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.

• Authors: Justin F Gainor, Alice T Shaw, Lecia V Sequist, Xiujun Fu, Christopher G Azzoli, Zofia Piotrowska, Tiffany G Huynh, Ling Zhao, Linnea Fulton, Katherine R Schultz, Emily Howe, Anna F Farago, Ryan J Sullivan, James R Stone, Subba Digumarthy, Teresa Moran, Aaron N Hata, Yukako Yagi, Beow Y Yeap, Jeffrey A Engelman, Mari Mino-Kenudson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 18 Pg. 4585-93 (Sep 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 27225694 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Immunological
• B7-H1 Antigen
• CD274 protein, human
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Protein Kinase Inhibitors
• ALK protein, human
• Anaplastic Lymphoma Kinase
• ErbB Receptors
• Receptor Protein-Tyrosine Kinases

Topics

• Adult
• Aged
• Anaplastic Lymphoma Kinase
• Antineoplastic Agents, Immunological (pharmacology, therapeutic use)
• B7-H1 Antigen (metabolism)
• Carcinoma, Non-Small-Cell Lung (diagnosis, drug therapy, genetics, metabolism)
• DNA Mutational Analysis
• ErbB Receptors (genetics)
• Female
• Genotype
• Humans
• Lung Neoplasms (diagnosis, drug therapy, genetics, metabolism)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, metabolism)
• Male
• Middle Aged
• Molecular Targeted Therapy
• Mutation
• Programmed Cell Death 1 Receptor (metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Receptor Protein-Tyrosine Kinases (genetics)
• Signal Transduction (drug effects)
• Tomography, X-Ray Computed
• Translocation, Genetic
• Treatment Outcome