Phase III Clinical Trial for the Combination of Erlotinib Plus Ramucirumab Compared With Osimertinib in Previously Untreated Advanced or Recurrent Non–Small Cell Lung Cancer Positive for the L858R Mutation of EGFR: REVOL858R (WJOG14420L)

Introduction: Osimertinib is a standard first-line treatment for non–small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor gene (EGFR). However, tumors with the L858R mutation appear to be less sensitive to EGFR–tyrosine kinase inhibitors (TKIs) than those with exon-19 deletions, and subgroup analysis of the FLAURA study revealed that osimertinib did not significantly prolong overall survival (OS) compared with gefitinib or erlotinib in patients with the L858R. The RELAY study revealed a similar high efficacy of combination therapy with erlotinib plus ramucirumab (E+RAM) in patients with L858R and in those with exon-19 deletions. Patients who acquire the TKI resistance–associated T790M mutation during E+RAM treatment can also expect to receive benefit from second-line osimertinib. We have therefore planned a phase III study to evaluate the clinical efficacy of E+RAM compared with osimertinib monotherapy for untreated patients with advanced NSCLC harboring L858R. Patients and Methods: A total of 230 patients will be enrolled. The primary end point is time to failure of strategy (TFS), which is defined for this study as the time from randomization of treatment until disease progression or death on osimertinib, or the time from randomization until first disease progression or death of the primary treatment when osimertinib is not administered in the E+RAM group. Secondary end points include OS and progression-free survival. Conclusion: This is the first phase III clinical trial to target only NSCLC patients with the L858R mutation. Its results may establish an optimal treatment for such individuals.