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

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 AACRSee related commentary by Gettinger and Politi, p. 4539.

Figure 1

A) Unconfirmed/Confirmed objective response rates (ORRs) to PD-1/PD-L1 inhibitors comparing EGFR-mutant or ALK-positive non-small cell lung cancer (NSCLC) patients versus EGFR wild-type and ALK-negative/unknown patients. B) ORRs to PD-1/PD-L1 inhibitors of never- or light-smokers versus heavy smokers (>10 pack years). C) Progression-free survival (PFS) on PD-1/PD-L1 inhibitors based upon EGFR mutation or ALK rearrangement status.

Figure 2

PD-L1 expression levels in paired, pre- and post-TKI biopsies among EGFR-mutant patients along with representative PD-L1 immunohistochemical images. A majority of EGFR-mutant patients (72%) exhibited consistent PD-L1 staining across both specimens, but 16 (28%) patients demonstrated variable staining across biopsies.

Figure 3

Computed tomography (CT) image of a patient with EGFR-mutant non-small cell lung cancer demonstrating the metastatic burden of disease along with representative images of PD-L1 immunohistochemical staining of corresponding autopsy samples. Diffuse PD-L1 expression (≥50% of tumor cells expressing PD-L1) was identified in 8 distinct metastatic sites, but not in normal lung tissue.