Not reported.

Original trial Checkmate 037 and updated analysis. ITT and PP analyses performed.

Author’s conclusion in 2015:

Findings from our study show that nivolumab leads to clinically meaningful improvements in the proportion of patients achieving an objective response and provide a manageable safety profile when compared with chemotherapy.

Authors ‘conclusion in 2018:

“Although there were no survival differences between nivolumab and ICC treatments, nivolumab treatment

after progression on ipilimumab with or without a BRAF inhibitor does provide a higher rate of response and more durable responses. Some situations may still exist that necessitate the use of ipilimumab as first-line therapy and nivolumab provides

a safer option with a better maintained quality of life for patients who have experienced failure with prior systemic therapies compared with cytotoxic chemotherapy. The OS outcome may

have been impacted by the increased dropout rate before treatment and increased systemic therapy received after assigned therapy in the ICC group, as well as an increased proportion of patients with poor prognostic factors in the nivolumab group.

Despite the lack of survival advantage, nivolumab remains an effective option for PD-1 inhibitor–naive patients who experienced failure with ipilimumab and a BRAF inhibitor if BRAF mutated.”

-Subgroup analysis was performed on the PD-1/PDL1 subgroup:

Median overall survival sensitivity analysis PD-1/PD-L1 group Larkin 2018

I: 16.4 months (95% CI, 12.9 to 20.3)
C: 11.8 months (95% CI, 9.9 to 14.4)

HR, 0.81; 99% CI, 0.59 to 1.1

Dummer 2018,

Dummer 2018-2,

Ascierto 2020,

COLUMBUS

Type of study: multicentre,

two-part, randomised, open-label, phase 3 study.

Setting and country: Multicentre, 162 hospitals in 28 countriest.

Funding and conflicts of interest:

Funded by Array BioPharma, Novartis. The

sponsors had a role in data collection, analysis, and

interpretation.

Detailed declarations of interests are provided in the article.

Inclusion criteria:
->= 18 years

-A histologically confirmed diagnosis of locally advanced, unresectable, or metastatic cutaneous melanoma or unknown primary melanoma classified as American Joint

Committee on Cancer (AJCC) stage IIIB, IIIC, or IV

-Treatment naive or had progressed on or after previous first-line immunotherapy

-Had a BRAFV600E or BRAFV600K mutation or both in tumour tissue as ascertained by central

genetic mutation analysis with the bioMérieux THxID

BRAF diagnostic test (bioMérieux, Marcy l’Etoile, France) before enrolment

-ECOG performance status of 0 or 1

-Adequate bone marrow, organ function, and laboratory parameters

-At least one measurable lesion, according to guidelines based on Response Evaluation

Criteria in Solid Tumors (RECIST), version 1.1.

Exclusion criteria:

-An untreated CNS lesions; uveal or mucosal melanoma

-A history of leptomeningeal metastases

-Gilbert’s syndrome

-history, current evidence,

Or risk of retinal vein occlusion

-Previous BRAF inhibitor or

MEK inhibitor treatment

-Previous use of systemic

chemotherapy

-Extensive radiotherapy as evaluated by local investigators, or an

investigational agent other than previous immunotherapy

for locally advanced, unresectable, or metastatic melanoma (immunotherapy must have ended ≥6 weeks before randomisation).

N total at baseline: 577

encorafenib & binimetinib (A): 192

encorafenib (B): 194

vemurafenib (C): 191

Important prognostic factors²:

Median age (IQR)

A: 57 (20–89; 48–66)

B: 54 (23–88; 46–63)

C: 56 (21–82; 45–65)

Sex:

A: 115 (60%) M

B: 108 (56%) M

C: 111 (58%) M

ECOG performance status:

A: 136 (71%) 0

B: 140 (72%) 0

C: 140 (73%) 0

BRAF mutation V600E:

A: 170 (89%)

B: 173 (89%)

C: 168 (88%)

Groups comparable at baseline?

Yes.

Describe intervention (treatment/procedure/test):

Oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib

group)

Describe control (treatment/procedure/test):

Encorafenib 300 mg once daily orally, or

vemurafenib 960 mg twice daily orally

Dummer 2018

Clinical data cutoff

May 19, 2016

Median follow-up

16·6 months (14·8–16·9)

Loss to follow-up:

A: 124 discontinued treatment

83 had progressive

disease

16 had adverse events

8 physician decision

7 patient or guardian

decision

7 died

2 protocol deviation

1 lost to follow-up

B: 146 discontinued

87 had progressive

disease

24 had adverse events

19 physician decision

13 patient or guardian

decision

1 died

1 protocol deviation

1 lost to follow-up

C: 159 discontinued

101 had progressive

disease

26 had adverse events

13 physician decision

15 patient or

guardian decision

4 died

Dummer 2018-2

Clinical data cutoff

Nov 7, 2017

Median follow-up

36·8 months (95% CI 35·9–37·5)

Loss-to-follow-up:

A: 149 discontinued

99 progressive disease

20 adverse events

9 physician decision

11 patient or guardian decision

8 died

1 protocol deviation

1 lost to follow-up

B: 168 discontinued

100 progressive disease

25 adverse events

24 physician decision

17 patient or guardian decision

1 died

1 protocol deviation

0 lost to follow-up

C: 173 discontinued

109 progressive disease

25 adverse events

17 physician decision

17 patient or guardian decision

4 died

1 new therapy for study indication

0 protocol deviation

0 lost to follow-up

Ascierto 2020

Clinical data cutoff

Nov 2018

Median follow-up

48.8 months

Loss-to-follow-up:

A: 156 discontinued

104 progressive disease

20 adverse events

21 physician decision/ patient or guardian decision

9 died

2 other

B: 172 discontinued

101 progressive disease

24 adverse events

35 physician decision/patient or guardian decision

1 died

1 other

C: 177 discontinued

111 progressive disease

26 adverse events

35 physician decision/patient or guardian decision

4 died

1 other

Dummer 2018

Median progression-free survival:

A: 14·9 months (95% CI

11·0–18.5)

B: 9·6 months (7·4–14·8)
C: 7·3 months (5·6–8.2)

Adverse events:

A: 66 (34%)

B: 65 (34%)

C: 69 (37%)

Grade 3-4 adverse events:

A: 111 (58%)

B: 127 (66%)

C: 118 (63%)

Quality of life:

Not reported.

Dummer 2018-2

Median overall survival:

A: 33·6 months (95% CI

24·4–39·2)

B: 23·5 months (19·6–33·6)

C: 16·9 months (14·0–24·5)

A vs C: HR 0·61 [95% CI 0·47–0·79)

A vs B: HR 0·81 [95% CI 0·61–1·06]

B vs C: HR 0·76 (95% CI 0·58–0·98)

Median 1 year survival:

A: 75·5% (95% CI 68·8–81·0)

B: 74·6% (67·6–80·3)

C: 63·1% (55·7–69·6)

Median 2 year survival:

A: 57·6% (95% CI 50·3–64·3)

B: 49·1% (41·5–56·2)

C: 43·2% (35·9–50·2)

Median progression-free survival:

A: 14·9 months (95% CI

11·0–20·2)

B: 9·6 months (7·4–14·8)
C: 7·3 months (5·6–7·9)

Adverse events:

Similar to Dummer 2018

Quality of life:

Not reported.

Ascierto 2020

Median overall survival:

A: 33.6 months (95% CI, 24.4-39.2),

B: 23.5 months (95% CI, 19.6-33.6)

C: 16.9 months (95% CI, 14.0-24.5

HR 0.61 (95%CI 0.48-0.79)

Median 3 year survival:

A: 47%

B: 41%

C: 31%

Median progression-free survival:

A: 14.9 months

(95% CI, 11.0- 20.2)

B: 9.6 months (95%

CI, 7.4-14.8)

C: 7.3 months (95% CI,

5.6-7.9)

HR (0.51, 95%CI 0.39-0.67)

Grade 3/4 adverse events:

A: 68%

B: 68%

C: 66%

Quality of life:

Not reported.

Author’s conclusion:

In conclusion, patients treated with encorafenib plus binimetinib had longer PFS and OS than those treated with vemurafenib, with landmark analyses showing consistent improved OS and PFS for COMBO450 vs VEM for each year. Safety results were consistent with

the known tolerability profile of COMBO450, and the toxicity burden was reduced over time. These data reinforce encorafenib plus binimetinib as an important treatment option for patients with BRAF-mutant melanoma.

Verantwoording

Beoordelingsdatum en geldigheid

Publicatiedatum : 09-10-2025

Beoordeeld op geldigheid : 01-08-2025

De richtlijnmodules zijn geautoriseerd door de: Nederlandse Vereniging voor Heelkunde, Nederlandse Vereniging voor Dermatologie en Venereologie, Nederlandse Internisten Vereniging, Nederlandse Vereniging voor Nucleaire Geneeskunde, Nederlandse Vereniging voor Radiologie, Nederlandse Vereniging voor Pathologie, Verpleegkundigen & Verzorgenden Nederland.

Initiatief en autorisatie

Initiatief:

Nederlandse Internisten Vereniging
Nederlandse Vereniging voor Heelkunde

Geautoriseerd door:

Nederlandse Internisten Vereniging
Nederlandse Vereniging voor Dermatologie en Venereologie
Nederlandse Vereniging voor Heelkunde
Nederlandse Vereniging voor Nucleaire geneeskunde
Nederlandse Vereniging voor Pathologie
Nederlandse Vereniging voor Radiologie
Nederlandse Vereniging voor Radiotherapie en Oncologie
Vereniging Klinische Genetica Nederland
Verpleegkundigen en Verzorgenden Nederland

Algemene gegevens

De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd uit de Stichting Kwaliteitsgelden Medisch Specialisten (SKMS). De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodule is in 2017 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) die betrokken zijn bij de zorg voor patiënten met Melanoom.

Huidige samenstelling van de werkgroep:

Dr. A.A.M. (Astrid) van der Veldt, voorzitter, internist-oncoloog, werkzaam in het Erasmus Medisch Centrum, NIV
Dr. M.J.B. (Maureen) Aarts, internist-oncoloog, werkzaam in het Maastricht Universitair Medisch Centrum, NIV
Prof. dr. A.J.M. (Fons) van den Eertwegh, internist-oncoloog, werkzaam in het Amsterdam Universitair Medisch Centrum, NIV
Dr. M. (Hilde) Jalving, internist-oncoloog, werkzaam in het Universitair Medisch Centrum Groningen, NIV
Dr. S. (Sofie) Wilgenhof, internist-oncoloog, werkzaam in het Antoni van Leeuwenhoek, NIV
Dr. J.J. (Han) Bonenkamp, chirurgisch oncoloog, werkzaam in het Radboudumc, NVvH
Dr. D.J. (Dirk) Grünhagen, chirurgisch oncoloog, werkzaam in het Erasmus Medisch Centrum, NVvH
Dr. A.B. (Anne Brecht) Francken, chirurgisch oncoloog, werkzaam in het Isala, NVvH
Dr. E.I. (Elsemieke) Plasmeijer, dermatoloog, werkzaam in het Antoni van Leeuwenhoek, NVDV
Dr. R. (Remco) van Doorn, dermatoloog, werkzaam in het Leids Universitair Medisch Centrum, NVDV
Dr. Q.G. (Quido) de Lussanet de la Sablonière, nucleair radioloog, werkzaam in het Erasmus Medisch Centrum, NVvR
Dr. E.H.J.G. (Erik) Aarntzen, nucleair geneeskundige, werkzaam in het Universitair Medisch Centrum Groningen, NVNG
Drs. B.A. (Beatrijs) Seinstra, radioloog, werkzaam in het Antoni van Leeuwenhoek, NVvR
H.C. (Hanna) van der Pol, MSC, verpleegkundig specialist melanoom, werkzaam in het Antoni van Leeuwenhoek, V&VN
Dr. T.P. (Thomas) Potjer, klinisch geneticus, werkzaam in het Leids Universitair Medisch Centrum, VKGN
Dr. W.A.M. (Willeke) Blokx, patholoog, werkzaam in het Universitair Medisch Centrum Utrecht, NVVP
Dr. A.M.L. (Anne) Jansen, klinisch moleculair bioloog in de pathologie, werkzaam in het Universitair Medisch Centrum Utrecht, NVVP
K. (Koen) van Elst, Stichting Melanoom

Met speciale dank aan:

Dr. B. Leeneman, Universitair docent, werkzaam in het Erasmus Medisch Centrum (bijdrage aan de doelmatigheidsmodule)

Met ondersteuning van:

Dr. D. (Dagmar) Nieboer, senior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Dr. R.J.S. (Rayna) Anijs, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Dr. L. (Lisanne) Verbruggen, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Drs. F. (Fieke) Pepping, junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten

Voormalig betrokken werkgroepleden:

Drs. J.G.M. (Anne) van den Hoek, radiotherapeut, werkzaam in het Universitair Medisch Centrum Groningen, NVRO (tot en met juni 2024)
Drs. B. (Bernies) van der Hiel, nucleair geneeskundige, werkzaam in het werkzaam in het Antoni van Leeuwenhoek, NVNG (tot en met mei 2024)
Drs. A. (Annemarie) Bruining, radioloog, werkzaam in het Nederlands Kanker Instituut, NVVR (tot en met mei 2024)

Belangenverklaringen

De Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement) hebben gehad. Gedurende de ontwikkeling of herziening van een module worden wijzigingen in belangen aan de voorzitter doorgegeven. De belangenverklaring wordt opnieuw bevestigd tijdens de commentaarfase.

Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten.

Werkgroeplid	Functie	Nevenfuncties	Gemelde belangen	Ondernomen actie
Veldt, van der (voorzitter)	Internist-oncoloog, afdeling Interne Oncologie (0,8 fte) en afdeling Radiologie & Nucleaire Geneeskunde (0,2 fte) Erasmus MC, Rotterdam	Adviesraden: BMS, MSD, Merck, Novartis, Pfizer, Eisai, Sanofi, Pierre-Fabre en Ipsen. Betaald aan het instituut (Erasmus MC) Roche (ook betaald aan het instituut Erasmus MC)	A.A.M. van der Veldt is principal investigator van meerdere studies van firma's (BMS, Exelexis, Novartis, Roche) en investigator-initiated studies (o.a. Safe Stop Trials) die financieel worden ondersteund door onder andere de zorgverzekeraars en non-profit organisaties Participatie aan NADINA-trial	Actie ondernomen bij modules over systemische behandelingen Zie hiervoor ‘Werkwijze en toelichting belangen richtlijn Melanoom’
Aarts	Internist-oncoloog Maastricht Universitair Medisch Centrum	* Bestuurslid WIN-O (Werkgroep Immunotherapie Nederland voor Oncologie) melanoom en nierkanker (onbetaald) * Bestuurslid TFG (tumor focus groep)-melanomen (Integraal kankercentrum Nederland) (onbetaald) * Bestuurslid PRO-RCC (Prospectief Nederlands Nierkanker Cohort) * Bestuurslid OncoZON (Oncologisch netwerk Zuid-Oost Nederland) melanoom * Adviesraad (betaald) BMS, Novartis, AMGEN, MSD, Roche, Ispen, Pfizer, Eisai, Merck, Sanofi, Astellas	* Pfizer - Tyrosine Inhibitor effect op trombocyten - Co-promotor Participatie aan NADINA-trial	Actie ondernomen bij modules over systemische behandelingen Zie hiervoor ‘Werkwijze en toelichting belangen richtlijn Melanoom’
Eertwegh, van den	Medisch-oncoloog, afdeling medische oncologie, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam Voorzitter DMTR (Dutch Melanoma Treatment registry)(vacatiegeld aan Amsterdam UMC)	Adviesraad (betaald aan Amsterdam UMC): Bristol-Myers Squibb, MSD Oncology, Ipsen, Pierre Fabre, Janssen Cilag BV	* Sanofi - Prostaat studies (cabazipet en RECAB) - Projectleider * TEVA - prostaat studie (RECAB) - Projectleider * Bristol-Myers Squibb - Onco-kompas - Geen projectleider Huidig:" * Idera - INTRIM melanoom studie - Projectleider * Roche - REPOSIT melanoom studie - Projecteider * Novartis, Pierre Fabre, MSD, BMS en ziektekosten - DMTR - Geen projectleider PI NADINA-trial	Actie ondernomen bij modules over systemische behandelingen Zie hiervoor ‘Werkwijze en toelichting belangen richtlijn Melanoom’
Jalving	Internist-oncoloog, UMCG Groningen	Adviesraden: Bristol-Myers Squibb, AstraZenica,Pierre Fabre (betaald aan instituut (UMCG)	* KWF - TAMIC: Dichloroacetate in patients with metastatic melanoma prior to treatment with immune-checkpoint inhibition - Projectleider * KWF - FORCE: Infrastructure for rare Cancers in the Netherlands - Geen projectleider	Actie ondernomen bij modules over systemische behandelingen Zie hiervoor ‘Werkwijze en toelichting belangen richtlijn Melanoom’
Wilgenhof	Internist-oncoloog in het Antoni van Leeuwenziekenhuis	Adviesraden: Eisai, Bristol-Myers Squibb, Pierre Fabre, Novartis, Pfizer en lpsen (betaald aan instituut (AVL)); educatief symposium: MSD en Bristol-Myers Squibb (betaald aan insituut (AVL))	* EU Horizon 2020 (no 875052) - CAPABLE: Pilot study of the eHealth application Cancer Patients Better Life Experience - Geen Projectleider * EU (101104801) - CARE-1: Optimizing Treatmensts for Metastatic Renal Carcinoma - Geen Projectleider Studies: principal investigator: CA224020 studie (Clinicalîrials.gov number, NCT01968109) R3767-ONC-2011 studie (NCT05352672) E2139 (NCT05270044) vorinostat studie (NCT02836548) subinvestigator: TIL studie (Clinicalîrials.gov number, NCT02278887) NADINA studie (Clinicalîrials.gov number, NCT04949113) safe stop studie safe stop ipi-nivo (NCT05652673) E1325 (NCT02362594) NIVEC studie (NCT04330430) NKTR-214 + nivolumab (NCT03635983) EBIN (NCT03235245) DONIMI (NCT04133948) MASTERKEY-115 (NCT04068181) IOB-013 (NCT05155254)	Actie ondernomen bij modules over systemische behandelingen Zie hiervoor ‘Werkwijze en toelichting belangen richtlijn Melanoom’
Bonenkamp	Chirurgisch oncoloog, RadboudUMC Nijmegen	* Lid DB TFG Melanoom (onbetaald) * Lid bestuur WIN-O (onbetaald) * Lid DB DMTR (onbetaald) * Lid DB Dutch sarcoma Group	Geen	Geen actie
Grünhagen	Chirurg, Erasmus MC	Lid bestuur WIN-O melanoom, onbetaald	Deelname NADINA-trial	Geen actie
Francken	Chirurgisch oncoloog, Isala	* Voorzitter werkgroep audit NVvH * Lid werkgroep endocriene chirurgue * Lid werkgroep mammachirurgie	Geen	Geen actie
Plasmeijer	Dermatoloog, AVL	* Bestuurslid Win-O: onbetaald * Lid JongCBG: 1500 EUR/jaar onkostenvergoeding * Bestuurslid SCOPE (Skin Care in organ transplantrecipients Europe): onbetaald * Lid NCI Keratinocyte Cancer Consortium (KeraCon) Immunosuppression Group: onbetaald * Lid domeingroep NVDV dermatotherapie: onbetaald * Raad van Advies HUKA's: onbetaald * Raad van Advies Lacune NVDV (kennisagenda)	Geen	Geen actie
Doorn, van	Dermatoloog, Leids Universitair Medisch Centrum	Onbetaald lid van enkele besturen (European Society for Dermatological Research, Nederlandse Vereniging voor Experimentele Dermatologie) adviseur van Stichting Melanoom (onbetaald)	Stichting KiKA - Therapeutic targeting of congenital melanocytic naevus and childhood melanoma using FOXO4 anti-senescence peptides - Projectleider Zeldzame Ziekten Fonds, onderzoek naar Familial Atypical Multiple Mole Melanoma syndrome -Stichting Dioraphte, onderzoek naar farmacologische therapie voor congenitale melanocytaire nevi	Geen actie
Lussanet de la Sablonière	Nucleair- en Abdomen radioloog, Erasmus Medisch Centrum, Rotterdam	Geen	Geen	Geen actie
Aarntzen	Nucleair geneeskundige, UMC Groningen (0,8 fte) * UMCGroningen, nucleair geneeskundige (0,8 fte) * Radboudumc, post-doc onderzoeker (0,1 fte) * Eberhard Karls University, Tuebingen, Duitsland (0,5 fte)	* Post-doc onderzoeker Radboudumc, betaald (0,1 fte) * Post-doc onderzoeker Eberhard Karls University Tuebingen (Duitsland), betaald (0,05 fte)	* EU Innovatieve Health Initiative (IHI) - IMAGIO - IMAGING and advanced guidance for workflow optimalization in interventionaal oncology - Projectleider * Bergh in het Zadel/ Radboud oncologie Fonds - 'Breek de barrière: 'een nieuwe lokale en gerichte behandelmethode voor alvleesklierkanker' - Projectleider * ImaginAB Inc - iPREDICT, Trial: A phase IIB, Open Label, Study of 89Zr-crefmirlimab berdoxam PET/CT in Subjects with Selected Advanced or Metastetic Malignancies to ? - Geen projectleider site PI * Bergh in het Zadel/Radboud oncologie Fonds - Inzet AI voor betere overleving niet-kleincellig longkanker - Projectleider * ImaginAB Inc - (89Zr)Df-lAB22MC anti-CD8 minibody PET/CT-imaging to assess the in vivo distribution of CD8+ T-cells in COVID-19 patienst (NCT04874818) - Projectleider * KWF - Imaging tumor-infiltrating CD8+ T-cells in non-small cell lung cancer patienst upon neo-adjuvant treatment with Durvalumab - Projectleider	Geen actie
Seinstra	Radioloog - Antoni van Leeuwenhoek Ziekenhuis	Betrokken bij NADINA-trial als mede-auteur	Geen	Geen actie
Van der Pol	Verpleegkkundig specialist, Antoni van Leeuwenhoekziekenhuis, Amsterdam	Geen	Geen	Geen actie
Potjer	Klinisch Geneticus, LUMC	Cluster expertisegroep Maligniteiten van de huid	Geen	Geen actie
Blokx	Klinisch patholoog, UMC Utrecht	Geen	Geen	Geen actie
Jansen	Klinisch Moleculair Bioloog in de Pathologie, UMC Utrecht	Bestuurslid Stichting PALGA (vacatiegelden)	Geen	Geen actie
Leeneman	Universitair docent, Erasmus Universiteit Rotterdam	Geen	* ZIN - Ontwikkeling van ziektemodel voor melanoom - Geen projectleider * ZIN - Actualisatie van ziektemodel voor melanoom - Projectleider	Geen actie
Van der Elst	Manager Quality and Improvement, Contour Advanced Systems B.V.	Bestuurslid Stichting Melanoom	Geen	Geen actie

Werkwijze en toelichting belangen richtlijn Melanoom

De NIV heeft vastgesteld dat het niet mogelijk was werkgroepleden af te vaardigen met voldoende expertise zonder potentiële belangenverstrengeling. Het gaat daarbij met name om werkgroepleden die deelnemen aan adviesraden/kennisuitwisselingsbijeenkomsten met de farmaceutische industrie of deel nemen of hebben genomen als onderzoeker van een klinische studie. Gedurende de ontwikkeling van de [richtlijn / modules] heeft daarom afstemming plaatsgevonden tussen de werkgroepvoorzitter, de belangencommissie van het Kennisinstituut van de Federatie Medisch Specialisten en de NIV over passende acties naar aanleiding van de gemelde belangen.

Restricties voor de modules over onderwerpen (medicamenteuze behandeling) waar de adviesraden betrekking op hebben:

Werkgroeplid werkt niet als enige inhoudsdeskundige aan de module;
Werkgroeplid werkt tenminste samen met een werkgroeplid met een vergelijkbare expertise in alle fasen (zoeken, studieselectie, data-extractie, evidence synthese, Evidence-to-decision, aanbevelingen formuleren) van het ontwikkelproces. Indien nodig worden werkgroepleden toegevoegd aan de werkgroep;
In alle fasen van het ontwikkelproces is een onafhankelijk methodoloog betrokken;
Overwegingen en aanbevelingen worden besproken en vastgesteld tijdens een werkgroepvergadering onder leiding van een onafhankelijk voorzitter (zonder gemelde belangen).

Aansluitend op de reguliere commentaarronde bij de achterban van de bij de richtlijn betrokken wetenschappelijke verenigingen, hebben (een aantal) leden van richtlijn- en kwaliteitscommissie van de NIV en een methodoloog van het Kennisinstituut die niet betrokken waren bij ontwikkeling van de modules, aanvullend beoordeeld of de aanbevelingen logischerwijs aansluiten bij het gevonden bewijs en de overwegingen, om de onafhankelijkheid van de richtlijn te waarborgen.

Wellicht ten overvloede willen wij erop wijzen dat medisch specialistische richtlijnen niet worden vastgesteld door de betreffende richtlijnwerkgroep maar door de besturen/ledenvergadering van de betrokken verenigingen.

Inbreng patiëntenperspectief

Bij elke module is het patiëntperspectief meegenomen door de werkgroep. Er werd aandacht besteed aan het patiënten perspectief door een afgevaardigde van een patiëntenvereniging, de Stichting Melanoom, in de werkgroep te laten participeren.

NHG-standaard Verdachte huidafwijkingen

Voor huisartsen is de NHG-Standaard Verdachte huidafwijkingen leidend. Deze sluit aan op de richtlijn Melanoom.

Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

Bij de richtlijnmodule is conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitgevoerd om te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema op de Richtlijnendatabase).

Module	Uitkomst raming	Toelichting
Systemische therapie - Tweedelijnsbehandeling BRAF-V600E/K gemuteerd irresectabel of gemetastaseerde stadium III/IV	Geen substantiële financiële gevolgen	Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (5.000-40.000 patiënten), volgt ook uit de toetsing dat het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft. Er worden daarom geen substantiële financiële gevolgen verwacht.

Werkwijze

AGREE

Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).

Knelpuntenanalyse en uitgangsvragen

De werkgroep beoordeelde de aanbeveling(en) uit de eerdere richtlijnmodules op noodzaak tot revisie.

Uitkomstmaten

Na het opstellen van de zoekvraag behorende bij de uitgangsvraag inventariseerde de werkgroep welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken. Hierbij werd een maximum van acht uitkomstmaten gehanteerd. De werkgroep waardeerde deze uitkomstmaten volgens hun relatieve belang bij de besluitvorming rondom aanbevelingen, als cruciaal (kritiek voor de besluitvorming), belangrijk (maar niet cruciaal) en onbelangrijk. Tevens definieerde de werkgroep tenminste voor de cruciale uitkomstmaten welke verschillen zij klinisch (patiënt) relevant vonden.

Methode literatuursamenvatting

Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur is te vinden onder ‘Zoeken en selecteren’ onder Onderbouwing. Indien mogelijk werd de data uit verschillende studies gepoold in een random-effects model. Review Manager 5.4 werd gebruikt voor de statistische analyses. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht.

Beoordelen van de kracht van het wetenschappelijke bewijs

De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/). De basisprincipes van de GRADE-methodiek zijn: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van de bewijskracht per uitkomstmaat op basis van de acht GRADE-domeinen (domeinen voor downgraden: risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias; domeinen voor upgraden: dosis-effect relatie, groot effect, en residuele plausibele confounding).

GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie, in het bijzonder de mate van zekerheid dat de literatuurconclusie de aanbeveling adequaat ondersteunt (Schünemann, 2013; Hultcrantz, 2017).

GRADE	Definitie
Hoog	er is hoge zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; het is zeer onwaarschijnlijk dat de literatuurconclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Redelijk	er is redelijke zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; het is mogelijk dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Laag	er is lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; er is een reële kans dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Zeer laag	er is zeer lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; de literatuurconclusie is zeer onzeker.

Bij het beoordelen (graderen) van de kracht van het wetenschappelijk bewijs in richtlijnen volgens de GRADE-methodiek spelen grenzen voor klinische besluitvorming een belangrijke rol (Hultcrantz, 2017). Dit zijn de grenzen die bij overschrijding aanleiding zouden geven tot een aanpassing van de aanbeveling. Om de grenzen voor klinische besluitvorming te bepalen moeten alle relevante uitkomstmaten en overwegingen worden meegewogen. De grenzen voor klinische besluitvorming zijn daarmee niet één op één vergelijkbaar met het minimaal klinisch relevant verschil (Minimal Clinically Important Difference, MCID). Met name in situaties waarin een interventie geen belangrijke nadelen heeft en de kosten relatief laag zijn, kan de grens voor klinische besluitvorming met betrekking tot de effectiviteit van de interventie bij een lagere waarde (dichter bij het nuleffect) liggen dan de MCID (Hultcrantz, 2017).

Overwegingen (van bewijs naar aanbeveling)

Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals aanvullende argumenten uit bijvoorbeeld de biomechanica of fysiologie, waarden en voorkeuren van patiënten, kosten (middelenbeslag), aanvaardbaarheid, haalbaarheid en implementatie. Deze aspecten zijn systematisch vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’ en kunnen (mede) gebaseerd zijn op expert opinion. Hierbij is gebruik gemaakt van een gestructureerd format gebaseerd op het evidence-to-decision framework van de internationale GRADE Working Group (Alonso-Coello, 2016a; Alonso-Coello 2016b). Dit evidence-to-decision framework is een integraal onderdeel van de GRADE methodiek.

Formuleren van aanbevelingen

De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk (Agoritsas, 2017; Neumann, 2016). De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen. De werkgroep heeft bij elke aanbeveling opgenomen hoe zij tot de richting en sterkte van de aanbeveling zijn gekomen.

In de GRADE-methodiek wordt onderscheid gemaakt tussen sterke en zwakke (of conditionele) aanbevelingen. De sterkte van een aanbeveling verwijst naar de mate van zekerheid dat de voordelen van de interventie opwegen tegen de nadelen (of vice versa), gezien over het hele spectrum van patiënten waarvoor de aanbeveling is bedoeld. De sterkte van een aanbeveling heeft duidelijke implicaties voor patiënten, behandelaars en beleidsmakers (zie onderstaande tabel). Een aanbeveling is geen dictaat, zelfs een sterke aanbeveling gebaseerd op bewijs van hoge kwaliteit (GRADE gradering HOOG) zal niet altijd van toepassing zijn, onder alle mogelijke omstandigheden en voor elke individuele patiënt.

Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers

	Sterke aanbeveling	Zwakke (conditionele) aanbeveling
Voor patiënten	De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet.	Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet.
Voor behandelaars	De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen.	Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren.
Voor beleidsmakers	De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid.	Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen.

Organisatie van zorg

In de knelpuntenanalyse en bij de ontwikkeling van de richtlijnmodule is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van deze specifieke uitgangsvraag zijn genoemd bij de overwegingen. Meer algemene, overkoepelende, of bijkomende aspecten van de organisatie van zorg worden behandeld in de module Organisatie van zorg.

Commentaar- en autorisatiefase

De conceptrichtlijnmodule werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijnmodule aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodule werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.

Literatuur

Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.

Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.

Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.

Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.

Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.

Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html

Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

Melanoom

Melanoom

Uitgangsvraag

Aanbeveling

Overwegingen

Onderbouwing

Conclusies / Summary of Findings

Samenvatting literatuur

Zoeken en selecteren

Referenties

Evidence tabellen

Verantwoording

Beoordelingsdatum en geldigheid

Initiatief en autorisatie

Algemene gegevens

Samenstelling werkgroep

Belangenverklaringen

Inbreng patiëntenperspectief

Werkwijze

Bijlagen

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