FDA Grants Priority Review to Pembrolizumab Monotherapy for TMB-High Tumors

The FDA granted priority review to pembrolizumab monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic TMB-high solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options.

The FDA granted priority review to a new supplemental biologics license application (sNDA) for pembrolizumab (Keytruda), according to Merck, the agent’s developer.1

The sNDA is seeking accelerated approval of pembrolizumab monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors with tissue tumor mutational burden-high (TMB-H) ≥10 mutations/megabase, as determined by an FDA-approved test, who have progressed following prior treatment and who have no satisfactory alternative treatment options.

The FDA set a prescription drug user fee act (PDUFA) date of June 16, 2020.

“From the start, biomarker research has been a critical aspect of our clinical program evaluating Keytruda monotherapy,” Scott Ebbinghaus, MD, vice president of clinical research at Merck, said in a press release.2 “TMB has been an area of scientific interest to help identify patients most likely to benefit from Keytruda. We look forward to working with the FDA throughout the review process to help bring Keytruda monotherapy to patients with cancer in the second-line or higher treatment setting, where options remain limited.”

The application was based, in part, on results from the phase II KEYNOTE-158 trial, which evaluated pembrolizumab in patients with solid tumors. The trial also supported the 2017 FDA approval of pembrolizumab as the first cancer treatment based on a biomarker, regardless of cancer type, in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors.

Data from the KEYNOTE-158 trial on the TMB-H patient population were presented at the European Society for Medical Oncology (ESMO) 2019 Congress.

In the study, tissue TMB was assessed using the FoundationOne CDx assay.2 Moreover, TMB-H status was defined as at least 10 mutations/megabase and all patients received 200 mg of intravenous pembrolizumab every 3 weeks.

Of the patients who were evaluable for tissue TMB status in the trial, 99 (13.2%) had TMB-high tumors. These patients were then followed for a median of 11.7 months (range, 0.5-33.0), and their outcomes were compared with 652 patients with non-TMB-H tumors who were followed for a median of 13.1 months (range, 0.4-34.3).

In the TMB-H group, 65.7% of patients had positive PD-L1 expression, and 14.1% had microsatellite instability—high (MSI-H) tumors. Further, all but 1 patient had received prior therapy in the recurrent or metastatic setting, and 12 patients had received at least 4 prior regimens.

The most common tumor types identified in the TMB-H group were small cell lung cancer (34.3%), cervical (16.2%), endometrial (15.2%), and anal (14.1%). Comparably, the most common tumor types found in the non-TMB-H group were mesothelioma (12.7%), neuroendocrine (12.3%), salivary (12.0%), and endometrial (10.3%).

An overall response rate (ORR) of 30.3% (95% CI, 21.5%-40.4%) was achieved in the TMB-H group, which included complete responses in 4.0% and partial responses in 26.3%. Stable disease was also observed in 14.1%. When patients with MSI-H tumors were excluded, the ORR was 27.1%, and in the non-TMB-H group, the ORR was 6.7%. However, the median duration of response was not reached in either group.

Median progression-free survival (PFS) in both groups was 2.1 months. At 1 year, the PFS rates were 26.4% and 14.1% in the TMB-H and non—TMB-H groups, respectively, and at 2 years the rates were 18.9% and 6.5%.

Additionally, the median overall survival (OS) was found to be higher in the non-TMB-H group at 13.0 months (95% CI, 11.5-14.6) compared with 11.7 months (95% CI, 8.2-19.1) in the TMB-H group. At 1 year, the OS rates were 49.1% for the TMB-H population and 52.5% for the non-TMB-H patients, and at 2 years the OS rates were 34.5% and 31.1%, respectively.

The safety findings in this study population were consistent with previously observed toxicity profiles for pembrolizumab.


1. Merck Receives Priority Review from FDA for Second Application for KEYTRUDA (pembrolizumab) Based on Biomarker, Regardless of Tumor Type [news release]. Kenilworth, NJ. Published April 7, 2020. mrknewsroom.com/news-release/oncology-newsroom/merck-receives-priority-review-fda-second-application-keytruda-pembro. Accessed April 7, 2020.

2. Marabelle A., Fakih M, Lopez J, et al. Association of Tumor Mutational Burden with Outcomes in Patients with Select Advanced Solid Tumors Treated with Pembrolizumab in KEYNOTE-158. Ann Oncol. doi:10.1093/annonc/mdz253.