Subbiah Tempers Concerns Regarding Pembrolizumab Approval in TMB-High Solid Tumors

October 8, 2020

Partner | Cancer Centers

In our exclusive interview, Vivek Subbiah, MD, discusses the FDA approval of pembrolizumab in tumor mutational burden–high solid tumors, shares the “transformative importance” of the regulatory decision, and speaks to the controversy surrounding the approval.

Welcome to a very special edition of OncLive® On Air! I’m your host today, Caroline Seymour.

OncLive On AirTM is a podcast from OncLive, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, OncLive covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

Today, we had the pleasure of speaking with Vivek Subbiah, MD, associate professor in the Investigational Cancer Therapeutics Department and center clinical medical director of the Clinical Center for Targeted Therapy, of the Cancer Medicine Division, at The University of Texas MD Anderson Cancer Center, to discuss the FDA approval of pembrolizumab (Keytruda) in tumor mutational burden (TMB)–high solid tumors.

One June 16, 2020, the FDA approved pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that are TMB-high, defined as 10 or more mutations/megabase, and have progressed following prior therapy and who have no satisfactory alternative treatment options. The FDA also approved the FoundationOneCDx assay, developed by Foundation Medicine, as a companion diagnostic for pembrolizumab.

The approval is based in part on data from a prospectively planned, retrospective analysis of 10 cohorts of patients with previously treated, unresectable or metastatic, TMB-high solid tumors who were enrolled on the phase 2 KEYNOTE-158 trial. In this trial, a link was established between TMB-high status and improved overall response rate (ORR) with the PD-1 inhibitor in patients with various solid tumors.

The multicenter, multicohort, nonrandomized, open-label trial enrolled patients with anal, biliary, cervical, endometrial, salivary, thyroid, or vulvar carcinoma, mesothelioma, a neuroendocrine tumor, or small cell lung cancer.

Among 102 patients who had tumors that were classified as TMB-high, the ORR with pembrolizumab was 29% (95% CI, 21-39). The median duration of response had not been reached; 57% of patients experienced response durations of 12 months or greater and 50% of patients had response durations of 24 months or greater.

In the TMB-high group, the 12-month progression-free survival and overall survival rates were 24.3% and 48.0%.

With regard to safety, the most commonly reported adverse effects (AEs) included fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. The agent is also associated with immune-related AEs, such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and adverse skin reactions.

Although some have welcomed the approval to the armamentarium, others have questioned the merits of the approval. In response, Subbiah and colleagues published an editorial in the Annals of Oncology explaining the basis for the approval.

In our exclusive interview, Subbiah shared the “transformative importance” of the FDA approval of pembrolizumab in TMB-high solid tumors.


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