Lenvima-Keytruda Combo Maintains Positive Results in Advanced Endometrial Cancer

Combination therapy with Lenvima (lenvatinib) and Keytruda (pembrolizumab) continues to show promising antitumor results in patients with advanced endometrial cancer, the most common cancer of the uterus, according to the final results of the KEYNOTE-146/Study 111 trial.

The combo was generally well-tolerated, and no new safety signals emerged. A Phase 3 confirmatory trial called KEYNOTE-775 (NCT03517449) is underway, with enrollment open at sites in the U.S., Norway and Spain.

The final results were presented at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain, on Sept. 29. Titled “Lenvatinib (LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC),” the presentation was given by medical oncologist Vicky Makker of Memorial Sloan Kettering Cancer Center, the study’s principal investigator.

Lenvima-Keytruda was recently approved in the U.S. for the treatment of women with advanced endometrial cancer whose tumors do not carry certain genetic defects, whose disease progressed after prior treatment with systemic therapy, and who are not candidates for curative surgery or radiation. Women may not be prescribed the combination therapy if their tumors are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

Under Project Orbis, an initiative of the U.S. Food and Drug Administration Oncology Center of Excellence, the Lenvima-Keytruda combination was simultaneously approved in Australia and Canada.

Following its breakthrough therapy designation by the FDA in 2018, marketing authorization was granted under accelerated approval in September 2019. For the combo to maintain this indication, the therapeutic effects would need to be confirmed in further trials.

The approval was based on data from KEYNOTE-146/Study 111 (NCT02501096), a Phase 1b/2, multicenter, open-label trial that enrolled 108 patients with metastatic — spread to other parts in the body — endometrial cancer, who were previously treated by at least one systemic therapy.

During the trial, participants were treated with Lenvima capsules, 20 mg once per day, and injected into the vein with Keytruda 200 mg, every three weeks. The median follow-up was 18.7 months.

Among the 108 patients, 94 had tumors that were not MSI-H or dMMR, 11 had tumors that were MSI-H or dMMR, and three had tumors of unknown status.

Results showed that at 24 weeks, 41 patients in total (38% of participants) had experienced a reduction in tumor size, regardless of the genetic status of their tumors (MSI-H/dMMR positive or not). At data cut-off in January 2019, eight women (7.4%) had a complete response — that is, their tumors completely disappeared to undetectable levels. Overall, responses lasted for a median of 21.2 months.

Among participants whose cancers had MSI-H or dMMR status (off-label indication), the tumors shrunk in seven out of 11 patients (63.6%) at week 24. At data cutoff, one of these women had experienced a complete disappearance of the cancer. Response duration was the same as in the overall population.

The median time participants lived without getting worse, called progression-free survival, was 18.9 months. The women’s median overall survival was not reached — meaning more than half of the patients were still alive.

Among patients whose tumors were not MSI-H or dMMR, 34 women (36.2%) experienced a response to the combination at week 24, and 7.4% had a complete response. The median progression-free survival was 5.4 months, while patients lived without cancer growth for a median of 16.4 months.

As to safety, adverse events related to treatment occurred in 105 out of 108 patients (97%). Most adverse events — 90% — were mild to severe, while 7% were life-threatening or associated with death. The most common treatment-related adverse events, serious or worse, were hypertension (32%), fatigue (8%), and diarrhea (7%).

These side effects led to treatment interruption of Keytruda, Lenvima, or both in 78 patients, and to tapering of Lenvima’s dose in 70 women.

“The results of this Keytruda plus Lenvima study are a welcome development in the treatment of women with advanced endometrial cancer, a patient group with an unmet medical need,” Makker,  the ESMO presenter, said in a press release.

Lenvima is an inhibitor of specific cellular enzymes known as kinases, which are associated with blood vessel formation, tumor growth, and progression. It is sold by Eisai and approved, on its own or in combination, to treat certain types of thyroid, kidney, and liver cancer, as well as endometrial cancer.

Keytruda is an anti-PD-1 therapy sold by Merck KGaA (known as EMD Serono in the U.S. and Canada) and approved for the treatment of multiple solid and blood cancers. It is an immunotherapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells.