FDA Approves Pembrolizumab for TMB-High Tumors

The FDA has approved pembrolizumab (Keytruda) to treat adult and pediatric patients with unresectable or metastatic solid tumors that are tissue tumor mutational burden (TMB)–high (≥10 mutations/megabase) and have progressed following prior therapy and who have no satisfactory alternative treatment options.¹

The FDA has also approved the FoundationOneCDx assay, deveoped 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 several 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 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.

Pembrolizumab was administered intravenously at 200 mg every 3 weeks for 35 cycles or until progressive disease, unacceptable toxicity, or physician/patient choice. The main efficacy outcome measures included ORR and duration of response (DOR) in patients who had received at least 1 dose of pembrolizumab as evaluated by blinded independent central review in accordance with RECIST v1.1 criteria, which were modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The key secondary outcome measures progression-free survival (PFS), overall survival (OS), and safety.

Overall, there were 755 patients with evaluable TMB, 102 (13%) of whom had tumors that were classified as TMB-high. Results showed that the ORR with pembrolizumab in these patients was 29% (95% CI, 21-39), which was comprised of a 4% complete response rate and a 25% partial response rate. The median DOR had not been reached; more than half, or 57%, of patients experienced response durations of ≥12 months and half (50%) of patients had response durations of ≥24 months.

Previously reported data showed that the median PFS for the TMB-high group with pembrolizumab 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.² 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.

With regard to safety, adverse events (AEs) between those with TMB-high tumors who were enrolled on the trial were found to be comparable to those occurring in patients with other solid tumors who had received the PD-1 inhibitor. The most commonly reported AEs included fatigue, musculoskeletal pain, decreased appetite, pruritis, 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.

Additionally, prescribing information for the agent includes a “Limitation of Use” in that the safety and effectiveness of the drug in pediatric patients with TMB-high central nervous system cancers have not yet been established.

Data from the KEYNOTE-158 trial previously supported pembrolizumab’s initial tumor-agnostic approval.³ 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.

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.

References

1. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. News release. FDA. June 16, 2020. Accessed June 16, 2020. bit.ly/3el8pck.
2. Marabelle A, Fakih MG, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. Ann Oncol. 2019;30(suppl 5):11920. doi:10.1093/annonc/mdz253.018
3. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. News release. FDA. May 23, 2017. Accessed June 16, 2020. bit.ly/2UV9yzC.