Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers

Abstract

Introduction Microsatellite 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. Methods Charts 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. Results MSI-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. Conclusion This 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.

Point of Care Molecular Testing: Community-Based Rapid Next-Generation Sequencing to Support Cancer Care

“…Biomarker results are often the rate-limiting step in initiating systemic therapy, particularly in diseases such as NSCLC. Previous studies from our group have showed the turnaround time of send-out testing to be as long as 64 days, with in-sourced rapid single-gene testing delivered with a turnaround of 4 days, and that this reduction in turnaround time is associated with reductions in time to systemic therapy initiation [9,12]. This study demonstrates that comprehensive NGS can also be offered rapidly, within 3 business days.…”

“…This approach to testing is costly and creates a lengthy and convoluted pathway to gaining complete biomarker data, which in turn can lead to delays in treatment [7,8]. One recent study reported a median turnaround time of 73 days using this approach [9].…”

Diagnostic Validation of a Comprehensive Targeted Panel for Broad Mutational and Biomarker Analysis in Solid Tumors

“…Next to PD-L1 expression, MSI and TMB are biomarkers that have shown clinical utility in predicting response to immunotherapy [4,5]. Upon the inactivation of mismatch repair genes, DNA replication errors accumulate and result in a high number of neoepitopes that stimulate the immune response.…”

Multi-Level Analysis and Identification of Tumor Mutational Burden Genes across Cancer Types

“…Thirdly, the process of immune cell infiltration is complex, and some oncogenic pathways of driving mutations [ 51 ] or virus infections may also influence the activation of the immune response [ 56 ]. Thus, experimental validation will be needed in future work [ 57 , 58 ].…”