FDA Approves Pembrolizumab for TMB-High Solid 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—high (≥10 mutations/megabase) and have progressed following prior therapy and who have no satisfactory alternative treatment options.

The approval is based in part on the phase 2 KEYNOTE-158 trial, 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.

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 end point 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.

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.

This article was originally published on OncLive as, "FDA Approves Pembrolizumab for TMB-High Tumors."