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

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-naive 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.