FDA Grants Regular Approval to Pembrolizumab Plus Lenvatinib for Advanced Endometrial Carcinoma

The FDA has granted a regular approval to pembrolizumab (Keytruda) plus lenvatinib (Lenvima) for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation.^1,2

The combination was previously granted an accelerated approval in September 2019, for use in patients with advanced endometrial carcinoma.³ At the time, the decision was based on findings from a study comprised of 94 patients with endometrial carcinoma who were not MSI-H or dMMR. The combination induced an overall response rate (ORR) of 38.3% in these patients, which included a complete response (CR) rate of 10.6% (n = 10) and a partial response (PR) rate of 27.7% (n = 26). A duration of response (DOR) of 6 months or longer was reported in 69% (n = 25) of participants.

The decision to convert the accelerated approval to a regular approval is based on updated data from the phase 3 KEYNOTE-775/Study 309 trial (NCT03517449), in which the doublet was found to significantly improve overall survival (OS) and progression-free survival (PFS) vs investigator's choice of chemotherapy in the form of doxorubicin or paclitaxel.

The median OS achieved with pembrolizumab/lenvatinib was 17.4 months (95% CI, 14.2-19.9) vs 12.0 months (95% CI, 10.8-13.3) with chemotherapy, translating to a 32% reduction in the risk of death (HR, 0.68; 95% CI, 0.56-0.84; P = .0001). Moreover, the median PFS in the investigative and control arms was 6.6 months (95% CI, 5.6-7.4) and 3.8 months (95% CI, 3.6-5.0), respectively; this translated to a 40% reduction in the risk of disease progression or death (HR, 0.60; 95% CI, 0.50-0.72; P < .0001) vs chemotherapy.

The combination also elicited an ORR of 30% (95% CI, 26%-36%) vs 15% (95% CI, 12%-19%) with chemotherapy; the CR rates in the investigator and control arms were 5% and 3%, respectively, and the PR rates were 25% and 13%, respectively. The median DOR with the doublet was 9.2 months (range, 1.6+ to 23.7+) vs 5.7 months (range, 0.0+ to 24.2+) with chemotherapy.

“With a five-year survival rate of just 17%, women with advanced endometrial cancer who are not candidates for curative therapy, particularly those with disease progression following prior systemic therapy, have limited treatment options,” Vicky Makker, MD, principal investigator and medical oncologist, Memorial Sloan Kettering Cancer Center, stated in a press release. “This approval is an important step forward in helping patients fight this difficult-to-treat malignancy, as physicians can now provide an option that may improve survival outcomes.”

The multicenter, open-label, randomized phase 3 trial enrolled a total of 827 patients with advanced endometrial carcinoma who received prior treatment with at least 1 prior platinum-based chemotherapy regimen in any setting, including neoadjuvant and adjuvant treatments.

If patients had endometrial sarcoma, including carcinosarcoma, or they had active autoimmune disease or a medical condition that required immunosuppression, they were excluded.

Moreover, patients with endometrial carcinoma that were not MSI-H or dMMR were stratified according to ECOG performance status, geographic region, and history of pelvic radiation.

Study participants were randomized 1:1 to receive either pembrolizumab at 200 mg every 3 weeks plus lenvatinib at 20 mg once daily or investigator's choice of either doxorubicin at 60 mg/m2 every 3 weeks or weekly paclitaxel at 80 mg/m² given 3-weeks-on/1-week-off.

The key efficacy outcome measures included PFS per blinded independent central review (BICR) and OS. Additional efficacy outcome measures included BICR-assessed ORR and DOR.

Regarding safety, the adverse effects that were most frequently experienced by 20% or more of patients in the trials of pembrolizumab plus lenvatinib included hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia and rash.

“When compared to the chemotherapies used in this trial, this combination treatment regimen was proven to extend the lives of certain patients diagnosed with previously treated, advanced endometrial cancer,” Gregory Lubiniecki, MD, vice president of Oncology Clinical Research at Merck Research Laboratories, stated in a press release. “Based on phase 3 data, today’s approval acts as the confirmatory trial to our previous accelerated approval of [pembrolizumab] plus [lenvatinib] in patients with certain types of advanced endometrial cancer and reinforces the impact of our joint research with Eisai in exploring the potential of this combination to treat more patients with challenging types of cancer.”

References

1. FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. News release. FDA. July 22, 2021. Accessed July 22, 2021. https://bit.ly/3wRB9Sw
2. FDA approves KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) combination for patients with certain types of advanced endometrial carcinoma. News release. Merck. July 22, 2021. Accessed July 22, 2021. https://bwnews.pr/3y0k5ee
3. Simultaneous review decisions for pembrolizumab plus lenvatinib in Australia, Canada and US. News release. FDA. September 17, 2019. Accessed July 22, 2021. https://bit.ly/3izkxcZ