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

Kazumi Nishino; Jin-Yuan Shih; Kazuhiko Nakagawa; Martin Reck; Edward B Garon; Michelle Carlsen; Tomoko Matsui; Carla Visseren-Grul; Ernest Nadal

doi:10.1016/j.jtocrr.2023.100624

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

JTO Clin Res Rep. 2023 Dec 19;5(2):100624. doi: 10.1016/j.jtocrr.2023.100624. eCollection 2024 Feb.

Authors

Kazumi Nishino¹, Jin-Yuan Shih², Kazuhiko Nakagawa³, Martin Reck⁴, Edward B Garon⁵, Michelle Carlsen⁶, Tomoko Matsui⁷, Carla Visseren-Grul⁸, Ernest Nadal⁹

Affiliations

¹ Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
² Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan.
³ Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.
⁴ Lung Clinic, Airway Research Center North, German Center of Lung Research, Grosshansdorf, Germany.
⁵ Department of Medicine, David Geffen School of Medicine at UCLA/TRIO-US Network, Los Angeles, California.
⁶ Eli Lilly and Company, Indianapolis, Indiana.
⁷ Eli Lilly Japan K.K., Kobe, Japan.
⁸ Eli Lilly Netherlands, Utrecht, The Netherlands.
⁹ Department of Medical Oncology, Catalan Institute of Oncology (ICO), and Preclinical and Experimental Research Group in Thoracic Tumors, Oncobell, l'Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet, Barcelona, Spain.

Abstract

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.

Keywords: Carcinoma; EGFR exon 19 deletion variant; Non–small cell lung; Ramucirumab; Targeted therapy; VEGFR inhibition.