Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis.

Background: For patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear and established biomarkers to inform the optimal choice for individual patients. Here, we examined the complementary roles of tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) to inform first-line therapy using a large real-world (rw) data set.
Materials and Methods: The study included patients with NSCLC from an rw de-identified clinico-genomic database. All patients underwent genomic testing using Foundation Medicine's tissue comprehensive genomic profiling assay and PD-L1 IHC assay scored for tumor cell staining (TS).
Results: Of 2165 patients included in the analysis, 150 exhibited durable benefit from first-line ICPI regimens (these patients were enriched for PD-L1 TS ≥50, non-squamous histology, and TMB ≥20 mutations/megabase (muts/Mb)). Comparing low TMB (<10 muts/Mb), high TMB (10-19 muts/Mb), and very high TMB (≥20 muts/Mb) receiving ICPI alone, we observed a stepwise increase in median rwPFS (real world-progression free survival) (6.5, 7.5, 17.2 months) and rwOS (real world-overall survival) (10.1, 11.8, 26.9 months) as TMB increased. In the low PD-L1 (TS <50%) cohort, TMB <20 muts/Mb showed a more favorable rwPFS (HR: 0.56 (95% CI: 0.40 to 0.79)) and rwOS (HR 0.74 (95% CI: 0.58 to 0.96)) on chemoICPI when compared with ICPI alone while the point estimate in rwPFS favored monoICPI in the TMB ≥20 muts/Mb cohort, the CI is wide and does not reach statistical significance (HR: 1.68 (95% CI: 0.52 to 5.48)).
Conclusion: This study provides evidence that higher TMB cut-offs, such as 20 muts/Mb, can identify patients with prolonged benefit from ICPI. TMB ≥20 muts/Mb is a potential biomarker that may identify patients in whom an ICPI without chemo could be considered, even in the setting of lower PD-L1 levels. Prospective validation of these findings could increase access to chemo-sparing regimens for the first-line treatment of advanced NSCLC.
Competing Interests: Competing interests: RSPH, GL, AS, RG, LZ, KM, JSR, KT, and GRO are employees of Foundation Medicine, a wholly owned subsidiary of Roche and these employees have equity interest in Roche. DC is an employee/paid consultant for AbbVie, Adaptimmune, Agenus, Amgen, Ariad, AstraZeneca, Biocept, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, EMD Serono, Foundation Medicine, Genentech/Roche, Gritstone, Guardant Health, Inovio, Merck, MSD, Novartis, Palobiofarma, Pfizer, prIME Oncology, and Takeda, and reports receiving commercial research grants from Bristol Myers Squibb. JSR has consulting/advisory board AstraZeneca, Curadev, Daiichi-Sankyo, Jazz Pharmaceuticals, Medtronic, Pharma Mar. DS reports receiving research funding from AstraZeneca, Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, AbbVie, Foundation Medicine, GlaxoSmithKline, Eli Lilly, Merck, Nektar, Takeda, Amgen, University of Texas Southwestern Medical Center–Simmons Cancer Center, G1 Therapeutics, Neon Therapeutics, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Astellas Pharma, GRAIL, Transgene, Aeglea Therapeutics, Tesaro, Ipsen, Janssen, BIND Therapeutics, Eisai, and ImClone Systems; and consulting, advisory, and/or speakers’ bureau fees from AstraZeneca, Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, AbbVie, Foundation Medicine, GlaxoSmithKline, Eli Lilly, Merck, Moderna, Nektar, Takeda, Amgen, TRM Oncology, Precision Oncology, Evelo Therapeutics, Illumina, Pharmamar, EMD Serono, Aptitude Health, Dracen Pharmaceuticals, Iksuda Therapeutics, Molecular Templates, Seattle Genetics, TRIPTYCH Health Partners, and Intellisphere.
(© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)