Wu, 2017

Mok, 2018

Paty, 2021

Mok, 2021

ARCHER 1050

NCT01774721

International multicentre, randomised, open-label, phase 3 study.

71 academic medical centres and university hospitals in seven countries (China, Hong Kong, Japan, South Korea, Poland, Italy, and Spain)

Patient enrolment between: May 9, 2013 - March 20, 2015.

Funding and conflicts of interest:

• Funding: SFJ Pharmaceuticals Group and Pfizer; Had a role in design of the study; data were collected by the principal investigators and verified by the sponsors; the sponsors had a role in the data analysis, data interpretation, and writing of the report.
• Declaration of interests of all authors is reported with the article.

Inclusion criteria:

• Aged ≥18 years old (or ≥20 years in Japan and South Korea)
• Histologically or cytopathologically confirmed newly diagnosed stage IIIB/IV or recurrent NSCLC (≥ 12 months disease-free interval between completion of adjuvant or neoadjuvant therapy and recurrence of NSCLC)
• ≥1 target lesion not previously been irradiated and measurable according to RECIST V. 1.1 criteria
• Presence of ≥1 documented EGFR mutation (exon 19 deletion or Leu858Arg mutation, with/without Thr790Met mutation).
• ECOG PS of 0–1;
• Adequate renal, hepatic, and haematological function;
• Availability of tumour specimens for central laboratory confirmation of an EGFR activating mutation.

Exclusion criteria:

• any evidence of mixed histology, cytology, or both that included elements of small cell or carcinoid lung cancer
• Atypical EGFR mutations;
• History of brain or leptomeningeal metastases;
• history of, or currently suspected, diffuse non-infectious pneumonitis or interstitial lung disease;
• Any previous anticancer systemic treatment of locally advanced or metastatic NSCLC;
• previous treatment with an EGFR TKI or other TKI;
• Uncontrolled or substantial cardiovascular disease.

Age, years

Median (range)

I: 62 (53–68)

C: 61 (54–68)

Female

I: 64%

C: 56 %

ECOG PS:

0 – I: 33.0%

0 – C: 27.6 %

1 – I: 67.0%

1 – C: 72.4%

Exon 19 deletion:

I: 134 (59%)

C: 133 (59%)

Exon 21 L858R mutation:

I: 93 (41%)

C: 92 (41%)

Groups were comparable at baseline.

Oral dacomitinib 45 mg once daily in 28-day cycles.

Dose reductions for a maximum of two dose levels were permitted for treatment-related toxicity in the case of ≥ grade 3 toxicity, or prolonged grade 2 AEs.

n=227

Oral gefitinib

250 mg once daily in 28-day cycles. Gefitinib was only

available as a 250 mg dose. If treatment was interrupted

for grade 3, grade 4, or intolerable grade 2 toxicity,

gefitinib was resumed at a daily or every-other-day dosing at the investigator’s discretion.

n=225

Mok 2021 data cut off 3, May 2019:

Median duration of follow-up for OS: 47.9 months

Still on treatment, n (%):

I: 11 (5%)

C: 0

Median duration of treatment, months (range):

I: 15.4 (0.07–60.5)

C: 12.0 (0.07–48.1)

Discontinuation due to treatment related AEs, n (%):

I: 23 (10.1%)

C: 15 (6.7%)

Mok 2018 data cut off 2, Feb 2017:

Each patient was observed for survival status and subsequent cancer therapies for up to 48 months from the date of first dosing.

Still on treatment, n (%):

I: 49 (21.6%)

C: 18 (8.0%)

Median duration of follow-up for OS, months (IQR):

I: 31.3

C: 31.4

Wu 2017 data cutoff 1, Jul 2016:

Median duration of treatment, months (IQR)

I: 15·3 (6·9–20·9)

C: 12·0 (7·3–18·4)

Still on treatment:

I: 66 (29%)

C: 38 (17%)

Median duration of follow-up for PFS months (IQR):

ITT:22·1 (20·3–23·9;

I: 22·1 (20·2–23·9)

C: 23·0 (20·3–25·8).

Mok 2021:

Deaths

I: 133 [58.6%]

C: 152 [67.6%]

Median OS, months (95% CI)

I: 34.1 (29.5–39.8)

C: 27.0 (24.4–31.6)

HR: 0.75; 95% CI 0.59–0.95; two-sided P = 0.016

12 month OS, months (95% CI):

I: 85.7% (80.4–89.7)

C: 86.0% (80.7–89.9)

42 month OS, months (95% CI):

I: 41.0% (34.3–47.6) 

C: 33.6% (27.2–40.0)

OS for Exon 19 del, HR (95% CI):

HR= 0.85 (0.62–1.16)

two-sided P = 0.30)

OS L858R mutation, HR (95% CI):

HR= 0.67 (0.47–0.94)

two-sided P = 0.02)

AEs were consistent with those reported in the primary analysis.

Serious AEs, n (%):

I: 69 (30.4%)

C: 53 (23.7%)

Treatment related serious AEs, n (%):

I: 22 (9.7%)

C: 10 (4.5%)

Deaths reported as AEs, n (%):

I: 24 (10.6%)

C: 22 (9.8%)

Paty 2021:

At baseline, PRO questionnaires were completed:

I: 226

C: 222

More than 90% of patients answering all questions

for almost all cycles in both treatment groups.

Global QoL scores:

Transformed GHS/QoL scores, range:

I: Between 61.5 (cycle 30) - 69.8 (cycle 28)

C: Between 68.5 (cycle 17) - 73.1 (cycle 28)

[against a possible total score of 100, where 100 represents excellent health]

Physical function transformed scores, range:

I: Between 81.7 (cycle 4) -

86.9 (cycle 13)

C: Between 82.4 (cycle 17) - 88.6 (cycle 5)

Dacomitinib-treated patients who received dose reductions (DR) reported improvement in GHS/QoL and physical functioning after DR compared with scores prior to the DR.

Mok 2018:

Deaths

I: 103/227 (45.4%)

C: 117/225 (52.0%)

Median OS, months (95% CI)

I: 34.1 (29.5 to 37.7)

C: 26.8 (23.7 to 32.1)

HR, 0.76; 95% CI, 0.58 to 0.99; P = .044).

OS for Exon 19 HR (95% CI)

HR= 0.88 (0.61 - 1.26)

OS for L858R HR (95% CI):

HR= 0.71 (0.48 - 1.05)

Wu 2017:

Median PFS by masked IRC review, months (95% CI)

I: 14·7 (11·1–16·6)

C: 9·2 (9·1–11·0)

HR 0·59 (95% CI 0·47–0·74); p<0·0001

ORR:

I: n= 170 (75%; 69–80)

C: n=161 (72%; 65–77)

Serious AEs any cause, n (%)

I: 62 (27%)

C: 50 (22%)

Treatment related serious AEs, n (%)

I: 21 (9%)

C: 10 (4%)

Deaths AEs related, n (%) (according to investigators)

I: 22 (10%)

C: 20 (9%)

Global quality of life

I: 0.20

C: 4·94

p=0·0002

• Data cutoff 1: July 29, 2016
• Data cutoff 2: February 17, 2017
• Data cutoff 3: 13 May 2019
• Designed by a steering committee of academic advisers and representatives from the sponsors of the study
• In both study groups, treatment was discontinued after progression of disease, initiation of new anticancer therapy, unacceptable toxicities, non-compliance, withdrawal of consent, or death. Treatment beyond radiological progression was permitted as long as there was evidence of clinical benefit as determined by the investigator in consultation with the sponsor.
• One patient randomly assigned to the gefitinib group received no treatment because of rapid disease progression and consent was withdrawn; safety analysis population N=451.
• After discontinuation of study treatment subsequent systemic therapies were received by:

I: 130 (57.3%)

C: 146 (64.9%)

Authors conclusions:

Mok 2021:

In conclusion, the OS benefit from first-line treatment

with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR-activating mutations and persisted in patients who had a dose reduction. Improvement of OS was observed in most of the predefined subgroups, including the Asian population and those with exon 21 L858R substitution mutation.

Paty 2021:

Dacomitinib was previously shown to improve PFS and OS versus gefitinib. Longer treatment duration, enabled by DR, allowed patients on dacomitinib to improve disease-related symptoms and maintain functioning and overall QoL for longer than patients on gefitinib.

Mok 2018:

In conclusion, dacomitinib is the first EGFR TKI to show a significant improvement in OS in a randomized, head-to-head

comparison with another EGFR TKI for the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR activating mutations. Therefore, dacomitinib should be considered one of the standard treatment options for this population.

Wu 2017: In conclusion, dacomitinib treatment was superior to gefitinib with respect to progression-free survival and duration of response in the first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population.

Ramalingam,

2020

Soria, 2018

FLAURA study

NCT02296125

Double-blind, phase 3 trial

Performed at 132 sites in 29 countries

Patients were enrolled between: From December 2014 through March 2016

Funding and conflicts of interest:

• Supported by AstraZeneca. The sponsor was responsible for the collection and analysis of the data and had a role in data interpretation.

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

Main inclusion criteria:

• Patients aged ≥18 years (Japan ≥20 years)
• Locally advanced or metastatic NSCLC with exon 19 deletion or L858R mutation
• No prior treatment for advanced disease
• Eligible to receive first-line treatment with gefitinib or erlotinib.
• Patients with CNS metastases whose condition was neurologically stable.

Main Exclusion criteria:

• Concurrent and/or other active malignancy that required treatment within 2 yrs of first dose of study drug
• Unresolved toxicities from prior systemic therapy
• Fulfilling cardiac criteria (see protocol)
• Inadequate bone marrow reserve or organ function
• Medical history of ILD

For more information on in-/exclusion see the trial protocol, available at NEJM.org.

Median age (range)

I: 64 yrs (26-85)

C: 64 yrs (35-93)

Sex:

I: Female: 64%

C: Female 62%

Mutation type at randomisation:

Exon 19 del: 63%

L858R: 37%

CNS metastases: n=116/556=21%

Asian:

I: 62%

C: 62%

• Groups were comparable at baseline.

Osimertinib 80 mg orally once daily

Randomized: N=279

A standard of Care EGFR-TKI (gefitinib at a dose of 250 mg orally once daily or erlotinib at a dose of 150 mg orally once daily)

Randomized: N=277

(n=183: gefitinib;
n=94: erlotinib)

After the analysis of the primary end point of PFS had been performed central collection of progression events was stopped.

At June 12, 2017 the median duration of total treatment exposure, months (range):

I: 16.2 (0.1 - 27.4)

C: 11.5 (0 - 26.2)

Continued to receive trial treatment:

I: N=141 (51%)

C: N=64 (23%)

At June 25, 2019 the median duration of total treatment exposure, months (range):

I: 20.7 (0.1 - 49.8)

C: 11.5 (0.0 - 50.6)

Continued to receive trial treatment:

I: N=61 (22%)

C: N=13 (5%)

Length of follow-up for overall survival (median):

I: 35.8 months

C: 27.0 months

Ramalingam 2020, data cutoff June 2019:

Death: N=321 (58% maturity)

Median OS, months (95% CI):

I: 38.6 (34.5 - 41.8)

C: 31.8 (26.6 - 36.0)
(HR for death, 0.80; 95.05% CI, 0.64 - 1.00; P = 0.046)

12 month OS, months (95% CI):

I: 89 % (85–92)

C: 83 % (77–87)

24 month OS, months (95% CI):

I: 74 % (69–79)

C: 59 % (53–65)

36 month OS, months (95% CI):

I: 54 %(48–60)

C: 44 % (38–50)

Objective response rate (95% CI):

I: 80% (75 - 85)

C: 76% (70 - 81)

(OR, 1.27; 0.85 - 1.90; P = 0.24)

Safety:

AEs grade ≥3

I: 42%

C: 47%

Serious AEs:

I: 27%

C: 27%

Fatal adverse events

I: 9 (3%)
Possibly related to osimertinib: N=0

C: 10 (4%)

Possibly related to standard EGFR-TKIs: N=2

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

Soria 2018 (data cutoff: June 2017):

Median PFS (investigator assessed), months (95% CI)

I: 18.9 ( 15.2 to 21.4)

C: 10.2 (9.6 to 11.1)

HR=0.46 (95% CI, 0.37–0.57); P<0.001

Subgroups (PFS):

Exon 19 deletion: HR=0.43 (0.32–0.56)

L858R: HR= 0.51 (0.36–0.71)

Median overall survival,

I: NC (NC–NC)

C: NC (NC–NC)

(NC=could not be calculated)

Percent of patients alive at 18 months (95% CI)

I: 83 (78–87)

C: 71 (65–76)

ORR (95% CI):

I: 80% (75 to 85)

C: 76% ( 70 to 81)

Odds ratio, 1.27; 95% CI, 0.85 to 1.90; P = 0.24)

AEs grade ≥3

I: 95/279=34%

C: 125/277=45%

Fatal adverse events

I: 6/ 279 patients (2%)

C: 10/277 patients (4%)

None of the fatal adverse events were considered

to be possibly related to osimertinib, and one

fatal adverse event (of diarrhea) was considered

to be possibly related to standard EGFR-TKIs.

• The primary PFS analysis data cutoff was June 12, 2017.
• The final OS analysis data cutoff was June 25, 2019.
• Trial was funded by the sponsor and was designed by the principal investigators and the sponsor.
• Treatment continued until disease progression, the development of unacceptable side effects, or withdrawal of consent.
• Patients who had been assigned to a standard EGFR-TKI allowed to cross over to open-label osimertinib after confirmation of objective disease progression.
• After progression, 133 patients (48%) in the osimertinib group and 180 (65%) in the comparator group started a first subsequent anticancer therapy. Of these, 85 of 180 (47%) in the standard EGFR-TKI group received osimertinib.

Authors conclusion:

Ramalingam 2020:

• Thus, we found that first-line treatment with osimertinib was associated with significantly longer overall survival than treatment with comparator EGFR-TKIs in patients with EGFR mutation–positive, locally advanced or metastatic NSCLC and had a similar safety profile.

Park, 2016

Paz-Ares, 2017

LUX-Lung 7

NCT01466660

A multicentre, international, randomised, open-label

phase IIb trial.

Performed at 64 sites; in 13 countries.

Patient enrolment between: Dec 13, 2011 - Aug 8, 2013.

Funding and conflicts of interest:

• Funder: Boehringer Ingelheim. Had a role in design of the trial, data analyses, data interpretation and article development. The article was written with independent medical writing assistance supported financially by the funder.
• Declaration of interests is reported with the article.

• Main inclusion criteria:
  - Age ≥ 18 years
• - Treatment-naive

pathologically confirmed stage IIIB (ineligible for

curative intent surgery or local radiotherapy) or IV

(recurrent or metastatic) adenocarcinoma of the lung

• - EGFR mutation (exon 19 deletion or Leu858Arg)
• - ECOG PS of 0 or 1
• - ≥ 1 measurable lesion

according to RECIST V.1.1

- adequate organ function

Main exclusion criteria:

• - Previous systemic chemotherapy or EGFR-targeted drugs for

advanced disease

• - Major surgery within 4 weeks of study randomisation
• - Active brain metastases
• - Leptomeningeal disease
• - Previous or concomitant

malignancies at other sites

• - Pre-existing interstitial lung

disease

• - History or presence of poorly controlled

gastrointestinal disorders

• - Cardiovascular abnormalities
• - Active hepatitis B or C infection, and/or known HIV infection.

The complete eligibility criteria are provided in the appendix of the article (p 1).

Median age (range)

I: 63 (30–86)

C: 63 (32–89)

Sex:

I: Female: 91 (57%)

C: Female: 106 (67%)

ECOG PS:

0 – I: 51 (32%)

0 – C: 47 (30%)

1 – I: 109 (68%)

1 – C: 112 (70%)

Adenocarcinoma

I: 159 (99%)

C: 158 (99%)

Mutation type:

Exon 19 del:

I: 93 (58%)

C: 93 (58%)

Leu858Arg:

I: 67 (42%)

C: 66 (42%)

Clinical stage:

IIIB:

I: 8 (5%)

C: 3 (2%)

IV:
I: 152 (95%)

C: 156 (98%)

Groups were comparable at baseline.

Afatinib

40 mg orally once daily.

Dose escalation to 50 mg was allowed after 4 weeks of treatment for patients who did not experience drug-related AE of grade >1.

N=160

Gefitinib

daily dose of 250 mg.

Modifications were allowed according to the summary of product characteristics or prescribing information or

institutional guidelines.

N=159

Paz-Ares, 2017

All randomised patients were included in the primary assessment of OS, and updated analysis of PFS.

Safety analysis included all patients who received at least one dose of study drug.

Median follow-up: 42.6 months

Median duration of treatment, months (range):

Afatinib: 13.7 ( 0–46.4)

Gefitinib: 11.5 (0.5–48.7)

Remained on treatment:

I: 14 (8.8%)

C: 8 (5.0%)

Park 2016:

Tumours were assessed by CT (preferred) or MRI scan after 4 and 8 weeks of treatment, then every 8 weeks until week 64 and every 12 weeks thereafter until permanent discontinuation of study treatment.

Median follow-up for PFS, months (IQR): 27·3 (15·3–33·9).

OS events at date cut-off :

I: 109 (68.1%)

C: 117 (73.6%)

Median OS, months

I: 27.9

C: 24.5

HR: 0.86; 95% CI 0.66–1.12; P=0.26

Exon 19 deletions, months:  

I: 30.7

C: 26.4

HR: 0.83, 95% CI 0.58–1.17, P=0.28

L858R mutation, months:

I: 25.0

C: 21.2

HR: 0.91, 95%CI 0.62–1.36,

P=0.66

ORR

I: 116/160=72.5%

C: 89/159=56.0%

Odds ratio 2.12 (95% CI

1.32–3.40)

All cause grade ≥3 AEs

I: 56.9%

C: 53.5%

Treatment related grade ≥3 AEs:

I: 50/161=31.3%

C: 31/159= 19.5%

Fatal AE related with gefitinib (Hepatic and renal failure): N=1

Park:

Overall survival data were immature at the time of this

primary analysis.

Median overall survival, months (95% CI)

I: 27·9 (25·1–32·2)

C: 25·0 (20·6–29·3)

HR= 0·87 (95% CI 0·66–1·15); p=0·33.

Median PFS by blinded independent review

I: 11.0 (10.6–12.9)

C: 10.9 (9.1–11.5)

HR 0.73, 95% CI 0.57–0.95

Median PFS

Subgroup Leu858Arg

I: 10·9 (8·1–12·9)

C: 10·8 (7·2–12·8)

HR= 0·71 (0·48–1·06)

Median PFS

Subgroup Exon 19 deletion

I: 12·7 (10·6–14·7)

C: 11·0 (9·1–12·7)

HR= 0·76 (0·55–1·06)

Objective response rate (ORR)

I: 112/160 (70%)

C: 89/159 (56%)

Odds ratio 1·87 [95% CI 1·18–2·99]; p=0·0083.

AEs grade ≥3:

I: n= 91 (57%)

C: n=83 (52%)

QoL, EQ 5D

Post-baseline adjusted mean (SE)

I: 0·77 (0·01)

C: 0·80 (0·01)

P=0.14

mean score up to median follow-up of 56 weeks.

• The funder designed the trial in collaboration with the LUX-Lung 7 steering committee

Data were collected by the investigators and were analysed jointly with the funder.

• Data cut-off: 8 April 2016.
• Independent review of tumour response was done in a blinded manner
• Treatment was continued until disease progression, intolerable adverse events as judged by the investigator, or other reasons necessitating withdrawal; treatment beyond radiological progression was allowed in the case of continued clinical benefit as judged by the investigator.
•  Following discontinuation of study treatment, the majority of patients received at least one systematic anti-cancer therapy (72.6% and 76.8% in the afatinib and gefitinib arms, respectively.

Authors conclusion:

Paz-Ares:

In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent

review), TTF and ORR data were significantly improved with afatinib.

Park:
In summary, although an exploratory trial, the totality

of data reported herein indicates that afatinib might

offer improved efficacy compared with gefitinib, while conferring a predictable tolerability profile. Our findings suggest that first-generation and second-generation EGFR targeted drugs might not be interchangeable. We believe that these data provide additional evidence to help to inform decision making when choosing a first-line treatment for patients with EGFR mutation positive NSCLC.

Nakagawa,

2019

Nadal, 2022,

Yoh 2020

RELAY study

NCT02411448

Double-blind, placebo-controlled, phase 3 trial

Performed in 100 hospitals, clinics, medical centres in 13 countries (UK, South Korea, Hong Kong, USA, Japan, Taiwan, Canada, France, Italy, Germany, Spain, Romania, Turkey).

Patients were enrolled between: Jan 28, 2016 - Feb 1, 2018.

Funding and conflicts of interest:

• The funder Eli Lilly was involved in study design, data collection, analysis,  interpretation, and writing of the report.
• Declaration of interests of all authors is reported with  the article.

Main inclusion criteria:

• Age ≥ 18 years (Japan & Taiwan: ≥20 years)
• Metastatic NSCLC patients (Stage IV)
• ex19del/Leu858Arg mutation
• Eligible for erlotinib as first line treatment
• ECOG PS ≤1
• Measurable disease (RECIST 1.1)
  
  

Main exclusion criteria:

• EGFR T790M mutation
• Metastatic CNS lesions
• Ophthalmologic abnormalities
• Active interstitial lung disease
• Prior systemic chemotherapy for advanced NSCLC incl. TKI therapy.
• Third-space fluid requiring frequent drainage
• Clinically relevant cardiovascular factors

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

N total at baseline:

I: N=224

C: N=225

Age, Median (IQR):

I: 65 (57-71)

C: 64 (56-70)

Sex:

I: 63% Female

C: 63% Female

East Asia:

I: 74%

C: 76%

• Groups were comparable at baseline.

Intravenous ramucirumab 10 mg/kg once every 2 weeks and oral erlotinib 150 mg/day.

Study treatment continued until radiographic progression as assessed by the investigator according to RECIST V. 1.1, or unacceptable toxicity or withdrawal of consent, non-compliance, or investigator decision.

Intravenous placebo once every 2 weeks and oral erlotinib 150 mg/day.

Study treatment continued until radiographic progression as assessed by the investigator according to RECIST V.1.1, or unacceptable toxicity or withdrawal of consent, non-compliance, or investigator decision.

Length of follow-up in months, median (IQR):

20·7 (15·8–27·2)

Patients who discontinued study treatment were followed up for survival until study completion.

Did not receive allocated treatment:

I: 3 (1.3%)

• 1 adverse event
• 1 physician decision
• 1 patient withdrawal

C: 0

Discontinued study treatment:

I: 157 (70.1 %)

Reasons:

• 106 progressive disease
• 27 adverse event
• 14 patient decision
• 6 physician decision
• 2 deaths
• 1 ECOG performance status 3
• 1 patient travelling

C: 182 (80.9%)

Reasons:

• 145 progressive disease
• 24 adverse event
• 9 patient withdrawal
• 3 physician decision
• 1 death

At data cutoff still on treatment:

I: 64/224=29%

C: 43/225=19%

OS:

Data were immature at data cutoff. Median interim OS was not reached in either group. A final analysis is planned when at least 300 OS events have occurred.

Median PFS, months (95% CI):

I: 19·4 (15·4–21·6)

C: 12·4 (11·0–13·5)

HR for progression/ death: 0·59 [95% CI 0·46–0·76], p<0·0001

1-year PFS (95% CI)

I: 71·9% (65·1–77·6)

C: 50·7% (43·7–57·3)

PFS in subgroups:

• Ex19del mutation:

I: 64/123

C: 84/120

Unstratified HR: 0·65 (0·47–0·90)

• Leu858Arg:

I: 58/99

C: 74/105

Unstratified HR: 0·62 (0·44–0·87)

AEs grade ≥3:

I: 159/221 (72%)

C: 121/225 (54%)

Overall response (95% CI):

I: 76% (71–82)

C: 75% (69–80)

Stratified p value: 0·74

Nadal (2022):
Deaths due to AEs during study treatment or within 30 days of treatment discontinuation:

I: n=6

C: n=0

Death related to study drug:

I: n=1 (hemothorax)

For a detailed list of AEs see appendix of the article Table S6 and separate publication by Nadal (2022).

•  Ramucirumab and Erlotinib could be delayed allowing for recovery from toxic effects.
• Ramucirumab and erlotinib dose reduction were permitted if a dose reduction criterion was fulfilled.  
• An interim futility analysis was conducted at 114 investigator-assessed PFS events (data cutoff date 16 October 2017).
• All efficacy endpoints, were assessed in the ITT population (I:N=224 and C: N=225).
• Safety was assessed in all patients who received at least one dose of study treatment (I: N=221 and C: N=225).
• EGFR Thr790Met analyses were done in the subset of ITT patients who had disease progression by data cutoff and had available NGS results.
• Another publication by Nakagawa (2022) showed the following results: No association was observed between RAM exposure and response, suggesting that the RELAY regimen of RAM 10 mg/kg Q2W with ERL is an optimized, efficacious, and safe first-line treatment for patients with untreated, metastatic, EGFR-mutated NSCLC.

Authors conclusion:

Nakagawa (2019):

In conclusion, ramucirumab plus erlotinib provided superior progression-free survival versus placebo plus erlotinib in first-line metastatic EGFR-mutated NSCLC. Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population. The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.

Yoh, 2020:

Patients’ overall quality of life and symptom burden did not differ with the addition of

ramucirumab to erlotinib compared to placebo/erlotinib. These data support the clinical benefit of

ramucirumab/erlotinib in untreated EGFR-mutated metastatic NSCLC.

• Nadal 2022: This in-depth safety analysis from RELAY supports that RAM + ERL, irrespective of the increased incidence of AEs, does not affect a patient’s ability to benefit from treatment.

Hosomi, 2020

Miyauchi, 2022

NEJ009 study

UMIN000006340

Randomised, phase 3 study

Performed in 47 institutions in Japan.

Patients were enrolled between: October 2011 and September 2015.

Funding and conflicts of interest: Supported by grant-in-aids from the Japan Society for Promotion of

Science and Japanese Foundation for the Multidisciplinary Treatment of

Cancer. Also supported by the North-East Japan Study Group. Disclosures by the authors are online available with the article.

Main inclusion criteria:

• Age 20-75 years
• Chemotherapy naïve, stage IIIB or IV or relapsed nonsquamous NSCLC with EGFR mutations (exon 19 deletion, L858R, G719A, G719C, G719S, and L861Q)
• ECOG PS 0-1
• Adequate organ function
  
  

Main exclusion criteria:

• Serious concomitant systemic disorders
• Interstitial pneumonia
• Other primary malignancy
• Pre-existence of T790M mutation
• Symptomatic brain metastases
• Pregnancy

N randomly assigned:

I: N=172

C: N=173

Age, Mean (SD, range):

I: 64.8 (7.8, 34-75)

C: 64 (8.4, 37-75)

Sex:

I: 67.1 % Female

C: 62.8 % Female

ECOG PS:

0 – I: 98 (57.6)

0 – C: 107 (62.2)

1 – I: 72 (42.4)

1 – C: 65 (37.8)

Adenocarcinoma

I: 168 (98.8)

C: 170 (98.8)

Mutation type:

Exon 19 del:

I: 93 (54.7)

C: 95 (55.2)

L858R:

I: 69 (40.6)

C: 67 (39.0)

Other:

I: 8 (4.7)

C: 10 (5.8)

Clinical stage:

IIIA

I: 0 (0.0)

C: 1 (0.6)

IIIB:

I: 6 (3.5)

C: 4 (2.3)

IV:

I: 139 (81.8)

C: 137 (79.7)

Postoperative relapse:

I: 24 (14.7)

C: 30 (17.4)

CNS metastases:

I: 50 (29.4)

C: 38 (22.1)

Groups were comparable at baseline.

GCP regimen:

Gefitinib 250 mg orally once every day combined with carboplatin area under the curve 5 and pemetrexed 500 mg/m2 in a 3-week cycle for up to six cycles, followed by concurrent gefitinib and pemetrexed maintenance.

The regimens

administered after the protocol treatment are summarized

in Appendix.

Gefitinib 250 mg orally once every day.

The regimens

administered after the protocol treatment are summarized

in Appendix.

Miyauchi 2022, with updated results:

Median follow-up duration on May 22, 2020: 84 months.

Hosomi 2020:

Median follow-up time at September 3, 2018: (with 195 events) 45 months.

Median duration of gefitinib treatment, months (range)

I: 22.4 (0.5 – 59.8)

C: 11.6 (1.0 – 70.8

Median duration of pemetrexed maintenance therapy, months (range)

I: 11.9 (0 – 57.9)

Miyauchi 2022, with updated results:

Deaths, n (%): 243 (71%)

Mean or median survival time (unclear: text and figure not in concordance):

I: 49.0 months

C: 38.5 months

HR: 0.822; 95% CI, 0.639 to 1.058; P = 0.127

2-year survival rate:

I: 77.1%,

C: 69%,

5-year survival rate

I: 39%

C: 34%

Subgroup analyses: Larger numerical between-group differences in the HRs for OS were observed between male and female patients.

5-year restricted mean survival time (RMST):

I: 43.6 months

C: 38.6 months

P = 0.017

7-year RMST:

I: 51.6 months

C: 45.3 months

P = 0.037

Updated median corrected PFS2, months (95% CI):

I: 20.9 (18.0 – 24.0)

C: 18.0 (16.3 – 20.7)

HR: 0.77; 95% CI 0.62 – 0.97; P= 0.027

Updated median PFS2 with the same definition, months (95% CI):

I: 32.5 (29.0 – 36.6)

C: 20.7 (17.9 – 24.6)

HR: 0.58; 95% CI, 0.46 – 0.73; P <0.001.

Updated result treatment related AEs:

Grade ≥3:

I: 66.5%

C: 31.0%

Odds ratio: 0.23; 95% CI, 0.15 – 0.36; P <0.001.

Hosomi 2020:

Overall survival, median (95% CI):

I: 50.9 (41.8 – 62.5)

C: 38.8 (31.1 – 47.3)

HR for death: 0.72 (0.55 – 0.95)

P = 0.021

Deaths, n (%): 195 (57%)

PFS in months, median (95% CI):

I: 20.9 (17.9 – 24.2)

C: 11.2 (9.0 – 13.4)

HR, 0.49; 95% CI, 0.39-0.62; P<0.001.

PFS2 in months, median (95% CI):

I: 20.9 (18.0 – 24.0)

C: 20.7 (15.7 –21.2)

HR: 0.99; P = 0.90

Corrected PFS2, months:

I: 20.9

C: 18.0

HR: 0.82 (95% CI, 0.65 to 1.03); P = 0.09

PFS2 with same definition, months

I: 32.5 (29.0 – 36.6)

C: 20.7 (17.9 – 24.9)

HR: 0.59; P<.001

ORR (95% CI):

I: 84% (79 – 90)

C: 67% (60 – 74)

P < 0.001

Treatment related AEs

I: 95.9%

C: 98.2%

Treatment related AEs grade ≥3

I: 65.3%

C: 31.0%

Fatal AEs (severe infection)

I: n=1

C: n=0

Treatment discontinued due to AES:

I: 10.7%

C: 9.9%

[For more information about the observed AEs see the article]

QOL:
QOL scores indicate that addition of pemetrexed to gefitinib did not impair global QOL.

After 24 months, more patients in the GCP group completed the questionnaire than those in the gefitinib group which indicates that informative censoring occurred in the gefitinib group more because of poorer prognosis.

• - Since sufficient numbers of events for PFS and PFS2 analyses were observed in October 2017, analysis for these primary end points was performed.
• - The date of final data lock was September 3, 2018.
• - Survival and extended follow-up safety data
• were re-evaluated at the data cutoff of May 22, 2020 (Miyauchi 2022).
• - OS analysis set:
• I: n=170
• C: n=172
• - PFS analysis set
• I: n=169
• C: n=172
• - Safety analysis set
• I: 170
• C: 171
• - In the GCP group, patients who were intolerant of gefitinib or chemotherapy were permitted to continue on the remaining agents.
• - Although the protocol treatment should be terminated when progressive disease (PD) on the basis of RECIST version 1.1 was observed, treatment beyond progression was allowed at the discretion of investigators.
• - Preplanned PFS2 was inappropriate because of the influence of beyond-progressive disease (PD) treatment period that was included only in the gefitinib
• group. Thus, we corrected the definition of PFS2 (corrected PFS2) in the gefitinib group to omit the beyond-PD period—duration since random assignment to PD after second-line therapy or death. Notably, the corrected PFS2 was a comparison of PFS1 (GCP) and PFS2 (gefitinib).
• - An additional analysis was carried out, comparing the two groups for PFS2 with the same definition; events were the actual time for the second PD in both groups.

Authors conclusion:

• In conclusion, NEJ009 is the first phase III study to evaluate the efficacy of a combination of EGFR TKI and platinum doublet chemotherapy in patients with untreated advanced NSCLC with EGFR mutations. Although its OS benefit requires further validation, the GCP regimen improved PFS with an acceptable safety profile and a similar QOL profile compared with gefitinib alone.

Saito, 2019

NEJ026

UMIN000017069

A randomised, open-label, multicentre,

phase 3 study

Performed in 69 centres across Japan

Patients were enrolled between: June 3, 2015, and Aug 31, 2016

Funding and conflicts of interest:

The funder Chugai Pharmaceutical approved the study design, and

was involved in the provision of information.

Funder had no role in data collection, data analysis, data interpretation,

or writing of the report. Declaration of interests is disclosed.

Main inclusion criteria:

• ≥ 20 years
• histologically or cytologically confirmed non-squamous NSCLC
• EGFR-positive status (exon 19 deletion or exon 21 Leu858Arg point mutation)
• stage IIIB–IV disease or recurrent disease
• ≥ 1 measurable lesions based RECIST 1.1
• ECOG PS ≤2
• life expectancy ≥ 3 months.

Main Exclusion criteria:

• Coexistent EGFRThr790Met mutations
• Prior chemotherapy treatment

For a full list of in-/exclusion, and eligibility criteria regarding pretreatments and washout periods before entry, see the appendix.

Median age (IQR)

I: 67 (61–73)

C: 68 (62–73)

Sex:

I: Female: 71 (63%)

C: Female: 73 (65%)

ECOG PS:

0 – I: 64 (57%)

0 – C: 68 (61%)

1 – I: 48 (43%)

1 – C: 42 (38%)

2 – I: 0

2 – C: 2 (2%)

Adenocarcinoma

I: 110 (98%)

C:112 (100%)

Mutation type:

Exon 19 del:

I: 56 (50%)

C: 55 (49%)

Postoperative recurrence      

I: 22 (20%)               

C: 20 (18%)

CNS metastases:

I: 36 (32%)

C: 36 (32%)

Groups were comparable at baseline.

Oral erlotinib 150 mg once daily and intravenous bevacizumab 15 mg/kg once every 21 days.

Randomized: n=114

Modified intention-to-treat analysis: n=112

Safety analysis:

n=112

Dose reductions:

• Erlotinib: permitted (to 100 mg and 50 mg per day) if a dose reduction criterion was

fulfilled.

• Bevacizumab: not permitted.

Patients

remained on treatment until disease progression or

intolerable toxicity.

Oral erlotinib 150 mg once daily.

Randomized:  n=114

Modified intention-to-treat analysis: n=112

Safety analysis:

n=114

Dose reductions:

• Erlotinib: permitted (to 100 mg and 50 mg per day) if a dose reduction criterion was

fulfilled.

Patients

remained on treatment until disease progression or

intolerable toxicity.

At Sept 21, 2017 median follow up was: 12·4 months (IQR 7·0–15·7).

Median duration of treatment, days (range)

Erlotinib

I: 405 (5–807)

C: 364 (43–736)

Bevacizumab

I: 350 (21–736)

Median PFS, months (95% CI)

I: 16·9 (14·2–21·0)

C: 13·3 (11·1–15·3)

HR= 0·605 (95% CI 0·417–0·877; p=0·016)

L858R subgroup PFS, months (95% CI):

I: 17·4 (12·6–not estimable)

C: 13·7 (8·8–15·5)

Objective response (OR) (95% CI):

I: 72% (63·1–80·4)

C: 66% (56·5–74·7)

p=0·31

Leu858Arg OR (95% CI)

I: 68%

C: 65%

Exon 19 deletion OR (95% CI)

I: 77%
C: 67%

AEs grade ≥3

I: 88%

C: 46%

Serious AEs:

I: 8%

C: 4%

Bevacizumab discontinuation due to AEs: 29%

Erlotinib discontinuation due to AEs:

I:19%

C: 15%

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

• The primary PFS analysis data cutoff was Sept 21, 2017.
•  The independent data monitoring committee held a meeting on Jan 23, 2018, and recommended early termination of the study based on the results of the interim analysis. However, the authors considered that the study had to be continued to obtain data for other endpoints in addition to PFS.
• Dosages are shown in the appendix. Erlotinib dose reduction was not associated with shorter PFS.

Authors conclusion:

In conclusion, NEJ026 met the primary endpoint at the preplanned interim analysis, showing that patients with EGFR-positive NSCLC treated with a combination of

bevacizumab and erlotinib had longer progression-free survival than patients treated with erlotinib alone. These results suggest that combination therapy with bevacizumab and erlotinib has the potential to become

a standard treatment for patients with EGFR-positive NSCLC if the overall survival data and quality of life analyses are favourable.

Zhou,

2021

ARTEMIS-CTONG1509

NCT02759614

A randomized, open-label, controlled, multicenter phase 3 study.

Conducted at 14 centers in China.

Patient enrolment: From May 2016 to July 2017.

Funding and conflicts of interest: Funded by the National Key R&D Program of China (grant no.

2016YFC1303800), the Chinese Thoracic Oncology Group (CTONG), and the

High-level Hospital Construction Project (grant no. DFJH201810 to Q.Z.). Editorial support was funded by CTONG. Declaration of interests is disclosed.

Main inclusion criteria:

• Male and female patients aged ≥18 years
• histologically or cytologically documented inoperable, locally advanced, metastatic, or recurrent non-squamous NSCLC
• ex19del or ex21 L858R mutation in EGFR
• ECOG PS of 0-1
• Life expectancy ≥12 weeks
• No prior systemic cytotoxic chemotherapy for locally advanced, metastatic, or recurrent disease;
• No antineoplastic agent administered intracavity during pleurodesis
• no pre-or postoperative

adjuvant chemotherapy in the previous 6 months since the final administration date;

• ≥1 lesion present measurable in accordance with RECIST V.1.1 criteria.
  
  

Main exclusion criteria:

Mixed adenosquamous carcinomas with squamous component and evidence of CNS metastases, except for patients without any symptoms or patients with symptoms but who had stable disease for at least 28 days after treatment of CNS metastases.

Age, Median (range):

I: 57 (33-78)

C: 59 (27-77)

Female, n (%):

I: 97 (61.8)

C: 96 (62.3)

ECOG PS:

0 – I: 25 (15.9)

0 – C: 17 (11.0)

1 – I: 132 (84.1)

1 – C: 137 (89.0)

Adenocarcinoma

I: 157 (100)

C: 154 (100)

Mutation type:

Exon 19 del:

I: 82 (52.2)

C: 79 (51.3)

CNS metastases at baseline:

I: 44 (28.0)

C: 47 (30.5)

Clinical stage:

IIIB:

I: 4 (2.6)

C: 6 (3.9)

IV:

I: 141 (89.8)

C: 133 (86.4)

Recurrence:

I: 12 (7.6)

C: 15 (9.7)

Groups were comparable at baseline.

Bevacizumab plus erlotinib

Oral erlotinib 150 mg/day with intravenous bevacizumab 15 mg/kg once every 3 weeks and study treatment

continued until disease progression, intolerable toxicity, or withdrawal of patient consent.

n=157

Erlotinib only

Oral erlotinib 150 mg/day and study treatment

continued until disease progression, intolerable toxicity, or withdrawal of patient consent.

n=154

At January 18, 2019 Treatment discontinuation:

I: 109 (69.4%) with a median time-to-treatment failure (TTF) of 18.2 months

C: 126 (81.8%) with a median TTF of 12.4 months

Median exposure to erlotinib, days(IQR):

I: 544.5 (20–928)

C: 377.0 (6–890)

Median exposure bevacizumab cycles (IQR):

I: 22 (1–45)

The independent review committee (IRC)-assessed PFS in months, median (95% CI):

I: 17.9 (15.2–19.9)

C: 11.2 (9.7–13.8)

(HR for progression/ death: 0·55 [95% CI 0.41–0.73], p<0·001)

IRC-assessed PFS in months per mutation type (95% CI):

• Ex19del mutation:

I: 7.7 13.8–19.5

C: 12.5 (11.1–16.6)

HR = 0.62; 95% CI, 0.42–0.93;

p = 0.017

• Leu858Arg:

I: 19.5 (15.3–22.2)

C: 9.7 (9.6–12.4)

HR = 0.50; 95% CI,

0.32–0.77; p = 0.001

IRC-assessed PFS in months in patients with brain metastases at baseline (95% CI):

I: 17.9 (15.2–20.7)

C: 11.1 (9.7–12.5)

HR = 0.48; 95% CI, 0.27–0.84;

p=0.008

OS:

At January 8, 2021:

OS data remained immature with 55% (172/311) of the events recorded.

Median OS, months (95% CI):

I: 36.2 (32.5–42.4)

C: 31.6 (27.2–40.0)
HR = 0.92; 95% CI, 0.69–1.23;

p=0.581

2- year OS, months (95% CI):

I: 70.1% (61.9–76.8)

C: 64.6% (56.1–71.8)

p=0.317

3- year OS, months (95% CI):

I: 51.1% (42.5–59.1)

C: 46.3% (37.8–54.4)

p=0.424

Median OS in months (95% CI):

• with brain metastases at baseline

I: 31.6 (23.0–44.3)

C: 26.8 (19.5–32.6)

HR = 0.62; 95% CI, 0.38–1.01; p = 0.052

- without brain metastases at baseline:

I: 37.9 (32.7–43.7)

C: 41.1 (27.9–not evaluable)

HR = 1.09; 95% CI, 0.76–1.58;

p=0.625

ORR (95% CI):

I: 86.8% (80.4–91.8)

C: 84.7% (77.9–90.0)

p=0.624

AEs grade ≥3:

I: 54.8%

C: 26.1%

[For more information about AEs see the article Table 4 and the appendix Table S2].

Erlotinib discontinuation due to AEs:

I: 7.0%

C: 3.3%

Bevacizumab discontinuation due to AEs:

I: 24.2 %

Death due to AEs:

I: n=1

C: n=1

QoL: QoL scores were comparable, with no change from baseline reported for either group (Figure S6). Our results demonstrate the addition of bevacizumab to erlotinib does not affect the patients’ overall QoL.

• Data cutoff: January 18, 2019
• Survival follow-up continued after the primary PFS analysis

Authors conclusion:

This study shows that bevacizumab plus erlotinib can provide superior PFS over erlotinib alone in Chinese patients with untreated

• Metastatic EGFR-mutated NSCLC. Safety was consistent with the established safety profiles of the individual therapeutic agents. Combination therapy with bevacizumab and erlotinib has the potential to become one of the standard first-line treatments for patients with EGFR mutation-positive NSCLC.

Piccirillo, 2022

The BEVERLY study

NCT02633189

EudraCT

2015-002235-17

Multicenter, randomized, phase 3 trial

(open label;

however, central radiologic revision and statistical analyses were conducted with blinded arms)

Performed in 43 centers in Italy.

Patients were enrolled between: Between April 11, 2016 - February 27, 2019

Funding and conflicts of interest: Hoffmann–La Roche provided

partial funding and experimental drugs. Hoffmann–La Roche had no role in the study design, protocol

writing, data collection, data analysis, data interpretation,

and writing of the report.

Declaration of interests is reported with the article.

Main inclusion criteria:

• Aged ≥18 years
• Metastatic/locally advanced nonsquamous NSCLC
• Harboring an activating EGFR mutation

[See protocol for full list of inclusion criteria]

Main exclusion criteria:

• prior treatment for advanced NSCLC (previous adjuvant or neoadjuvant chemotherapy was allowed if ended >6 mo before randomization)
• mixed adenosquamous histotype with a predominant squamous component
• EGFR T790M mutation or exon 20 insertions as unique mutations
• Brain metastases
• Concomitant pathologies, laboratory alterations, or concomitant medication use that prevents or contraindicates use of erlotinib/bevacizumab.

Age, Median (IQR):

I: 65.9 (57.9–71.8)

C: 67.7 (60.7–73.6)

Age >65 years, n (%)

I: 42 (52.5)

C: 49 (61.3)

Sex:

I: 65.0 Female

C: 62.5 Female

Smoking status, n (%)

Never

I: 46 (57.5)

C: 37 (46.3)

Former/Current

I: 34 (42.5)

C: 43 (53.8)

ECOG PS:

0 – I: 52 (65.0)

0 – C: 47 (58.8)

1 – I: 26 (32.5)

1 – C: 29 (36.3)

2 – I: 2 (2.5)

2 – C: 4 (5.0)

Exon 19 del:

I: 44 (55.0)

C: 44 (55.0)

L858R:

I: 34 (42.5)

C: 32 (40.0)

Other:

I: 2 (2.5)

C: 4 (5.0)

Clinical stage IIIB:

I: 3 (3.8)

C: 5 (6.3)

Clinical stage IV:

I: 77 (96.3)

C: 75 (93.8)

Groups were comparable at baseline.

Erlotinib 150 mg orally once daily + bevacizumab, 15 mg/kg intravenously, every 21 days.

Treatment continued until disease progression, unacceptable toxicity or patient’s or physician’s motivated decision.

Randomly assigned: N=80

Erlotinib 150 mg orally once daily.

Treatment continued until disease progression or unacceptable toxicity or patient’s or physician’s motivated decision.

Randomly assigned: N=80

Median follow-up:

36.3 months (95% CI: 30.7–40.9)

With 140 PFS events (87.5%) reported:

I: 68 (85.0%)

C: 72 (90.0%)

Median duration of erlotinib treatment, months (IQR):

I: 14.4 (8.8–24.2)

C: 9.3 (4.6–14.7)

Median duration of bevacizumab, months (IQR):

I: 14.2 (5.8–22.3)

Continued to receive trial treatment:

I: N=9 (11.3%)

C: N=1 (1.3%)

n.

Discontinuation of erlotinib, n (%):

I: 11 patients (13.8%) C: 13 patients (16.5%)

Discontinuation of bevacizumab for toxicity, n (%):

I: 24 (30.0%)

Deaths, n (%):

I: 41 (51.3%)

C: 49 (61.3%)

Overall survival, median (95% CI):

I: 33.3 (24.3–45.1)

C: 22.8 (18.3–33.0)

HR: 0.72 [95% CI: 0.47–1.10], p = 0.132

Median investigator-assessed (IA)-PFS, months (95% CI):

I: 15.4 (12.2–18.6)

C: 9.6 (8.2–10.6)

HR = 0.66 [95% CI: 0.47–0.92], p = 0.015.

Subgroup analysis:

OS for former or

current smokers, months (95% CI):

I: 35.3 (25.6–not estimated)

C: 19.7 (12.5–23.4)

Interaction effect of smoking with treatment for OS: p = 0.0077

IA-PFS for former or

current smokers, months (95% CI):

I: 16.9 (10.2–21.8]

C: 8.8 (5.6–9.6)

Interaction effect of smoking with treatment for IA-PFS: p = 0.0323

ORR (complete or partial response ) (%; 95% CI):

I: 56 (70%; 60% – 80%)

C: 40 (50%; 39% – 61%)

P= 0.010

Serious AEs, n:

I: 45

C: 30

Likely or certainly treatment related AEs

I: 9 of 45 (20.0%)

C: 1 of 30 (3.3%)

Fatal AEs:

I: 4 (5.0%)

C: 4 (5.0%)

Death due to intracranial hemorrhage related to the study treatment

I: 1

C: 0

AEs grade ≥3

I: 45 (56%)

C: 39 (49%)

[For more info on AEs see Table 2 and sup. Table 7]

Completed QoL questionnaires baseline:

I: 74 (92.5%)

C: 76 (95.0%)

• - Analyses end date was July 31, 2021.
• - To recognize a 0.60 HR of progression or death, with 80% power and 0.05 two-tailed a, 126PFS events were needed and 200 patients, to be randomized in 20 months, were the initially estimated sample size. On October 2017, owing to slow enrolment, the sample size was amended at 160 patients, without changing the study hypothesis and two interim analyses were added.

- Dose reduction for adverse events was allowed for erlotinib.

- Dose reduction of bevacizumab was not planned, but drug could be temporarily or permanently suspended in case of hypertension, proteinuria,

thrombosis/embolism, hemorrhage, cardiac heart failure, or wound healing complications in addition to any other grade 3 or 4 bevacizumab-related toxicity.

• - An interim analysis, performed on October 2019, (enrolment completed and 58% of planned events reported) did not reveal futility; no further interim
• analyses were performed (due to problems caused by the SARS-CoV-2 pandemic) and final analysis is reported here.
• - One patient assigned to erlotinib alone, with missing
• information on treatment, was excluded from safety
• analysis.

Authors conclusion:

In conclusion, bevacizumab plus erlotinib might be considered among the first-line therapeutic option in patients who cannot receive osimertinib and the strategy of combining an antiangiogenic drug with a TKI is worth of further investigation.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

ARCHER 1050

(Wu, 2017
Mok, 2018
Paty, 2021
Mok, 2021)

NCT01774721

Definitely yes;

Reason:

Using a computer-generated random code that was assigned by a central interactive web response system (IWRS). The IWRS was managed by a vendor who had no clinical

involvement with the trial. The allocation sequence, based on a randomisation-requirement specification form (prepared by the IWRS vendor in accordance with the requirements of the study sponsor), was generated by the IWRS.

Probably yes;

Reason:
The investigators at the clinical sites enrolled the patients by using the IWRS, entered each patient’s race and EGFR mutation type (the stratification

variables), and assigned each patient to a treatment group on the basis of the IWRS output.

Definitely no;

Reason:

Patients were not masked to treatment assignment. Sites were unmasked to study drug but the

vendors and sponsor remained masked.

Tumour assessment by

independent review was masked. Central imaging was masked to the reviewers by BioClinica.

Investigators were not masked to treatment assignment. Study sponsor personnel were unmasked at database lock for the primary analysis of progression-free survival.

Probably yes;

Reason:

I: assigned to dacomitinib N=227

C: assigned to gefitinib N=225

Discontinued treatment:

I: Wu (2017) N=161

I: Mok (2018) N=178

C: Wu (2017) N=186

Mok (2018) N=206

Included in the intention to treat analysis:

I: N=227

C: N=225

Mature OS analysis for the ITT population is presented.

WU (2017):

Efficacy analysis, PFS and time to treatment failure was calculated in the ITT population. Duration of response among the objective responders in the ITT population.

Patients in the ITT population who received at least one dose of study drug were included in the safety analysis. PROs were evaluated in the ITT population who also had a baseline assessment and at least one post-baseline assessment.

Probably yes;

Reason:

Secondary outcomes not reported:

• Best Overall Response Based on Investigator assessment
• Urinalysis
• Clinically Significant Abnormalities in Vital Signs
• Clinically Significant Abnormality in ECG
• Maximum Relative Decrease From Baseline >20% in LVEF
• Maximum Observed Plasma Concentration of Dacomitinib and Its Metabolite PF-05199265
• Time to Reach Maximum Observed Plasma Concentration of Dacomitinib and Its Metabolite PF-05199265
• Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval of Dacomitinib and Its Metabolite PF-05199265
• Averaged Plasma Concentration at Steady State of Dacomitinib and Its Metabolite PF-05199265
• Minimum Observed Plasma Concentration of Dacomitinib and Its Metabolite PF-05199265
• Fluctuation Coefficient Between Trough and Peak Plasma Concentration of Dacomitinib and Its Metabolite PF-05199265
• Apparent Clearance of Dacomitinib
• Pre-dose Plasma Concentrations of Dacomitinib and Its Metabolite PF-05199265

Definitely no;

Reason:
Study designed by a steering committee of academic advisers and representatives from the sponsors of the study, SFJ Pharmaceuticals, and Pfizer (appendix p3). Data were collected by the PIs and verified by the sponsors of the study. The sponsors had a role in the data analysis, data interpretation, and writing of the report. All the authors, including those employed by the sponsors of the study, vouch for the completeness and accuracy of the data and the data analyses and adherence to the protocol. All the authors had access to the data, prepared the report, and reviewed and approved the final submission.

Some concerns

(no blinding, role of the funder)

OS, PFS and ORR: Low

QoL some concerns

FLAURA trial

(Ramalingam,

2020

Soria, 2018)

Definitely yes;

Reason:

In study protocol:

A unique 7-digit enrolment number obtained by the investigator through the Interactive Voice Response System /Interactive Web Response System.

At visit 2, once the patient is confirmed to be eligible, the PI or suitably trained delegate will obtain a unique randomisation number via IVRS/IWRS.

Probably yes;

Reason:

Eligible patients will be centrally randomised in a 1:1 ratio using the IVRS/IWRS system. The actual EGFR TKI has to be selected at a site/country level according to country’s marketing authorisation prior to the site initiation.

The IVRS/IWRS will assign the bottles of study material to be dispensed to each patient.

Probably yes;

Reason: Not explicitly described.

The investigational product will be labelled using a unique material pack code, which is linked to the randomisation code. (…) The active and placebo tablets will be identical and presented in the same packaging to ensure blinding of the medication.

A protocol amendment allowed patients who had been assigned to a standard EGFR-TKI to cross over to open-label osimertinib after confirmation of objective disease progression by blinded independent central review and post-progression documentation of T790M-positive mutation status

Definitely no;

Reason:

Randomized: N=556
I: 279
C: 277 (183 gefitinib, 94 erlotinib)

Continued to receive trial treatment at time of data cut off:
I: N=61 (22%)
C: N=13 (5%)

Loss to follow-up was more frequent in the comparator group.

Probably yes;

Reason: All relevant outcomes were reported.

Secondary outcomes not reported:

• Plasma concentrations of metabolite
• Cancer Therapy Satisfaction Questionnaire 16 Items (CTSQ-16 questionnaire)
• (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13)
• European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30)

Definitely no;

Reason:

• This trial was funded by the sponsor and was designed by the principal investigators (the first and last authors) and the sponsor. The sponsor was responsible for the collection and analysis of the data and had a role in data interpretation.
• A protocol amendment allowed patients who had been assigned to a standard EGFR-TKI to cross over to open-label osimertinib after confirmation of objective disease progression by blinded independent central review and post-progression documentation of T790M-positive mutation status by means of plasma or tissue testing (local or central). Intervening anticancer therapy was not allowed before crossover to open-label osimertinib.

Some concerns
(role of the funder)

LUX-Lung 7 (Park, 2016

Paz-Ares, 2017)

Definitely yes;

Reason:

Permuted blocks of size four were created with a validated random number generating system at Boehringer Ingelheim verified by trial-independent statistician, and implemented centrally

via an interactive voice or web-based response system.

Probably yes;

Reason:

Randomisation was implemented centrally

via an interactive voice or web-based response system.

Probably no;

Reason:

Patients and clinicians were not masked to treatment allocation.

Individuals directly involved in the conduct and analysis of the trial did not have access to the randomisation schedule.

Independent review of tumour response was

done in a blinded manner.

Probably yes;

Reason:

I: assigned to afatinib N=160

C: assigned to gefitinib N=159

Discontinued treatment:

I: Park (2016): N=140

I: Paz-Ares (2017): N=146

C: Park (2016): N=149

C: Paz-Ares: N=151

Included in the ITT analysis:

I: N=160

C: N=159

Park (2016): Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug.

Paz-Ares (2020): All randomised patients were included in the primary assessment of

OS, and updated analysis of PFS and TTF.

Safety analysis included all patients who received at least one dose of study drug.

Definitely yes;

Reason:

All relevant outcomes were reported.

Definitely no;

The funder designed the trial in collaboration with the

steering committee. Data were collected by the investigators and were analysed jointly with the funder.

The funder and all authors were responsible for data

interpretation and the development of the Article, and

approved the final version. The Article was written by the

corresponding author in collaboration with the coauthors,

with independent medical writing assistance, supported

financially by the funder. The steering committee had

access to the raw data.

Some concerns

(role of the funder)

For OS, PFS, ORR Low

For QoL some concerns

RELAY study (Nakagawa, 2019
Nadal, 2021)

Definitely yes;

Reason:

Patients were randomly allocated (1:1) to treatment with

ramucirumab plus erlotinib or placebo plus erlotinib via

an interactive web-response system with a computer generated

random sequence.

Probably yes;

Reason:

The IWRS registration consists of assigning the patient a unique

study identification number for all patients (Parts A and B) and patients in Part B will be randomized into 1 of the 2 treatment arms on a 1:1 basis.

Patient-level unblinded data will not be shared with sites until the study is completed. Treatment

assignment will be scrambled in the reporting database until the database lock for data analysis.

This will ensure that unblinded aggregate efficacy and safety results are not available until the

time of final data analysis.

Probably yes;

Reason:

Physicians, patients, and all clinical study personnel were masked to assigned treatment.

For the primary analysis, some sponsor personnel were unmasked to collate, analyse, and communicate data to authors.

Definitely no;

Reason:

Randomized: N=449
I: 224
C: 225

Continued to receive trial treatment at time of data cut off:
I: N=64 (29%)
C: N=43 (19%)

Loss to follow-up was more frequent in the comparator group.

Definitely yes;

Reason:
All relevant outcomes were reported.

Secondary patient-reported outcomes (on the Lung Cancer Symptom Scale and EuroQol 5-dimension, 5-level questionnaire) will be reported elsewhere.

Definitely no;

Reason:

The funder was involved in study design, data collection,

data analysis, data interpretation, and writing of the report.

Some concerns
(Role of the funder)

NEJ026
(Saito, 2019)

Probably yes.

Patients were randomly assigned (1:1).

Randomisation was

done by minimisation, stratified by sex,

smoking status, clinical stage, and EGFR mutation subtype.

Probably yes

Central randomisation was done at a data centre (AC Medical, Tokyo, Japan) using patient enrolment sheets provided by the investigators. The data centre notified investigators of treatment allocation for each patient.

Definitely no.

All patients and investigators were unmasked to treatment allocation.

Definitely yes.

Probably yes.

(Secondary endpoints will be reported once follow-up is completed.

Probably no

The sample size

was small. The study was not powered for subgroup analysis of the primary endpoint.

The independent data monitoring committee held a meeting on Jan 23, 2018, and recommended early termination of the study based on the results of the interim analysis. However, the authors considered that the study had to be continued to obtain data for other endpoints in addition to PFS.

 Some concerns

ARTEMIS-CTONG1509
(Zhou, 2021)

Probably yes.

Randomly allocated (1:1) to treatment with erlotinib or using a dynamic randomization process.

Probably no.

Not described.

All patients and investigators were unblinded to treatment allocation.

Probably yes

Definitely yes;

Reason:

All relevant outcomes were reported.

Probably yes.

High
(unclear randomization process)

NEJ009 study
(Hosomi, 2020
Miyauchi, 2022)

Definitely yes.

Eligible patients were randomly assigned.

Definitely yes.

Protocol: TCOG Enrollment Center: the patient is numbered and anonymized and entered in the intra-institution communication chart. (…). The Assignment Results Report is faxed to the attending physician and Tohoku University’s Trial office.

Probably no.

Not reported

Definitely yes.

Definitely yes;

Reason:

All relevant outcomes were reported.

Probably yes.

Low

The BEVERLY study

(Piccirillo, 2022)

Probably yes.

The participants

were randomly assigned (1:1).

Registration was web based.

Definitely yes.

Registration, randomization, and data collection were

web based at Clinical Trials Unit of Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico, Fondazione G. Pascale (Naples, Italy).

Probably no.

The trial was open label; however, central radiologic revision and statistical analyses

were conducted with blinded arms.

Definitely yes.

Definitely yes

Reason:

All relevant outcomes were reported.

Probably yes.

Low