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Association Between Smoking and Survival Benefit of Immunotherapy in Advanced Malignancies

A Systematic Review and Meta-Analysis

Wallis, Christopher J.D. MD, PhD*; Satkunasivam, Raj MD, MS; Butaney, Mohit MD; Khan, Usman A. MD§; Goldberg, Hanan A. MD*; Freedland, Stephen J. MD∥,¶; Patel, Sandip P. MD#; Hamid, Omid MD**; Pal, Sumanta K. MD††; Klaassen, Zachary MD‡‡,§§

American Journal of Clinical Oncology: September 2019 - Volume 42 - Issue 9 - p 711–716
doi: 10.1097/COC.0000000000000577
Original Articles: Experimental Therapeutics

Objectives: Smoking is associated with an increased tumor mutational burden. As tumor mutational burden has been shown to correlate with response to immunotherapy (IO), we hypothesized that a history of smoking may be associated with better response to IO.

Methods: We utilized a systematic review with stratified meta-analysis of randomized clinical trials of IO versus standard of care in patients with advanced solid organ malignancies.

Results: Among 9 relevant studies, we found no significant difference in the benefit of IO, compared with other systemic therapies, between ever smokers (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.58-1.04; P=0.09) and never smokers (HR, 0.75; 95% CI, 0.67-0.86; P<0.0001) (test for difference P=0.83). We also observed no significant difference between current (HR, 0.92; 95% CI, 0.63-1.34; P=0.66; I2=67%) and never smokers (HR, 0.74; 95% CI, 0.59-0.93; P=0.01; I2=46%) (test for difference P=0.35).

Conclusions: Stratified meta-analysis demonstrates that smoking status is not significantly associated with the response to IO in the treatment of advanced solid organ malignancies.

*Department of Surgery, Division of Urology, University of Toronto, Toronto, ON, Canada

Department of Urology and Center for Outcomes Research

§Department of Medical Oncology, Houston Methodist Hospital, Houston, TX

Royal College of Surgeons in Ireland School of Medicine, Dublin, Ireland

Section of Urology, Durham VA Medical Center, Durham, NC

Division of Urology, Department of Surgery, Cedars-Sinai Medical Center

**The Angeles Clinic & Research Institute, Los Angeles

#Department of Medicine, UC San Diego Health—La Jolla, La Jolla

††Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA

‡‡Department of Surgery, Division of Urology, Medical College of Georgia at Augusta University

§§Georgia Cancer Center, Augusta University, Augusta, GA

S.J.F. reported receiving grants from Merck outside of the submitted work. S.P.P. reported receiving scientific advisory income from AstraZeneca, BMS, Illumina, Tempus, and Novartis. S.P.P.’s university receives research funding from Bristol-Myers Squibb, Eli Lilly, Fate, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance. S.K.P. reported receiving personal fees from Genentech, Pfizer, and BMS outside of the submitted work. The other authors declare no conflicts of interest.

Reprints: Mohit Butaney, MD, Mayo Clinic, 200 1st Street SW, Rochester, MN 55902. E-mail:

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