Abstract CT215: RELAY, ramucirumab plus erlotinib (RAM+ERL) versus placebo plus erlotinib (PBO+ERL) in previously untreated EGFR mutation-positive metastatic NSCLC: Next generation sequencing (NGS) results
Authors: Garon Edward , Reck Martin , Nishio Kazuto , Heymach John Victor , Nishio Makoto , Novello Silvia , Paz-Ares Luis , Popat Sanjay , Aix Santiago Ponce , Wijayawardana Sameera , Hozak Rebecca R. , Visseren-Grul Carla , Nakagawa Kazuhiko 
Published: September 2020

RELAY (NCT02411448) showed a superior progression free survival benefit with RAM+ERL versus (v) PBO+ ERL (mPFS 19.4 vs 12.4mo, HR 0.59, p-value &lt;0.0001). We investigated the mutational landscape for potential a) baseline biomarkers and b) treatment emergent (TE) alterations. Eligible patients (untreated metastatic NSCLC, EGFR exon 19 deletion or exon 21 L858R mutation-positive by local testing, ECOG PS of 0 or 1, and without CNS metastases) were randomized to receive ERL (150 mg oral) daily with either RAM (10 mg/kg iv) or PBO Q2W until progressive disease, unacceptable toxicity, withdrawal, non-compliance, or investigator decision. Liquid biopsies (baseline, cycle 4 (C4), and post-treatment discontinuation 30-day follow-up) underwent Guardant360® NGS for pre-specified exploratory biomarker analyses. For baseline analyses, alterations (single nucleotide variants, gene fusions, or copy number changes) in ALK, MET, and TP53 were among the 69 genes with alterations co-occurring at baseline with ex19del or ex21.L858R (not shown). Baseline ALK and MET alterations did not appear to impact the observed PFS or DOR. However, altered baseline TP53 associated with a worse prognosis (p&lt;0.001), and had a trend for better ram efficacy. For evaluating TE alterations, two populations were assessed to address factors like disease progression and ctDNA shedding (footnote). The distribution of TE alterations in the 30-day follow-up samples was similar for RAM+ERL v PBO+ERL (TABLE). Additional results, including associations with baseline characteristics, C4, 30-day follow-up, and PFS will be presented. Understanding the potential clinical impact of co-occurring baseline alterations provides important information to evaluate treatment options. Sample size was limited, but the types and frequency of TE alterations appeared similar between treatment arms.

TablePts (≥2 in either treatment group) with treatment emergent alterationsaPop1bPop2bGene NameRAM+ERL (n=36)PBO+ERL (n=60)p-valuecRAM+ERL (n=98)PBO+ERL (n=129)p-valuecEGFRd16 (44)33 (55).3227 (28)47 (36).16TP538 (22)7 (12).1717 (17)16 (12).30NF15 (14)1 (2).027 (7)3 (2).08APC4 (11)1 (2).055 (5)3 (2).26MET3 (8)5 (8)1.006 (6)7 (5).82KRAS2 (6)3 (5).917 (7)3 (2).08FGFR22 (6)2 (3).603 (3)3 (2).73GNAS2 (6)0.052(2)1 (1).41BRAF1 (3)6 (10).163 (3)6 (5).54PI3KA1 (3)4 (7).391 (1)7 (5).06BRCA203 (5).094 (4)6 (5).84ERBB21 (3)3 (5).594 (4)4 (3).69AR02 (3).171 (1)2 (2).73CDK61 (3)2 (3).881 (1)2 (2).73RB11 (3)1 (2).722 (2)3 (2).88CDK41 (3)1 (2).721 (1)2 (2).73SMAD41 (3)1 (2).721 (1)2 (2).73KIT1 (3)1 (2).723 (3)1 (1).19PTEN1 (3)2 (3).882 (2)2 (2).78ARID1A1 (3)1 (2).723 (3)3 (2).73FGFR11 (3)0.162 (2)1 (1).41MAP2K11 (3)0.162 (2)0.07MAPK31 (3)0.162 (2)0.07MTOR01 (2).332 (2)1 (1).41MYC1 (3)0.162 (2)2 (2).78RET00–2 (2)0.07ROS100–2 (2)0.07STK1100–1 (1)2 (2).73Evaluable baseline NGS results were obtained for 390 out of 449 ITT patients (87%).aPts are included in more than one row if alterations arose in more than one gene.bAnalysis population 1 (Pop1, N=96) had disease progression by the 30-day post treatment discontinuation follow-up and had detectable EGFR ex19del or ex21.L858R mutation in baseline and 30 day follow-up blood samples. There is a greater confidence that alterations related to mechanisms of resistance would be detectable in this population since the patients had all progressed by 30-day follow-up and since the EGFR ex19del and ex21.L858R were detectable as shed circulating tumor DNA in the blood. Analysis population 2 (Pop2, N=227) had discontinued study treatment for any reason by the 30-day post treatment discontinuation follow-up and had any alteration detectable at baseline and at 30 day follow-up. Pop2 is a larger population (includes all Pop1 pts) and offers the opportunity to detect less common TE alterations that may not be found in the smaller Pop1. Seven (19%) RAM+ERL v 19 (32%) PBO+ERL of Pop1 and 33 (34%) v 59 (46%) of Pop2 pts had not acquired any of the evaluated alterations.cFisher's exact testdIncludes T790M; the frequencies of TE T790M in RAM+ERL v PBO+ERL for Pop1 were 42% v 50%, respectively, and for Pop2, 19% v 25%

Citation Format: Edward Garon, Martin Reck, Kazuto Nishio, John Victor Heymach, Makoto Nishio, Silvia Novello, Luis Paz-Ares, Sanjay Popat, Santiago Ponce Aix, Sameera Wijayawardana, Rebecca R. Hozak, Carla Visseren-Grul, Kazuhiko Nakagawa. RELAY, ramucirumab plus erlotinib (RAM+ERL) versus placebo plus erlotinib (PBO+ERL) in previously untreated EGFR mutation-positive metastatic NSCLC: Next generation sequencing (NGS) results [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT215.