Microsatellite-Stable Tumors with High Mutational Burden Benefit from Immunotherapy

Area of Science:

• Oncology
• Immunotherapy
• Genomics

Background:

• Programmed death receptor-1/ligand 1 (PD-1/L1) antibodies show durable responses in malignancies.
• Response rates are limited in unselected patients but higher in microsatellite instability-high (MSI-high) tumors, linked to high tumor mutational burden (TMB).
• Pembrolizumab is approved for MSI-high tumors, but most cancers are not MSI-high, limiting treatment access.

Purpose of the Study:

• To investigate if microsatellite-stable (MS-stable) tumors with high TMB respond to PD-1/L1 blockade.
• To determine the prevalence and clinical benefit of TMB as a biomarker in MS-stable cancers.

Main Methods:

• Next-generation sequencing (NGS) was used to assess TMB and MSI status in 60 patients with 14 different histologies treated with checkpoint blockade.
• TMB was categorized as low-to-intermediate (0-19 mutations/mb) or high (≥20 mutations/mb).
• Benefit rate was defined as stable disease for ≥6 months, partial response, or complete response.

Main Results:

• 1.5% of samples were MSI-high, and 6.6% were TMB-high; 7,972 samples were MS-stable/TMB-high.
• While most MSI-high tumors were TMB-high (82.1%), only 18.3% of TMB-high tumors were MSI-high.
• Median progression-free survival was significantly longer for MS-stable/TMB-high tumors (26.8 months) compared to MS-stable/TMB-low/intermediate tumors (4.3 months), P = 0.0173.

Conclusions:

• MS-stable tumors with high TMB are more prevalent than MSI-high cancers.
• High TMB in MS-stable tumors is associated with improved outcomes with PD-1/L1 blockade immunotherapy.
• TMB may serve as a predictive biomarker for immunotherapy response in a broader patient population.