Microsatellite-Stable Tumors with High Mutational Burden Benefit from Immunotherapy

Abstract

Programmed death receptor-1/ligand 1 (PD-1/L1) antibodies can induce durable remissions in malignancies. However, response rates are only ~10–20% in unselected patients versus ~50% in microsatellite instability-high (MSI-high) tumors, probably related to high tumor mutational burden (TMB). Pembrolizumab is approved for MSI-high or deficient mismatch repair tumors. However, outside of colorectal and endometrial carcinoma, only a small subset of tumors are MSI-high, making this treatment option unavailable to most patients. It is not known if MSIstable tumors with high TMB respond to PD-1/PD-L1 blockade. Next generation sequencing (NGS) was performed on 60 patients (14 different histologies) treated with checkpoint blockade using the FoundationOne assay to determine the TMB and MSI status. TMB was dichotomized into two groups; low-to-intermediate (0–19 mutations/mb) vs. high (≥20 mutations/mb). . Benefit rate (stable disease for ≥6 months and partial or complete response) was determined:2,179 of 148,803 samples (1.5%) were MSI-high; 9,762 (6.6%), TMB-high (7,972, MS-stable/TMB-high). The majority (82.1%) of MSI-H tumors were TMB-high; however, only 18.3% of TMB-high tumors were MSI-H. Median progression-free survival for MS-stable/TMB-high versus MS-stable/TMB-Low/TMB-Intermediate tumors was 26.8 vs. 4.3 months (P = 0.0173). Thus, our data demonstrate that MS-stable/TMB-high tumors are more common than MSI-high cancers and may benefit from immunotherapy.