The safety and efficacy of erlotinib and ramucirumab combination in EGFR-mutant non-small-cell lung cancer

ABSTRACT

Introduction

EGFR-tyrosine kinase inhibitors (TKIs) changed the natural history of EGFR-mutant advanced NSCLC patients, but acquired resistance is inevitable. New strategies are being tested to overcome or prevent the emergence of resistance mechanisms to first-line TKIs, among which combinations of TKIs with antiangiogenic agents.

Areas covered

We performed a literature search for preclinical and clinical data on the interplay and dual inhibition of EGFR/VEGF pathways, particularly in EGFR-mutant NSCLC. We then focused on RELAY, a placebo-controlled phase 3 trial evaluating ramucirumab combined to erlotinib in treatment-naïve advanced EGFR-mutant NSCLC patients. This article aims to summarize efficacy and safety of the ramucirumab-erlotinib combination in this setting.

Expert opinion

RELAY confirmed the clinical relevance of combining EGFR and VEGF(R)-targeting therapies, previously investigated in smaller phase 2–3 trials of erlotinib and bevacizumab. However, the meaningful PFS benefit observed in the ramucirumab + erlotinib arm is counterbalanced by the toxicity profile of ramucirumab and the need for bimonthly infusions. Pending OS results are, therefore, critical to assess the real benefit from this combination, especially as first-line osimertinib has improved survival in EGFR-mutant NSCLC patients and will probably remain the pivotal EGFR-TKI in this setting. However, its heterogeneous efficacy across subgroups paves the way for osimertinib-based combinations, which are being investigated in ongoing trials.

KEYWORDS:

• Erlotinib
• ramucirumab
• EGFR-mutant
• VEGF
• angiogenesis
• first line
• non-small cell lung cancer

Article highlights

• Delaying emergence of acquired resistance to EGFR-TKIs has become a major challenge in advanced EGFR-mutant NSCLC.

• There is a strong preclinical data to support the use of VEGF(R)-targeting antibodies and EGFR-TKIs, particularly in EGFR-mutant NSCLC.

• In the phase 3, placebo-controlled clinical trial RELAY, the adjunction of ramucirumab, a fully human monoclonal antibody targeting VEGFR-2, to erlotinib significantly prolonged progression-free survival at the cost of increased toxicities, including hypertension, proteinuria, and bleeding.

• T790M was the most frequent acquired resistance mechanism identified at progression in both arms, implying that ramucirumab did not preclude the subsequent use of osimertinib.

• Final survival results from RELAY will be critical to determine if this combination could be a reliable option for the first line along with osimertinib, considering its less favorable toxicity profile and the need for bimonthly infusions.

Declaration of interest

M Pérol has served in a consulting role for Roche, Eli Lilly, Pfizer, Boehringer Ingelheim, AstraZeneca; Lectures: Eli Lilly, Roche, AstraZeneca, Pfizer, Boehringer Ingelheim, and has received institutional research grants from Roche, AstraZeneca, Boehringer Ingelheim.

A Swalduz has received lecture fees from AstraZeneca and Boehringer Ingelheim.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.