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.

I:

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.

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