Data from <i>EGFR</i> Mutations and <i>ALK</i> Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non–Small Cell Lung Cancer: A Retrospective Analysis

Abstract

<div>Abstract<p><b>Purpose:</b> 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 <i>EGFR wild-type</i>/ALK-negative patients.</p><p><b>Experimental Design:</b> 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<sup>+</sup> tumor-infiltrating lymphocytes (TIL) were evaluated by IHC.</p><p><b>Results:</b> Objective responses were observed in 1 of 28 (3.6%) EGFR-mutant or ALK-positive patients versus 7 of 30 (23.3%) <i>EGFR wild-type</i> and ALK-negative/unknown patients (<i>P</i> = 0.053). The ORR among never- or light- (≤10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (<i>P</i> = 0.123). In an independent cohort of advanced EGFR-mutant (<i>N</i> = 68) and ALK-positive (<i>N</i> = 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 (<i>N</i> = 57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (≥5%) and high levels of CD8<sup>+</sup> 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.</p><p><b>Conclusions:</b> NSCLCs harboring <i>EGFR</i> mutations or <i>ALK</i> rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8<sup>+</sup> TILs within the tumor microenvironment may underlie these clinical observations. <i>Clin Cancer Res; 22(18); 4585–93. ©2016 AACR</i>.</p><p><i>See related commentary by Gettinger and Politi, p. 4539</i></p></div>