Pembrolizumab plus lenvatinib induced a statistically significant and clinically meaningful improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy in patients with advanced endometrial cancer after prior systemic therapy in the phase 3 KEYNOTE-775/Study 309 trial.
The combination of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) induced a statistically significant and clinically meaningful improvement in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared with chemotherapy as treatment of patients with advanced endometrial cancer after prior systemic therapy in the phase 3 KEYNOTE-775/Study 309 clinical trial (NCT03517449), according to a press release from Merck and Esai, developers of the regimen.1
The companies plan to discuss the findings from this study with regulatory authorities around the globe with intentions of submitting marketing authorization applications based on these data. The full data will be presented at an upcoming medical meeting.
"Women with advanced endometrial cancer are faced with high mortality rates and limited treatment options following initial systemic therapy," said Gregory Lubiniecki, MD, associate vice president, Oncology Clinical Research, Merck Research Laboratories, in a statement. "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 versus chemotherapy. 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."
The dual primary end points of OS and PFS, as well as the secondary efficacy end point of ORR, were achieved with the combination of the anti-PD-1 therapy and lenvatinib, an orally available multiple receptor tyrosine kinase inhibitor. Investigators observed these positive results in both the mismatch repair proficient (pMMR) subgroup and the intention-to-treat (ITT) group, and this included both patients with endometrial cancer that is pMMR and those with microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR).
The combination also appeared to have a safety profile consistent with prior findings for the pembrolizumab plus lenvatinib regimen.
"We are encouraged by the data observed in KEYNOTE-775/Study 309, which represent a possible step forward for patients impacted by advanced endometrial carcinoma and support the results seen in the advanced endometrial cancer cohort of KEYNOTE-146/Study 111," stated Takashi Owa, vice president, chief medicine creation officer and chief discovery officer, Oncology Business Group at Eisai. "As more clinical data from the LEAP (LEnvatinib And Pembrolizumab) program are revealed, we cannot help but be energized by the trajectory of our collaboration with Merck and the benefits we hope to provide to patients together. Most importantly, we are grateful for the trust that the patients and healthcare professionals who participated in this trial have shown us."
The KEYNOTE-755/Study 309 trial is the confirmatory study for KEYNOTE-146/Study 111 (NCT02501096), which served as supportive data for the FDA’s accelerated approval of the combination regimen in 2019 for the treatment of patients with advanced endometrial carcinoma that are not MSI-H or dMMR, have disease progression following previous systemic therapy, and are not candidate for curative surgery or radiation therapy.
In KEYNOTE-146/Study 111, the ORR was 38.3% with the combination of lenvatinib and pembrolizumab per RECIST 1.1 criteria among patients with non-MSI-H/dMMR tumors, and the complete response and partial response rates, respectively, were 10.6% and 27.7%.2
The most common toxicities with the regimen included fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.
To be included in the multicenter, open-label, randomized phase 3 KEYNOTE-755/Study 309 trial, patients had to have a histologically confirmed diagnosis of endometrial carcinoma, documented evidence of advanced, recurrent, or metastatic disease, and radiographic evidence of disease progression 1 year following prior systemic, platinum-based chemotherapy. They also had to have at least 1 measurable target lesion according to RECIST 1.1 and an ECOG performance status of 0 or 1. Patients were ineligible if they had carcinosarcoma, unstable central nervous system metastases, or an active malignancy except for endometrial cancer.
Additional secondary end points included health-related quality of life, number of patients with adverse events (AEs), number of patients with serious AEs, number of patients with immune-related AEs, number of patients with treatment discontinuations due to AEs, and time to treatment failure due to treatment-emergent AEs.
1. Keytruda® (pembrolizumab) plus lenvima® (lenvatinib) combination demonstrated statistically significant improvement in overall survival, progression-free survival and objective response rate versus chemotherapy in patients with advanced endometrial cancer following prior systemic therapy in phase 3 study. News Release. Merck. December 16, 2020. Accessed December 16, 2020. https://yhoo.it/2WjJ8b6
2. Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20(5):711-718. doi: 10.1016/S1470-2045(19)30020-8.