1. Baseline Plasma Tumor Mutation Burden Predicts Response to Pembrolizumab-based Therapy in Patients with Metastatic Non-Small Cell Lung Cancer
- Author
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Michael J. LaRiviere, Elena Helman, Taylor A. Black, Wei-Ting Hwang, Rebecca J. Nagy, Theresa Christensen, Benjamin A. Silva, Katie Quinn, Charu Aggarwal, Austin L. Chien, Abigail T. Berman, Erica L. Carpenter, Joshua Bauml, Jeffrey C. Thompson, Corey J. Langer, Christine Ciunci, Kimberly C. Banks, Jeffrey S. Wasser, Stephanie S. Yee, Aditi P. Singh, and Roger B. Cohen
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Article ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Predictive Value of Tests ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Carcinoma ,Biomarkers, Tumor ,Humans ,Progression-free survival ,Prospective Studies ,Neoplasm Metastasis ,Lung cancer ,Prospective cohort study ,Survival rate ,Antineoplastic Agents, Alkylating ,Aged ,Aged, 80 and over ,Chemotherapy ,business.industry ,Middle Aged ,medicine.disease ,Survival Rate ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Monoclonal ,Mutation ,Female ,business - Abstract
Purpose: The role of plasma-based tumor mutation burden (pTMB) in predicting response to pembrolizumab-based first-line standard-of-care therapy for metastatic non–small cell lung cancer (mNSCLC) has not been explored. Experimental Design: A 500-gene next-generation sequencing panel was used to assess pTMB. Sixty-six patients with newly diagnosed mNSCLC starting first-line pembrolizumab-based therapy, either alone or in combination with chemotherapy, were enrolled (Clinicaltrial.gov identifier: NCT03047616). Response was assessed using RECIST 1.1. Associations were made for patient characteristics, 6-month durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS). Results: Of 66 patients, 52 (78.8%) were pTMB-evaluable. Median pTMB was 16.8 mutations per megabase (mut/Mb; range, 1.9–52.5) and was significantly higher for patients achieving DCB compared with no durable benefit (21.3 mut/Mb vs. 12.4 mut/Mb, P = 0.003). For patients with pTMB ≥ 16 mut/Mb, median PFS was 14.1 versus 4.7 months for patients with pTMB < 16 mut/Mb [HR, 0.30 (0.16–0.60); P < 0.001]. Median OS for patients with pTMB ≥ 16 was not reached versus 8.8 months for patients with pTMB < 16 mut/Mb [HR, 0.48 (0.22–1.03); P = 0.061]. Mutations in ERBB2 exon 20, STK11, KEAP1, or PTEN were more common in patients with no DCB. A combination of pTMB ≥ 16 and absence of negative predictor mutations was associated with PFS [HR, 0.24 (0.11–0.49); P < 0.001] and OS [HR, 0.31 (0.13–0.74); P = 0.009]. Conclusions: pTMB ≥ 16 mut/Mb is associated with improved PFS after first-line standard-of-care pembrolizumab-based therapy in mNSCLC. STK11/KEAP1/PTEN and ERBB2 mutations may help identify pTMB-high patients unlikely to respond. These results should be validated in larger prospective studies.
- Published
- 2019