Elsevier

The Lancet Oncology

Volume 20, Issue 12, December 2019, Pages 1655-1669
The Lancet Oncology

Articles
Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(19)30634-5Get rights and content

Summary

Background

Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.

Methods

This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.

Findings

Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8–27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4–21·6]) than in the placebo plus erlotinib group (12·4 months [11·0–13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46–0·76; p<0·0001). Grade 3–4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3–4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.

Interpretation

Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.

Funding

Eli Lilly.

Introduction

Nearly 85% of primary lung cancers worldwide are of the non-small-cell lung cancer (NSCLC) type, and most patients present with advanced or metastatic disease at diagnosis.1 EGFR mutation-driven NSCLC occurs at frequencies of about 10–20% in white patients and 40–60% in Asian patients.1, 2 90% of EGFR mutations comprise a deletion within exon 19 (ex19del) or a leucine to arginine substitution mutation in exon 21 (Leu858Arg).2 The presence of these activating EGFR mutations in advanced NSCLC is associated with sensitivity to small-molecule EGFR tyrosine kinase inhibitors (TKIs),2, 3 which are the first-line standard-of-care.2, 4, 5, 6, 7 However, the degree of benefit might differ by type of mutation, with greater benefit from EGFR TKIs in patients who have NSCLC with the ex19del mutation.8 Despite durable responses, median progression-free survival with initial therapy for advanced disease is about 1 year with first-generation TKIs (gefitinib and erlotinib).2 Second-generation and third-generation drugs have shown median progression-free survival of 11·0 months (afatinib), 14·7 months (dacomitinib), and 18·9 months (osimertinib).4, 5, 6, 9, 10 About 30–60% of patients whose disease progresses on a first-generation or second-generation TKI acquire the EGFR Thr790Met substitution mutation, which is sensitive to osimertinib.7, 11, 12 When these targeted therapies are exhausted, chemotherapy, palliative care, or a clinical trial is recommended.13, 14 Immune checkpoint inhibitors have been less effective in EGFR-mutated disease and optimal approaches to incorporate such therapies in this population are under investigation.15 Thus, there is a crucial need for novel EGFR TKI-based strategies to prolong remission and promote tumour control.

Research in context

Evidence before this study

We did a literature search on April 1, 2019, for preclinical reports and clinical trials published in English through Jan 1, 2015, using Medline and Ovid, abstracts of major oncology congresses, and the National Cancer Institute's cancer trial registry website (ClinicalTrials.gov). The search terms were “non-small cell lung cancer”, “advanced non-small cell lung cancer”, “metastatic non-small cell lung cancer”, “EGFR”, “anti-angiogenesis”, “targeted therapy”, “VEGFR”, “clinical trial”, and combinations thereof. Findings showed that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) had significantly improved efficacy over systemic chemotherapy in EGFR-mutated advanced non-small-cell lung cancer (NSCLC) in the first-line setting. Three EGFR TKIs (erlotinib, gefitinib, and afatinib) had been studied and approved in this setting. At the time of RELAY's design and initiation (2014–15), no head-to-head studies had demonstrated that one TKI had superior efficacy to another and the safety profiles were similar. Since erlotinib was the only EGFR TKI that was globally approved at the time, it was chosen as the control for RELAY. EGFR TKIs are associated with inevitable treatment resistance, and most patients will eventually experience loss of clinical benefit. Thus, there is an ongoing unmet need in EGFR-mutated metastatic NSCLC for new treatment strategies, such as drug combinations, to delay the emergence of acquired resistance and, therefore, disease progression. In preclinical studies, dual blockade of the EGFR and VEGF pathways improved antitumour activity compared with inhibition of the EGFR pathway alone. Several clinical trials have shown promising results with the anti-VEGFA antibody, bevacizumab, in combination with an EGFR TKI, supporting the potential for dual EGFR and VEGF pathway inhibition. However, conclusions in those trials were limited by small sample sizes, Japanese-only populations, and open-label designs. Ramucirumab is a human IgG1 antibody selective for VEGFR2 that blocks binding of the VEGFA, VEGFC, and VEGFD ligands to VEGFR2, and therefore might have broader effects than does bevacizumab. The RELAY study was done to investigate the efficacy and safety of ramucirumab plus erlotinib versus placebo plus erlotinib in patients with EGFR-mutated metastatic NSCLC.

Added value of this study

Compared with placebo plus erlotinib, ramucirumab plus erlotinib led to a significant improvement in progression-free survival, both in the overall population as well as across subgroups, including ex19del versus Leu858Arg and east Asian versus non-east Asian. Additional support for the combination regimen includes the increase in duration of response observed over that of the control group. RELAY, as a large, global, phase 3, placebo-controlled and double-blind trial, provides the strongest clinical evidence reported so far for dual EGFR and VEGF pathway inhibition and establishes dual blockade of VEGFR2 and EGFR pathways as a viable first-line treatment strategy applicable to patients with metastatic NSCLC with common EGFR mutations and no CNS metastases. Additionally, to our knowledge, we recorded the longest median progression-free survival thus far for patients with a baseline Leu858Arg mutation, with similar outcomes reported for ramucirumab plus erlotinib in patients with the ex19del and Leu858Arg mutations. This regimen has a safety profile consistent with the established safety profiles of the individual drugs in the setting of advanced NSCLC. After disease progression, EGFR Thr790Met frequencies were similar between treatment groups—suggesting that the addition of ramucirumab did not affect the erlotinib-associated Thr790Met frequency at disease progression and that treatment with EGFR TKI targeted therapies, such as osimertinib, continues to be an option.

Implications of all the available evidence

Additional first-line treatment options that provide clinically meaningful benefits, including delaying disease progression and the emergence of acquired resistance, are still needed for patients with advanced NSCLC. Expanding the selection of first-line options available for the treatment of metastatic EGFR-mutated NSCLC would allow oncologists greater strategic choice on how to use the available drugs, such as sequential EGFR TKI treatment, to provide the best chance of long-term progression-free survival and potentially prolonging time on targeted therapy (thereby delaying time to chemotherapy). In this context, the combination of ramucirumab and erlotinib is a valuable treatment option for patients with EGFR-mutated NSCLC.

One such strategy supported by preclinical and clinical evidence is the dual blockade of the EGFR and VEGF pathways.16, 17, 18, 19, 20, 21 Preclinical studies have demonstrated that the VEGF and EGFR pathways are interrelated (appendix p 5).16 In the clinical setting, the dual EGFR and VEGF inhibition approach was initially tested in the BeTa22 (bevacizumab plus erlotinib vs erlotinib alone) and ATLAS23 (bevacizumab vs bevacizumab plus erlotinib) trials. Although in these studies the primary outcome results (progression-free survival for ATLAS and overall survival for BeTa) were negative for the subgroup of patients with wild-type NSCLC, improved efficacy was noted in the EGFR-mutated subgroup of patients in both trials, with overall survival hazard ratios (HRs) favouring the anti-VEGFA antibody, bevacizumab, plus erlotinib combination. The JO25567 trial19 was a randomised, phase 2, open-label study assessing first-line bevacizumab plus erlotinib versus erlotinib alone in 154 Japanese patients with EGFR-mutated NSCLC (median progression-free survival 16·0 months [95% CI 13·9–18·1] with the combination vs 9·7 months [5·7–11·1] with erlotinib) and was the basis for the regulatory approval of bevacizumab plus erlotinib for first-line treatment of EGFR-mutated NSCLC in the EU and for inclusion in EU and Japanese NSCLC treatment guidelines.14, 19, 24 These results were confirmed in the phase 3, open-label, NEJ026 trial of 228 Japanese patients (median progression-free survival 16·9 [95% CI 14·2–21·0] in the erlotinib plus bevacizumab group vs 13·3 months [11·1–15·3] in the erlotinib group).18 Given the limitations of those studies (small sample sizes, open-label, and being done in Japan only), the question remains as to whether dual inhibition of EGFR and VEGF pathways is a viable treatment strategy in a global EGFR-mutated NSCLC population.

Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR2, thereby blocking signalling mediated by VEGFA, VEGFC, and VEGFD in NSCLC.25 Therefore, ramucirumab has the potential for broader antitumour activity than inhibitors of VEGFA.25 Ramucirumab in combination with docetaxel has gained regulatory approval for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Ramucirumab, as a single drug or in combination with different chemotherapy regimens, has also been approved for second-line gastric or gastro-oesophageal junction adenocarcinoma, colorectal cancer, and hepatocellular carcinoma.26 The RELAY trial investigating the effect of dual inhibition of EGFR and VEGFR2 in patients with untreated, metastatic, EGFR-mutated NSCLC, initiated in December, 2014, is a global study in three parts: a phase 1b single-arm safety lead-in (part A);27 a phase 3, randomised, double-blind, placebo-controlled study (part B);28 and an open-label, single-arm, exploratory east Asian cohort (part C;29 appendix p 10). This report focuses on the phase 3 primary analysis.

Section snippets

Study design and participants

This worldwide, double-blind, placebo-controlled phase 3 trial was done in 100 hospitals, clinics, and medical centres in 13 countries (South Korea, Hong Kong, Japan, Taiwan, Canada, France, Germany, Italy, Romania, Spain, Turkey, the USA, and the UK) and was initiated after confirmation of the dose and schedule of ramucirumab with erlotinib in the phase 1b part of the study (started in December, 2014).27 The protocol is in the appendix (pp 26–182).

Eligibility criteria were age of at least 18

Results

From Jan 28, 2016, to Feb 1, 2018, 611 patients were screened, of whom 449 (intention-to-treat population) were enrolled and randomly assigned to either ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225; figure 1). Baseline characteristics were balanced between treatment groups (table 1).

At data cutoff, 64 (29%) of 224 patients in the ramucirumab plus erlotinib group and 43 (19%) of 225 in the placebo plus erlotinib group were still on treatment (figure 1). 108 (48%) patients

Discussion

RELAY showed that in patients with previously untreated metastatic EGFR-mutated NSCLC without CNS metastases, ramucirumab plus erlotinib treatment resulted in a significant improvement in progression-free survival, with a median progression-free survival of 19·4 months (95% CI 15·4–21·6) for ramucirumab plus erlotinib versus 12·4 months (95% CI 11·0–13·5) with placebo plus erlotinib. The sensitivity analyses results support the robustness of the investigator-based statistical results and

Data sharing

Eli Lilly provides access to all individual participant data collected during the trial, after anonymisation, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once they are made available. Access is provided after a proposal has been approved by an independent review

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  • Cited by (0)

    RELAY investigators are listed in the appendix pp 2–4

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