American Association for Cancer Research
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Figure S5 from RELAY Subgroup Analyses by EGFR Ex19del and Ex21L858R Mutations for Ramucirumab Plus Erlotinib in Metastatic Non–Small Cell Lung Cancer

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journal contribution
posted on 2023-06-09, 14:00 authored by Kazuhiko Nakagawa, Ernest Nadal, Edward B. Garon, Makoto Nishio, Takashi Seto, Nobuyuki Yamamoto, Keunchil Park, Jin-Yuan Shih, Luis Paz-Ares, Bente Frimodt-Moller, Annamaria H. Zimmermann, Sameera Wijayawardana, Carla Visseren-Grul, Martin Reck

Patterns for post-study discontinuation therapies by first through third subsequent lines of treatment of the baseline EGFR-activating mutation subgroups. Sankey diagrams for (A) ex19del and (B) ex21L858R subgroups present therapies post-RAM+ERL and post-PBO+ERL study treatment discontinuation. Shown from left to right are first subsequent therapy, ie, second line of therapy; second subsequent therapy, ie, third line of therapy; and third or more subsequent lines of therapy, ie, fourth or more lines of therapy. Therapies are subgrouped by color family as follows: EGFR-TKIs (erlotinib, osimertinib, EGFR-TKI plus VEGF and other EGFR-TKI) in green; platinum-based chemotherapy with or without VEGF inhibitor in red; non-platinum-based chemotherapy with or without VEGF inhibitor) in purple; and immunotherapy or investigational drugs in brown. Further details on post-study discontinuation therapies are provided in Supplementary Table S5.





In EGFR-mutated metastatic non–small cell lung cancer (NSCLC), outcomes from EGFR tyrosine kinase inhibitors have differed historically by mutation type present, with lower benefit reported in patients with ex21L858R versus ex19del mutations. We investigated if EGFR-activating mutation subtypes impact treatment outcomes in the phase III RELAY study. Associations between EGFR mutation type and preexisting co-occurring and treatment-emergent genetic alterations were also explored. Patients with metastatic NSCLC, an EGFR ex19del or ex21L858R mutation, and no central nervous system metastases were randomized (1:1) to erlotinib (150 mg/day) with either ramucirumab (10 mg/kg; RAM+ERL) or placebo (PBO+ERL), every 2 weeks, until RECIST v1.1–defined progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary and exploratory endpoints included overall response rate (ORR), duration of response (DOR), PFS2, time-to-chemotherapy (TTCT), safety, and next-generation sequencing analyses. Patients with ex19del and ex21L858R mutations had similar clinical characteristics and comutational profiles. One-year PFS rates for ex19del patients were 74% for RAM+ERL versus 54% for PBO+ERL; for ex21L858R rates were 70% (RAM+ERL) versus 47% (PBO+ERL). Similar treatment benefits (ORR, DOR, PFS2, and TTCT) were observed in RAM+ERL–treated patients with ex19del and ex21L858R. Baseline TP53 comutation was associated with superior outcomes for RAM+ERL in both ex19del and ex21L858R subgroups. EGFR T790M mutation rate at progression was similar between treatment arms and by mutation type. RAM+ERL provided significant clinical benefit for both EGFR ex19del and ex21L858R NSCLC, supporting this regimen as suitable for patients with either of these EGFR mutation types.

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