EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD 1 Pathway Blockade in Non Small Cell Lung Cancer: A Retrospective Analysis
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. (c)2016 AACR. See related commentary by Gettinger and Politi, p. 4539
Clinical Cancer Research