FDA Approves Pembrolizumab for TMB-High Solid Tumors

"KEYNOTE-158 has confirmed clinical activity of pembrolizumab in tumors harboring a TMB ≥10 across a variety of solid tumors including anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small cell lung, thyroid, and vulvar cancers."

The FDA has approved pembrolizumab (Keytruda) 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 have no satisfactory alternative treatment options.1,2

This marks the second tumor-agnostic approval for pembrolizumab, which is also approved for the treatment of patients with microsatellite instability–high (MSI-H) or mismatch repair deficient solid tumors.

“KEYNOTE-158 has confirmed clinical activity of pembrolizumab in tumors harboring a TMB ≥10 (TMB-High) across a variety of previously treated solid tumors including anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small cell lung, thyroid, and vulvar cancers. A response rate of 29% (versus 6% in patients with a TMB <10) in this biomarker-defined population is quite impressive, especially given the refractory nature of their disease. When limiting the analysis to the TMB high, non–MSI-H patients, the response rate was still 4-fold that of the non-MSI-H group (24% vs 6%),” investigator Marwan G. Fakih, MD, professor, Department of Medical Oncology & Therapeutics Research; medical director, Judy & Bernard Briskin Center for Clinical Research; co-director, Gastrointestinal (GI) Cancer Program; and section head, GI Medical Oncology, City of Hope, told Targeted Oncology

This new indication for pembrolizumab was granted under accelerated approval and may be contingent upon verification of clinical benefit in confirmatory trials.2

The FDA also approved the FoundationOneCDx assay as a companion diagnostic for pembrolizumab to identify patients who TMB high solid tumors who may benefit from the immunotherapy.1

The approval is based off of findings from an analysis of 10 cohorts of patients with various previously treated unresectable or metastatic solid tumors and high TMB from the ongoing phase 2 KEYNOTE-158 trial, which is exploring the use of the PD-1 inhibitor in patients with advanced solid tumors. These patients were compared with 652 patients who did not have high TMB.

Tissue TMB was assessed using the FoundationOne CDx assay and TMB-H status was defined as at least 10 mutations/megabase. All patients received 200 mg of intravenous pembrolizumab every 3 weeks until unacceptable toxicity or disease progression.

Among the patients with TMB-H tumors (n=102), the most common tumor types were small cell lung cancer (34.3%), cervical (16.2%, endometrial (15.2%), and anal (14.1%). The most common tumor types were mesothelioma (12.7%), neuroendocrine (12.3%), salivary (12.0%), and endometrial (10.3%) in the non–TMB-H group.

The overall response rate was 29% (95% CI, 21%-39%) with complete responses in 4% of patients and partial responses in 25%. The median duration of response (DOR) has not yet been reached, but 57% of patients had responses lasting at least 1 year and 50% having responses lasting at least 2 years.

According to prior data presented at the 2019 ESMO Annual Congress, among the patients with TMB-H tumors, the objective response rate (ORR) was 30.3% (95% CI, 21.5%-40.4%); the complete response rate was 4.0% and the partial response rate was 26.3%. The median DOR was not reached. The ORR when excluding patients with MSI-H tumors was 27.1% and was 6.7% in the patients with non–TMB-H tumors.

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

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

A low correlation was found between tissue TMB status and PD-L1 expression (P = .18).

“I believe the FDA made the right decision to approve pembrolizumab based on these findings. However, much still needs to be learned regarding the extent of benefit within each of these tumor types and others,” Fakih added. “The non–MSI-H high TMB (≥10) group data was based on only 105 patients across 10 diseases. The ability to accurately estimate the benefits from treatment within each of these tumor types with TMB ≥10 is quite limited and will require further study. In addition, more data is needed in other solid tumors that were not the subject of study on KEYNOTE-158."

Safety findings in the TMB-H population were consistent with the known toxicity profile for pembrolizumab.

Common immune-mediated adverse events observed with pembrolizumab treatment include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Severe or life-threatening infusion-related reactions have also been reported with pembrolizumab.

“As physicians, we are always looking to find new options for patients, especially in the second-line or higher treatment setting,” said Roy S. Herbst, MD, PhD, ensign professor of medicine (medical oncology) and professor of pharmacology, Yale School of Medicine; chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital; and associate cancer center director for translational research, Yale Cancer Center, in a statement. “It’s great to see the use of innovative biomarkers and immunotherapy come together with this approval and encouraging that we now have an option for patients with TMB-H tumors across cancer types, including rare cancers.”


1. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. News release. FDA. June 17, 2020. Accessed June 17, 2020. https://bit.ly/30QEt40

2. FDA Approves Second Biomarker-Based Indication for Merck’s KEYTRUDA® (pembrolizumab), Regardless of Tumor Type. News release. Merck. June 17, 2020. Accessed June 17, 2020. https://bit.ly/3frQfWq

3. 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. 2019;30(suppl_5):v475-v532. doi: 10.1093/annonc/mdz253