Clinical activity of programmed cell death 1 (PD-1) blockade in never, light, and heavy smokers with non-small-cell lung cancer and PD-L1 expression ≥50

Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for d...

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Published in:	Annals of oncology Vol. 31; no. 3; pp. 404 - 411
Main Authors:	Gainor, J.F., Rizvi, H., Jimenez Aguilar, E., Skoulidis, F., Yeap, B.Y., Naidoo, J., Khosrowjerdi, S., Mooradian, M., Lydon, C., Illei, P., Zhang, J., Peterson, R., Ricciuti, B., Nishino, M., Roth, J.A., Grishman, J., Anderson, D., Little, B.P., Carter, B.W., Arbour, K., Sauter, J.L., Mino-Kenudson, M., Heymach, J.V., Digumarthy, S., Shaw, A.T., Awad, M.M., Hellmann, M.D.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-03-2020
Subjects:	Apoptosis B7-H1 Antigen - genetics Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Humans Lung Neoplasms - drug therapy Lung Neoplasms - genetics NSCLC PD-1 inhibitor PD-L1 expression Phospholipase D - metabolism Programmed Cell Death 1 Receptor Retrospective Studies Smokers tumor mutation burden PD-L1 expression PD-1 inhibitor NSCLC tumor mutation burden
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Summary:	Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined. To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB. We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different [PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141]. PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade. •In patients with NSCLC and PD-L1 ≥50%, TMB is lower in never and light smokers compared with heavy smokers.•PD-(L)1 inhibitors are active in a significant subset of never and light smokers with NSCLC and PD-L1 ≥50%.•Nonetheless, we observed numerically shorter PFS/DOR among never and light smokers compared to heavy smokers.•Distinct immunobiologic features may underlie initial response versus durability of response to PD-1 inhibitors in NSCLC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0923-7534 1569-8041
DOI:	10.1016/j.annonc.2019.11.015