Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non–Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel

Abstract

This study explores whether blood tumor mutational burden estimated by a next-generation sequencing gene panel is associated with clinical outcomes of patients with non–small cell lung cancer treated with anti–programmed cell death 1 and anti–programmed cell death ligand 1 agents.

Key Points

Question

Is blood tumor mutational burden estimated by a next-generation gene sequencing panel with an optimized panel size and algorithm associated with clinical outcomes in patients with non–small cell lung cancer treated with anti–programmed cell death 1 (anti–PD-1) and anti–programmed cell death ligand 1 (anti–PD-L1) agents?

Findings

This study of 2 independent cohorts of patients (48 in cohort 1 and 50 in cohort 2) found that NCC-GP150 was a cost-effective panel for tumor mutational burden estimation with satisfactory performance. Blood tumor mutational burden estimated by NCC-GP150 correlated well with tissue tumor mutational burden calculated by whole-exome sequencing, and a blood tumor mutational burden of 6 or higher was positively associated with clinical benefits of anti–PD-1 and anti–PD-L1 therapy in patients with advanced non–small cell lung cancer.

Meaning

The findings suggest that blood tumor mutational burden measured by NCC-GP150 is a potential biomarker to identify patients with non–small cell lung cancer who could benefit from anti–PD-1 and anti–PD-L1 therapy.

Abstract

Importance

Tumor mutational burden (TMB), as measured by whole-exome sequencing (WES) or a cancer gene panel (CGP), is associated with immunotherapy responses. However, whether TMB estimated by circulating tumor DNA in blood (bTMB) is associated with clinical outcomes of immunotherapy remains to be explored.

Objectives

To explore the optimal gene panel size and algorithm to design a CGP for TMB estimation, evaluate the panel reliability, and further validate the feasibility of bTMB as a clinical actionable biomarker for immunotherapy.

Design, Setting, and Participants

In this cohort study, a CGP named NCC-GP150 was designed and virtually validated using The Cancer Genome Atlas database. The correlation between bTMB estimated by NCC-GP150 and tissue TMB (tTMB) measured by WES was evaluated in matched blood and tissue samples from 48 patients with advanced NSCLC. An independent cohort of 50 patients with advanced NSCLC was used to identify the utility of bTMB estimated by NCC-GP150 in distinguishing patients who would benefit from anti–programmed cell death 1 (anti–PD-1) and anti–programmed cell death ligand 1 (anti–PD-L1) therapy. The study was performed from July 19, 2016, to April 20, 2018.

Main Outcomes and Measures

Assessment of the Spearman correlation coefficient between bTMB estimated by NCC-GP150 and tTMB calculated by WES. Evaluation of the association of bTMB level with progression-free survival and response to anti–PD-1 and anti–PD-L1 therapy.

Results

This study used 2 independent cohorts of patients with NSCLC (cohort 1: 48 patients; mean [SD] age, 60 [13] years; 15 [31.2%] female; cohort 2: 50 patients; mean [SD] age, 58 [8] years; 15 [30.0%] female). A CGP, including 150 genes, demonstrated stable correlations with WES for TMB estimation (median r ² = 0.91; interquartile range, 0.89-0.92), especially when synonymous mutations were included (median r ² = 0.92; interquartile range, 0.91-0.93), whereas TMB estimated by the NCC-GP150 panel found higher correlations with TMB estimated by WES than most of the randomly sampled 150-gene panels. Blood TMB estimated by NCC-GP150 correlated well with the matched tTMB calculated by WES (Spearman correlation = 0.62). In the anti–PD-1 and anti–PD-L1 treatment cohort, a bTMB of 6 or higher was associated with superior progression-free survival (hazard ratio, 0.39; 95% CI, 0.18-0.84; log-rank P = .01) and objective response rates (bTMB ≥6: 39.3%; 95% CI, 23.9%-56.5%; bTMB <6: 9.1%; 95% CI, 1.6%-25.9%; P = .02).

Conclusions and Relevance

The findings suggest that established NCC-GP150 with an optimized gene panel size and algorithm is feasible for bTMB estimation, which may serve as a potential biomarker of clinical benefit in patients with NSCLC treated with anti–PD-1 and anti–PD-L1 agents.