Pembrolizumab Plus Lenvatinib Misses Both Survival End Points in Advanced, Recurrent Endometrial Cancer

The combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) failed to produce a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) vs platinum-based chemotherapy with carboplatin and paclitaxel as frontline therapy in patients with advanced or recurrent endometrial cancer whose disease in mismatch repair proficient (pMMR)/not microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR/MSI-H), according to findings from the final analysis of the phase 3 LEAP-001 trial (NCT03884101).¹

The safety profile of the combination was consistent with that seen in prior trials evaluating the regimen. Full evaluation of the data from the trial is ongoing and will be completed prior to sharing the results with the scientific community. Results from LEAP-001 will not affect any current approved indications for the combination or other ongoing clinical trials from the LEAP program.

“We remain confident in the proven benefit of [pembrolizumab] plus [lenvatinib] for the treatment of appropriate patients with certain types of previously treated advanced endometrial carcinoma based on results from the KEYNOTE-775/Study 309 trial and will continue to research the [pembrolizumab] plus [lenvatinib] combination in patients with other types of difficult-to-treat cancers,” Dr Gregory Lubiniecki, vice president, Global Clinical Development, Merck Research Laboratories, stated in a news release. “We are disappointed that the LEAP-001 trial did not reach its primary endpoints, as we had hoped to bring another potential treatment option to patients when first diagnosed with certain types of advanced or recurrent endometrial carcinoma.”

Earlier findings from the single-arm, phase 1b/2 KEYNOTE-146/Study 111 trial (NCT02501096) showed that the combination of pembrolizumab and lenvatinib led to high response rates in patients with advanced endometrial cancer who had received at least 2 prior lines of therapy. Subsequently, the regimen demonstrated improved PFS and OS vs chemotherapy in the phase 3 KEYNOTE-775/Study 309 trial (NCT03517449) in patients with advanced endometrial cancer who had received between 1 and 2 lines of prior therapy, including in the neoadjuvant or adjuvant setting.²

In July 2021, the FDA granted full approval to the combination for patients with advanced endometrial carcinoma that is not MSI-H/dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation based on findings from KEYNOTE-775.³

To be eligible for enrollment in the LEAP-001 trial patients had to have stage III, IV, or recurrent, histologically confirmed and radiographically visible endometrial cancer; an ECOG performance status of 0 or 1; adequately controlled blood pressure within 7 days prior to randomization; and adequate organ function within 7 days prior to the first dose of study therapy. Regarding prior therapy, patients could have received prior chemotherapy only if it had been given concurrently with radiation; prior radiation without concurrent chemotherapy; prior hormonal therapy for the treatment of endometrial carcinoma if it was discontinued at least 1 week prior to randomization; and 1 prior line of systemic platinum-based adjuvant and/or neoadjuvant chemotherapy.⁴

PFS, one of the dual primary end points of the randomized, open-label, phase 3 LEAP-001 trial, was evaluated by blinded independent central review (BICR) per RECIST v1.1 criteria modified to follow up to 10 target lesions and at most, 5 target lesions per organ. Secondary end points included BICR-assessed objective response rate per RECIST v1.1 criteria, quality of life, and safety.¹

Approximately 842 patients were randomly assigned to receive 200 mg of intravenous (IV) pembrolizumab on day 1 of every 3-week cycle plus 20 mg of oral lenvatinib once daily; or 175 mg/m2 of IV paclitaxel on day of every 3-week cycle plus an IV infusion of carboplatin at a total dose of area under the curve 6 per Calvert’s formula on day 1 of each 3-week cycle.

“Results from the LEAP-001 trial underscore the challenges of treating patients with advanced or recurrent endometrial carcinoma in the first-line setting,” Dr Corina Dutcus, senior vice president, Oncology Global Clinical Development Lead at Eisai Inc, said. “We remain optimistic about the clinical development program for [pembrolizumab] plus [lenvatinib] and are proud that the combination has become a standard of care option for patients with certain types of advanced or recurrent endometrial carcinoma whose disease has progressed following prior systemic therapy and will continue our efforts to contribute to these patients. We are grateful to the patients, their loved ones, and the investigators whose participation is what makes scientific advancement possible.”

References

1. Merck and Eisai provide update on phase 3 LEAP-001 trial evaluating KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) as first-line treatment for patients with advanced or recurrent endometrial carcinoma. News release. Merck. December 8, 2023. Accessed December 15, 2023. https://www.merck.com/news/merck-and-eisai-provide-update-on-phase-3-leap-001-trial-evaluating-pembrolizumab-plus-lenvima-lenvatinib-as-first-line-treatment-for-patients-with-advanced-or-recurrent-endometrial-carcinom/
2. Marth C, Tarnawski R, Tyulyandina A, et al. Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. Int J Gynecol Cancer. 2022;32(1):93-100. doi:10.1136/ijgc-2021-003017
3. FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. FDA. July 21, 2021. Accessed December 15, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-pembrolizumab-and-lenvatinib-advanced-endometrial-carcinoma
4. Pembrolizumab (MK-3475) plus lenvatinib (E7080/MK-7902) versus chemotherapy for endometrial carcinoma (ENGOT-en9 / MK-7902-001) (LEAP-001). ClinicalTrials.gov. Updated November 2, 2023. Accessed December 15, 2023. https://www.clinicaltrials.gov/study/NCT03884101