FDA Grants Pembrolizumab Priority Review for TMB-High Tumors

The FDA has granted a priority review designation to pembrolizumab for the treatment of patients with unresectable or metastatic solid tumors with tissue tumor mutational burden-high status.

The FDA has granted a priority review designation to pembrolizumab (Keytruda) for the treatment of patients with unresectable or metastatic solid tumors with tissue tumor mutational burden-high (TMB-H) status (≥10 mutations/megabase), as determined by an FDA-approved test, who have progressed following prior treatment and who have no satisfactory alternative treatment options.1

UPDATE 6/16/20: FDA Approves Pembrolizumab for TMB-High Tumors

The pembrolizumab application is based in part on the phase II KEYNOTE-158 trial,2 in which 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.

Under the Prescription Drug User Fee Act, the FDA is scheduled to decide on the application on or before June 16, 2020.

“From the start, biomarker research has been a critical aspect of our clinical program evaluating Keytruda monotherapy,” Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, stated in a press release. “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 multicenter, multicohort, nonrandomized, open-label KEYNOTE-158 trial accrued patients with anal, biliary, cervical, endometrial, salivary, thyroid, or vulvar carcinoma, mesothelioma, a neuroendocrine tumor, or small cell lung cancer. Patients had to have an ECOG performance status of 0 or 1 and have progressed on or be intolerant to at least 1 prior line of standard treatment. The investigators used the FoundationOne CDx assay to assess TMB in FFPE tumor samples, with 10 Mut/Mb used as the threshold for TMB-high status.

Overall, there were 755 patients with evaluable TMB, of whom 120 (15.9%) were TMB-high. Of these 120 patients, 15 (12.5%) were microsatellite instability-high (MSI-H). The investigators reported that baseline characteristics were comparable between patients with either TMB-high or -low status. The correlation was low between TMB and PD-L1 expression (P  = .19).

Pembrolizumab was administered at 200 mg every 3 weeks for 35 cycles or until progressive disease, unacceptable toxicity, or physician/patient choice. The primary endpoint was ORR, with key secondary outcome measures being duration of response, progression-free survival (PFS), overall survival (OS), and safety.

For TMB-high patients, the ORR was 28.3% (95% CI, 20.5-37.3), including 24.8% (95% CI, 16.9-34.1) in non—MSI-H patients. In TMB-low patients the ORR was 6.5% (95% CI, 4.7-8.7). The median duration of response was not reached in either the TMB-high (range, 2.2+ to 28.8+) or TMB-low (4.1 to 30.6+) groups.

The median PFS for the TMB-high group was 2.1 months (95% CI, 2.1-3.7), and was also 2.1 months (95% CI, 2.1-2.3) in the TMB-low cohort. The 12-month PFS rates were 24.3% versus 14.0%, respectively.

The median OS was 11.1 months (95% CI, 8.1-16.1) in the TMB-high group, compared with 13.3 months (95% CI, 11.5-14.8) in the TMB-low group. The 12-months OS rates were 48.0% versus 52.9%, respectively.

There were no new safety signals compared with earlier published research with pembrolizumab.

Data from the KEYNOTE-158 trial previously supported pembrolizumab’s initial tumor-agnostic approval. In May 2017, pembrolizumab was approved for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-H or mismatch repair deficient (dMMR) solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR colorectal cancer following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.3

The approval was based on data from 149 patients with MSI-H or dMMR cancers enrolled across 5 single-arm clinical trials, one of which was KEYNOTE-158. Ninety patients had colorectal cancer (CRC) and the remaining 59 patients had 1 of 14 other tumor types.

The ORR with pembrolizumab was 39.6% (95% CI, 31.7-47.9), including 11 (7.4%) complete responses and 48 (32.2%) partial responses. The ORR was 36% in patients with CRC and 46% in patients with other tumor types. The median duration of response was not yet reached (range, 1.6+ months to 22.7+ months). Among patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 months.


  1. Merck Receives Priority Review from FDA for Second Application for KEYTRUDA® (pembrolizumab) Based on Biomarker, Regardless of Tumor Type. Published April 7, 2020. https://www.mrknewsroom.com/news-release/oncology-newsroom/merck-receives-priority-review-fda-second-application-keytruda-pembro. Accessed April 7, 2020.
  2. Marabelle A, Fakih MG, 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 (2019) 30 (suppl_5): v475-v532. 10.1093/annonc/mdz253
  3. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. Published May 23, 2017.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication. Accessed April 7, 2020.