SUMMARY: Tumor Mutational Burden (TMB) is a measure of the somatic mutation rate within a tumor genome and is emerging as a quantitative indicator for predicting response to Immune Checkpoint Inhibitors such as KEYTRUDA®, across a wide range of malignancies. These non-synonymous somatic mutations in the tumor genome generate larger number of neo-antigens which are more immunogenic. Immune Checkpoint Inhibitors are able to unleash the immune system to detect these neoantigens and destroy the tumor. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/Megabase as High and less than 10 mutations/Megabase as Low. (A megabase is 1,000,000 DNA basepairs). KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1 monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response, and unleashing the tumor-specific effector T cells.
The authors in this publication prospectively explored the association of high tissue TMB with outcomes, following treatment with KEYTRUDA®, in patients with selected, previously treated, advanced solid tumors. KEYNOTE-158 is a multicenter, multicohort, non-randomized, open-label, Phase II basket trial investigating the antitumor activity and safety of KEYTRUDA® in multiple advanced solid tumors. Eligible patients had advanced unresectable or metastatic solid tumors (Anal, Biliary, Cervical, Endometrial, Mesothelioma, Neuroendocrine, Salivary, Small-cell lung, Thyroid, and Vulvar), who had progressed on, or were intolerant to one or more lines of standard therapy, had measurable disease, as well as tumor sample available for biomarker analysis.
This study enrolled 1073 patients of whom 1,050 patients were included in the efficacy analysis and TMB was analyzed in the subset of 790 patients, with sufficient tissue for testing. Of these 790 patients, 102 patients (13%) had tumors identified as TMB-High, defined 10 or more mutations /Megabase. TMB status was assessed in Formalin-Fixed Paraffin-Embedded tumor samples using the FoundationOne® CDx assay. Patients received KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles. The median age in this study population of 102 patients was 61 years, ECOG PS was 0-1, and 56% of patients had at least 2 prior lines of therapy. Tumor response was assessed every 9 weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) in the patients who received at least one dose of KEYTRUDA®. The key Secondary outcome measures included Progression Free Survival (PFS), Overall Survival (OS), and safety. The median study follow up was 37.1 months.
In the 102 patients whose tumors were TMB-H, KEYTRUDA® demonstrated an ORR of 29%, with a Complete Response rate of 4% and a Partial Response rate of 25%. The ORR in the non-TMB-High group was 6%. The median duration of response was not reached in the TMB-H group and was 33.1 months in those without high TMB, at the time of data cutoff. There was low correlation between TMB and PD-L1 expression. The most common adverse reactions for KEYTRUDA® were fatigue, decreased appetite, rash, pruritus, fever, nausea, diarrhea, cough, dyspnea, constipation, abdominal pain and musculoskeletal pain.
The authors concluded that high Tumor Mutational Burden status identifies a subgroup of patients who could have a robust tumor response to KEYTRUDA® monotherapy . They added that tissue TMB therefore could be a novel and useful predictive biomarker for response to KEYTRUDA® monotherapy in patients with previously treated recurrent or metastatic advanced solid tumors.
Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Marabelle A, Fakih MG, Lopez J, et al. Lancet Oncol. 2020;21:1353-1365.