EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer (NSCLC): A Retrospective Analysis
By J. Gainor, A. Shaw, L. Sequist, Xiujun Fu, C. Azzoli, Z. Piotrowska, Tiffany Huynh, Ling Zhao, L. Fulton, Katherine R. Schultz and 11 more. Clinical Cancer Research, 2016
1,124 citations recorded by the source corpus.
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
Subfields: Oncology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/6935247f3d29bceeea7144c2a0c42f55e2acefce
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Citations in the corpus
- Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry (2019, background): “also suggested that a dearth of tumor-infiltrating CD8þ lymphocytes, may explain the low response rate to PD-1 axis inhibitors observed amongst EGFR- and ALK-driven NSCLC [24].”
- Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer (2018, positive): “were associated with low response rates to PD-1/PD-L1 inhibitors, which may have resulted from low rates of concurrent PD-L1 expression and CD8(+) TILs within the tumor microenvironment [119].”
- Checkpoint Inhibitors in Metastatic EGFR‐Mutated Non–Small Cell Lung Cancer—A Meta‐Analysis (2017, background): “Murine models have demonstrated significant response to the treatment with anti–PD-1 antibody in EGFRmutant but not KRAS-driven lung tumors(8); however, in a retrospective analysis of 58 patients with advanced NSCLC treated with PD-1/programmed death ligand 1 (PD-L1) inhibitors, only 4% of patients ”
- Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma (2016, background): “The GSE72094 cohort recruited 442 patients with detailed mRNA expression data and EGFR/KRAS/TP53/STK11sanger sequencing analysis (19).”