RELAY, Erlotinib Plus Ramucirumab in Untreated, EGFR-Mutated, Metastatic NSCLC: Outcomes by EGFR Exon 19 Deletion Variants

Introduction: EGFR gene mutations are drivers of NSCLC. The RELAY double-blind, placebo (PBO)-controlled phase 3 study revealed superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus PBO (PBO + ERL) in patients with untreated advanced NSCLC and an EGFR-activating mutation. This exploratory analysis evaluated potential associations between EGFR exon 19 deletion (ex19del) variants and clinical outcomes. Methods: Patients (N = 449) were randomized (1:1) to RAM plus ERL or PBO plus ERL. Plasma samples were collected at baseline, on treatment, and at 30-day post-study treatment discontinuation follow-up. Baseline and treatment-emergent gene alterations were investigated by Guardant360 next-generation sequencing. Patients with a valid baseline plasma sample and ex19del were included (RAM + ERL, n = 62; PBO + ERL, n = 72). Results: The most common ex19del variant was E746_A750del (67.2%); EGFR E746 deletions (E746del) occurred more frequently than L747 deletions (74.6% versus 25.4%, respectively). TP53 mutations were the most frequently co-occurring baseline gene alterations. With treatment arms combined, median PFS was 18.0 months versus 12.5 months for patients with uncommon (non-E746_A750del, n = 44) versus common (E746_A750del, n = 90) ex19del variants (hazard ratio [HR] = 1.657 [95% confidence interval or CI:1.044–2.630]). Median PFS was longer with RAM plus ERL versus PBO plus ERL for patients with the common (15.2 versus 9.9 mo; HR = 0.564 [95% CI: 0.344–0.926]) and E746del (15.4 versus 9.9 mo; HR = 0.587 [95% CI: 0.363–0.951]) variants. Treatment-emergent post-progression EGFR T790M rates were higher in the common versus uncommon and E746del versus L747 deletion subgroups. Conclusions: RAM plus ERL provides benefit and improves treatment outcomes for patients with metastatic NSCLC with EGFR ex19del variants

Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Untreated Metastatic EGFR-Mutated NSCLC: RELAY Japanese Subset

Introduction: The phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46–0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan. Methods: Patients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing. Results: The Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431–0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424–1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317–0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients). Conclusions: Clinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression