Combination treatment with the VEGFR2 antagonist ramucirumab plus the EGFR tyrosine kinase inhibitor erlotinib led to better progression-free survival (PFS) outcomes in metastatic non–small-cell lung cancer (NSCLC) compared with treatment with erlotinib alone, according to results from the randomized phase III RELAY trial (abstract 9000). The results were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago.
Between 30% and 60% of patients acquire resistance to tyrosine kinase inhibitors (TKIs) through the EGFR T790M mutation, which creates a need for regimens that could extend EGFR TKI efficacy.
Preclinical and early clinical data showed that targeting both the EGFR and VEGFR pathways produces better results than targeting just EGFR. To test that idea, researchers carried out the RELAY trial of erlotinib combined with ramucirumab or placebo.
The study randomized 449 previously untreated metastatic NSCLC patients with exon 19 deletion or exon 21 (L8585R) deletion to daily erlotinib plus ramucirumab, or erlotinib plus placebo; 77% of patients were Asian, 63% were women, and 54% had the exon 19 deletion. Erlotinib plus ramucirumab was associated with better median PFS (19.4 months vs 12.4 months; hazard ratio [HR], 0.591; P < .0001), a longer duration of response (median, 18.0 months vs 11.1 months; HR, 0.619; P = .0003), and a better 2-year PFS rate (HR, 0.690; 95% CI, 0.490–0.972). There was no significant difference in overall response rate or interim overall survival.
After progression, 43% of patients in the ramucirumab group were found to have a T790M mutation, compared with 47% in the placebo group (P = .849).
Patients receiving ramucirumab experienced a higher frequency of grade 3 or higher treatment-emergent adverse events (72% vs 54%), which was due in large part to differences in hypertension (24% vs 5%), though none of the events were grade 4. There was one treatment death in the combination group, due to hemothorax, and none in the erlotinib-only arm.
“They demonstrated a pretty impressive progression-free survival,” said study discussant Ticiana Leal, MD, an assistant professor and thoracic oncology program leader at the University of Wisconsin.
“The difficulty is you’re comparing it to erlotinib, which we no longer use. And I still have concerns about CNS activity, and what about quality of life? Certainly from a patient perspective it would be interesting to have some data regarding patient-reported outcomes,” said Leal.
Ultimately, Leal doesn’t feel it will be practice changing. “But it’s something to consider in terms of where adding an antiangiogenesis agent fits into the sequence of treating patients with EGFR-mutant NSCLC. When is the right time to use it? I think that question still is not answered by this study,” she said.