EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non–Small Cell Lung Cancer: A Retrospective …

JF Gainor, AT Shaw, LV Sequist, X Fu, CG Azzoli… - Clinical cancer …, 2016 - AACR
JF Gainor, AT Shaw, LV Sequist, X Fu, CG Azzoli, Z Piotrowska, TG Huynh, L Zhao, L Fulton…
Clinical cancer research, 2016AACR
Purpose: PD-1 inhibitors are established agents in the management of non–small cell lung
cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine
the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we
retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma
kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients. Experimental Design: We
identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORR) …
Abstract
Purpose: PD-1 inhibitors are established agents in the management of non–small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients.
Experimental Design: We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORR) were assessed using RECIST v1.1. PD-L1 expression and CD8+ tumor-infiltrating lymphocytes (TIL) were evaluated by IHC.
Results: Objective responses were observed in 1 of 28 (3.6%) EGFR-mutant or ALK-positive patients versus 7 of 30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- (≤10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced EGFR-mutant (N = 68) and ALK-positive (N = 27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre–tyrosine kinase inhibitor (TKI) biopsies using cutoffs of ≥1%, ≥5%, and ≥50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI–resistant biopsies (N = 57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (≥5%) and high levels of CD8+ TILs (grade ≥2) were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens and was not observed in any ALK-positive, pre- or post-TKI specimens.
Conclusions: NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8+ TILs within the tumor microenvironment may underlie these clinical observations. Clin Cancer Res; 22(18); 4585–93. ©2016 AACR.
See related commentary by Gettinger and Politi, p. 4539
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