TY - JOUR
T1 - EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer
T2 - A retrospective analysis
AU - Gainor, Justin F.
AU - Shaw, Alice T.
AU - Sequist, Lecia V.
AU - Fu, Xiujun
AU - Azzoli, Christopher G.
AU - Piotrowska, Zofia
AU - Huynh, Tiffany G.
AU - Zhao, Ling
AU - Fulton, Linnea
AU - Schultz, Katherine R.
AU - Howe, Emily
AU - Farago, Anna F.
AU - Sullivan, Ryan J.
AU - Stone, James R.
AU - Digumarthy, Subba
AU - Moran, Teresa
AU - Hata, Aaron N.
AU - Yagi, Yukako
AU - Yeap, Beow Y.
AU - Engelman, Jeffrey A.
AU - Mino-Kenudson, Mari
N1 - Publisher Copyright:
©2016 American Association for Cancer Research.
PY - 2016/9/15
Y1 - 2016/9/15
N2 - 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≥11%, ≥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%) EGFRmutant 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.
AB - 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≥11%, ≥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%) EGFRmutant 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.
UR - http://www.scopus.com/inward/record.url?scp=84990938506&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-3101
DO - 10.1158/1078-0432.CCR-15-3101
M3 - Article
C2 - 27225694
AN - SCOPUS:84990938506
SN - 1078-0432
VL - 22
SP - 4585
EP - 4593
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -
