December 16, 2020 - Pembrolizumab/lenvatinib has significantly improved survival and responses compared with chemotherapy in patients with advanced endometrial cancer who have received previous systemic treatment.
The combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) has led to a statistically significant improvement in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared with chemotherapy in patients with advanced endometrial cancer who have received previous systemic treatment, meeting the dual primary end points and secondary end point of the phase 3 KEYNOTE-775 trial (Study 309; NCT03517449).1
The benefit with the regimen was reported in the intention-to-treat population and the subgroup of patients with mismatch repair proficient (pMMR)–disease, which comprise patients with endometrial carcinoma that is pMMR and those with microsatellite instability–high/mismatch repair deficient (dMMR) disease.
The safety profile of pembrolizumab/lenvatinib proved to be consistent with what has previously been reported with the agents.
Merck and Eisai plan to share these data with regulatory authorities on a global scale. The pharmaceutical companies have also announced the intention to submit marketing authorization applications based on the positive findings and plans to share the results at an upcoming medical conference.
“These are the first results from a phase 3 trial of a combination regimen including immunotherapy in advanced endometrial carcinoma that have shown a statistically significant improvement in OS, PFS, and ORR vs chemotherapy,” Gregory Lubiniecki, MD, associate vice president of Oncology Clinical Research at Merck Research Laboratories, stated in a press release. “Merck and Eisai are dedicated to continuing to research the [pembrolizumab] plus [lenvatinib] combination and discover new approaches to address unmet needs for devastating diseases such as endometrial carcinoma.”
In the multicenter, open-label phase 3 trial, investigators sought to evaluate pembrolizumab plus lenvatinib vs physician’s choice of doxorubicin or paclitaxel in the treatment of patients with advanced endometrial cancer.
To be eligible for enrollment, patients had to be at least 18 years of age, have advanced endometrial cancer that progressed following 1 prior platinum-based treatment, have measurable disease per RECIST v1.1 criteria, and have an ECOG performance status of 0-1. Patients also had to have mismatch repair status that was confirmed by central laboratory through immunohistochemistry on either archived or fresh tumor biopsy.2,3
A total of 827 patients were enrolled to the trial; of these patients, 697 had tumors that were determined to be non–MSI-H or pMMR, while 130 had tumors that were either MSI-H or dMMR. In the trial, participants were randomized 1:1 to receive either intravenous (IV) pembrolizumab at 200 mg every 3 weeks for up to 35 treatment cycles for about 2 years in combination with oral lenvatinib at a daily dose of 20 mg or physician’s choice of chemotherapy. If patients received doxorubicin, they received an IV dose of 60 mg/m2 every 3 weeks for up to a maximum cumulative dose of 500 mg/m2. Those who received IV paclitaxel were given a dose of 80 mg/m2 on a 28-day treatment cycle, with 3 weeks of receiving weekly paclitaxel and 1 week of not receiving the agent.1
The co-primary end points of the trial were OS and PFS, as evaluated by blinded independent central review (BICR) per RECIST v1.1 criteria, while key secondary end points comprised ORR by BICR per RECIST v1.1, as well as safety and tolerability.
KEYNOTE-775 was the confirmatory trial for KEYNOTE-146/Study 111, results of which supported the September 2019 FDA approval of pembrolizumab/lenvatinib for use in patients with advanced endometrial carcinoma that is not MSI-H or dMMR and who have disease progression after previous systemic treatment but are not eligible for curative surgery or radiation.
Among 94 patients with endometrial cancer that were not MSI-H or dMMR, the ORR was 38.3%; this comprised a complete response (CR) rate of 10.6% (n = 10) and a 27.7% partial response (PR) rate (n = 26). Sixty-nine percent (n = 25) of patients experienced a duration of response that persisted for at least 6 months.4
Common adverse effects reported in the trial included fatigue, high blood pressure, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, and stomatitis. Additional toxicities comprised vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, plamar-plantar erythrodysesthesia, dyspnea, cough, and rash.
Previously, in August 2019, the FDA granted a breakthrough therapy designation to the combination for use in patients with advanced and/or metastatic non–MSI-H/proficient mismatch repair endometrial carcinoma who progressed following 1 or more prior systemic therapy. The decision was on interim data from the phase 1b/2 basket KEYNOTE-146/Study 111 trial, in which the doublet elicited an ORR of 45.3% at week 24 per independent radiology review in the 53-patient endometrial carcinoma subgroup.5 The overall ORR was 47.2%, which comprised 3 CRs and 25 PRs.