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, 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 (ORRs) were assessed using RECIST v1.1. PD-L1 expression and CD8+ tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry. Results Objective responses were observed in 1/28 (3.6%) EGFR-mutant or ALK-positive patients versus 7/30 (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 pre-treatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens, and was not observed in any ALK-positive, pre- or post-TKI specimens. Conclusion 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.

EGFR inhibition in NSCLC: New findings…. and opened questions?

“…Even if EGFR-mutated tumors are often associated with PDL1 overexpression (D'Incecco et al, 2015), the low rate of tumor infiltrate lymphocytes (TILs) suggests a very low immune-dependence of these tumors. Recently Gainor et al have found a concurrent PD-L1 overexpression and high rate of TILs in the tumor microenvironment of only 1/57 TKI-naive and 5/57 TKI-resistant patients with EGFR-mutated NSCLC (Gainor et al, 2016), confirming a lack of immunogenicity in the majority of such tumors. Even if PD-L1 expression levels changed in 16 patients evaluated after EGFR-TKI therapy, however not significant variations in both TILs and PDL1 expression have been found before and after TKI.…”

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

“…For example, the use of epidermal growth factor receptor (EGFR) TKIs is standard of care in patients with EGFR-mutation-positive NSCLC [92][93][94], and studies suggest that this population may not derive benefit from immunotherapy versus EGFR TKIs [95] or chemotherapy [96]. Therefore, the clinical benefit from monotherapy with anti-PD-1/PD-L1 antibodies remains suboptimal in EGFR-mutation-positive NSCLC, and novel combination and therapeutic approaches are needed [96].…”

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

“…Gainor et al conducted a retrospective review on EGFR -mutated and ALK -rearranged NSCLC patients treated with PD-1/PD-L1 inhibitors after progression on TKIs. Though their sample size was small, zero of six patients with ALK -rearranged NSCLC had an objective radiographic response to checkpoint inhibition [59]. They also assessed PD-L1 expression in ALK -rearranged NSCLC prior to crizotinib and at the time of crizotinib resistance.…”