Molecular Determinants of Response to Anti–Programmed Cell Death (PD)-1 and Anti–Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non–Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing

Abstract

Purpose Treatment of advanced non-small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known. Methods Detailed clinical annotation and response data were collected for patients with advanced non-small-cell lung cancer treated with anti-programmed death-1 or anti-programmed death-ligand 1 [anti-programmed cell death (PD)-1] therapy and profiled by targeted NGS (MSK-IMPACT; n = 240). Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and durable clinical benefit (DCB) was defined as partial response/stable disease that lasted > 6 months. Tumor mutation burden (TMB), fraction of copy number-altered genome, and gene alterations were compared among patients with DCB and no durable benefit (NDB). Whole-exome sequencing (WES) was performed for 49 patients to compare quantification of TMB by targeted NGS versus WES. Results Estimates of TMB by targeted NGS correlated well with WES (ρ = 0.86; P < .001). TMB was greater in patients with DCB than with NDB ( P = .006). DCB was more common, and progression-free survival was longer in patients at increasing thresholds above versus below the 50th percentile of TMB (38.6% v 25.1%; P < .001; hazard ratio, 1.38; P = .024). The fraction of copy number-altered genome was highest in those with NDB. Variants in EGFR and STK11 associated with a lack of benefit. TMB and PD-L1 expression were independent variables, and a composite of TMB plus PD-L1 further enriched for benefit to ICIs. Conclusion Targeted NGS accurately estimates TMB and elevated TMB further improved likelihood of benefit to ICIs. TMB did not correlate with PD-L1 expression; both variables had similar predictive capacity. The incorporation of both TMB and PD-L1 expression into multivariable predictive models should result in greater predictive power.

Ultraviolet light‐related DNA damage mutation signature distinguishes cutaneous from mucosal or other origin for head and neck squamous cell carcinoma of unknown primary site

“…Clinical trial subgroup analyses have suggested that these biomarkers are associated with improved response and survival in patients with mucosal SCC . Tumor mutational burden and PD‐L1 expression level are also both under active investigation as biomarkers of response to immunotherapy in other cancers such as lung cancers …”

Patient Selection for Anti-PD-1/PD-L1 Therapy in Advanced Non-Small-Cell Lung Cancer: Implications for Clinical Practice

“…Rizvi et al demonstrated that quantification of TMB by targeted next-generation sequencing correlated well with whole-exome sequencing and that TMB was greater in patients with durable clinical benefit than those without. Furthermore, combining TMB with PD-L1 expression provided greater predictive power and further enriched for benefit to anti-PD-1/PD-L1 therapy [32]. The recently reported CheckMate 227 trial showed that chemotherapy-naive patients with advanced NSCLC and a high TMB (≥10 mutations/Mb) treated with nivolumab plus ipilimumab experienced a longer PFS than the group treated with chemotherapy (7.2 vs 5.5 months; HR: 0.58, 97.5% CI: 0.41-0.81; p < 0.001).…”

Biliary Tract Cancer: Implicated Immune-Mediated Pathways and Their Associated Potential Targets

“…A study evaluated 240 patients with advanced NSCLC to review differences between patients who had durable clinical benefit versus no benefit with immune checkpoint inhibitors by performing targeted next generation sequencing as well as whole exome sequencing. It was noted that TMB was higher in patients who had a durable clinical benefit (p = 0.006), suggesting its significance as a potential predictive marker [58]. Data for TMB in BTC is limited.…”