Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC

Marina C Garassino; Shirish Gadgeel; Silvia Novello; Balazs Halmos; Enriqueta Felip; Giovanna Speranza; Rina Hui; Edward B Garon; Hidehito Horinouchi; Shunichi Sugawara; Delvys Rodriguez-Abreu; Martin Reck; Razvan Cristescu; Deepti Aurora-Garg; Andrey Loboda; Jared Lunceford; Julie Kobie; Mark Ayers; Bilal Piperdi; M Catherine Pietanza; Luis Paz-Ares

doi:10.1016/j.jtocrr.2022.100431

Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC

JTO Clin Res Rep. 2022 Nov 8;4(1):100431. doi: 10.1016/j.jtocrr.2022.100431. eCollection 2023 Jan.

Authors

Marina C Garassino¹, Shirish Gadgeel², Silvia Novello³, Balazs Halmos⁴, Enriqueta Felip⁵, Giovanna Speranza⁶, Rina Hui⁷, Edward B Garon⁸, Hidehito Horinouchi⁹, Shunichi Sugawara¹⁰, Delvys Rodriguez-Abreu¹¹, Martin Reck¹², Razvan Cristescu¹³, Deepti Aurora-Garg¹³, Andrey Loboda¹³, Jared Lunceford¹³, Julie Kobie¹³, Mark Ayers¹³, Bilal Piperdi¹³, M Catherine Pietanza¹³, Luis Paz-Ares¹⁴

Affiliations

¹ Section of Hematology/Oncology, Thoracic Oncology program, University of Chicago, Chicago, Illinois, and IRCCS Istituto Nazionale dei Tumori, Milano.
² Division of Hematology/Oncology, Department of Internal Medicine, Henry Ford Cancer Institute/Henry Ford Health System, Detroit, Michigan.
³ Department of Oncology, University of Turin, Orbassano, Italy.
⁴ Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York.
⁵ Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University, Barcelona, Spain.
⁶ Centre integré de cancérologie de la Montérégie, Université de Sherbrooke, Greenfield Park, Quebec, Canada.
⁷ Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.
⁸ David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
⁹ Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁰ Department of Pulmonary Medicine, Sendai Kousei Hospital, Miyagi, Japan.
¹¹ Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
¹² LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.
¹³ Merck & Co., Inc., Rahway, New Jersey.
¹⁴ Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center, Universidad Complutense and Ciberonc, Madrid, Spain.

Abstract

Introduction: We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials.

Methods: This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1, and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11, KEAP1, and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome.

Results: Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n = 293; KEYNOTE-407, n = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1, STK11, or KRAS mutation status.

Conclusions: These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen.

Keywords: Biomarker; Metastatic non‒small-cell lung cancer; Pembrolizumab; Single-gene genetic alterations; Tissue tumor mutational burden.

Associated data

ClinicalTrials.gov/NCT02578680
ClinicalTrials.gov/NCT02775435

Grants and funding

P30 CA016042/CA/NCI NIH HHS/United States