RELAY: Combo Ramucirumab/Erlotinib Superior to Erlotinib Alone for EGFR Mutation-Positive NSCLC

By Jeff Craven /alert Contributor
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Ramucirumab and erlotinib as a first-line treatment for epidermal growth factor receptor mutation-positive non-small lung cancer improved progression-free survival compared with standard-of-care treatment with erlotinib and placebo, according to recent research.

“Treatment with CYRAMZA [ramucirumab] plus erlotinib demonstrated a statistically significant and clinically meaningful improvement in the time patients lived without their cancer growing or spreading after starting treatment, compared to erlotinib alone,” Kazuhiko Nakagawa, MD, PhD, from Kindai University Hospital in Osaka, Japan, said in an interview with MD /alert.

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Nakagawa and colleagues recently presented results from the phase 3, double-blinded, randomized RELAY study at the ASCO meeting in Chicago. The RELAY study analyzed erlotinib (ERL), an epidermal growth factor receptor mutation-positive (EGFRm) tyrosine kinase inhibitor (TKI), together with ramucirumab (RAM), a human immunoglobulin G1 vascular endothelial growth factor receptor-2 antagonist, and placebo in patients with EGFRm non-small cell lung cancer (NSCLC).

“At the time of the RELAY study design (2014/2015), several preclinical studies had shown that the vascular endothelial growth factor (VEGF)/VEGF receptor and EGFR pathways were interrelated,” Nakagawa said in the interview. “These studies suggested that dual blockade of the VEGF and EGFR pathways would be more effective than either approach alone and could also have activity in tumors with acquired resistance to EGFR inhibitors.”

Patients were included in the study if they had untreated metastatic NSCLC consisting of EGFR mutation Exon 19 deletion, L858R mutation and central nervous system (CNS) metastasis. There were 449 patients enrolled who were randomized to receive ERL at a dose of 150 mg per day and RAM at 10 mg/kg every 2 weeks, or ERL alone in combination with placebo. The researchers noted the randomization was grouped based on gender, geographic region (East Asian vs. other regions), type of EGFRm (Ex19del vs. L858R mutation) and method of EGFR testing. The cohort consisted of 77% patients from Asia, 63% women, and 54% with an Exon 19 deletion. While the primary outcome was progression-free survival (PFS), duration of response, overall response rate (ORR), progression after next line of therapy (PFS2), overall survival, safety and plasma T790M mutation were also studied as secondary outcomes.

Median PFS in the RAM and ERL group was significantly higher at 19.4 months compared with 12.4 months in the group that received ERL and placebo (hazard ratio, 0.591; 95% confidence interval, 0.461-0.760; P < .0001). Duration of response (median 18.0 months vs. 11.1 months; HR, 0.619; 95% CI, 0.477-0.805) and PFS2 (median follow-up not reached; HR, 0.69; 95% CI, 0.490-0.972) were also significantly prolonged in the RAM and ERL group compared to the group that received ERL with placebo.

Researchers also discussed results of which patients developed the EGFR T790M mutation, which was an exclusion criterium for the study. “The most common mechanism of resistance to 1st and 2nd generation EGFR TKIs is acquisition of the EGFR T790M mutation,” said Dr. Nakagawa.

They found that there was a similar rate of treatment-emergent EGFR T790M mutation, between both groups (43% vs. 47%, P  = .849). “These data suggest that the addition of ramucirumab to erlotinib does not alter the T790M resistance mechanism pathway and that subsequent treatment with an T790M targeting agent (like osimertinib) may remain a viable therapeutic option as next-line therapy,” Nakagawa said.

With regard to adverse events, patients who received RAM and ERL had a higher rate of grade 3 or higher treatment emergent adverse events (TEAE) at 72% compared with the placebo group, and these events were related to hypertension (24% vs. 5%). The researchers noted the safety profile of combination RAM and ERL was “consistent with the established safety profiles of the individual compounds.”

“Based on the totality of the data, the RELAY regimen is a new treatment option for the initial treatment of metastatic EGFR-mutated NSCLC patients,” once regulatory approved, Nakagawa concluded.

Nakagawa K, et al. Abstract 9000. ASCO 2019 Annual Meeting; May 31 - Jun 5; Chicago, Il.