Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers
Matteo Palmeri, Janice M. Mehnert, Ann W. Silk, Salma K. Jabbour, Shridar Ganesan, Pallvi Popli, Gregory Riedlinger, Ryan D. Stephenson, Alexandre Buckley de Meritens, Aliza Leiser, Tina Mayer, Nancy Chan, Kristen Spencer, Eugenia Girda, Jyoti Malhotra, Timothy A. Chan, Vivek Subbiah, Roman Groisberg
Abstract
•This retrospective study examined the real-world use of immune checkpoint inhibitors (ICIs) in TMB/MSI-high patients with a diverse set of cancer types.•TMB is an emerging tumor-agnostic biomarker for response to treatment with ICIs that may expand personalized cancer care.•ICIs remain underutilized as a first-line therapy for TMB/MSI-H patients without specific histologic approval for ICIs.•The PFS2 to PFS1 ratio was 4.7, favoring immunotherapy over chemotherapy even as a second-line therapy.•Our study reinforces the real-world evidence that TMB is a valid surrogate marker for MSI and can predict response to ICIs. IntroductionMicrosatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune checkpoint inhibitors. Pembrolizumab was recently approved by the Food and Drug Administration for use in TMB-high (TMB-H) tumors, regardless of histology, based on KEYNOTE-158. The primary objective of this retrospective study was real-world applicability and use of immunotherapy in TMB/MSI-high patients to lend credence to and refine this biomarker.MethodsCharts of patients with advanced solid tumors who had MSI/TMB status determined by next generation sequencing (NGS) (FoundationOne CDx) were reviewed. Demographics, diagnosis, treatment history, and overall response rate (ORR) were abstracted. Progression-free survival (PFS) was determined from Kaplan–Meier curves. PFS1 (chemotherapy PFS) and PFS2 (immunotherapy PFS) were determined for patients who received immunotherapy after progressing on chemotherapy. The median PFS2/PFS1 ratio was recorded.ResultsMSI-high or TMB-H [≥20 mutations per megabase (mut/MB)] was detected in 157 adults with a total of 27 distinct tumor histologies. Median turnaround time for NGS was 73 days. ORR for most recent chemotherapy was 34.4%. ORR for immunotherapy was 55.9%. Median PFS for patients who received chemotherapy versus immunotherapy was 6.75 months (95% confidence interval, 3.9-10.9 months) and 24.2 months (95% confidence interval, 9.6 months to not reached), respectively (P = 0.042). Median PFS2/PFS1 ratio was 4.7 in favor of immunotherapy.ConclusionThis real-world study reinforces the use of TMB as a predictive biomarker. Barriers exist to the timely implementation of NGS-based biomarkers and more data are needed to raise awareness about the clinical utility of TMB. Clinicians should consider treating TMB-H patients with immunotherapy regardless of their histology.