In the first report from the pivotal phase III KEYNOTE-775/Study 309 trial, the combination of lenvatinib and pembrolizumab significantly improved multiple outcomes compared to standard single-agent chemotherapy in patients with advanced, metastatic, or recurrent endometrial cancer that had progressed after a prior platinum-based regimen.
The study was reported at the opening scientific Plenary Session of the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer, held virtually, by Vicky Makker, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York (Abstract ID 11512).
Vicky Makker, MD
KEYNOTE-775/Study 309 met the dual primary endpoints assessed by blinded independent central review—progression-free and overall survival—as well as the secondary endpoint of objective response rate in the all-comer population (mismatch repair proficient [pMMR] and mismatch repair deficient [dMMR]) and in the pMMR subgroup. Lenvatinib/pembrolizumab was also favored over treatment of physician’s choice (doxorubicin or paclitaxel) in all evaluated subgroups.
“Lenvatinib/pembrolizumab showed a statistically significant and clinically meaningful improvement in overall survival, progression-free survival, and objective response rate vs treatment by physician’s choice, regardless of MMR status, in patients with endometrial cancer progressing after prior platinum-based therapy,” commented Dr. Makker.
KEYNOTE-775/Study 309 is the confirmatory trial for KEYNOTE-146/Study 111, which supported the U.S. Food and Drug Administration’s 2019 accelerated approval of the combination in patients who have advanced endometrial carcinoma that is not dMMR or microsatellite instability–high (MSI-H) with disease progression following systemic therapy and are not candidates for curative surgery or radiotherapy.
Study Details
The study enrolled 827 patients with advanced, metastatic, or recurrent endometrial cancer that had progressed after one prior platinum-based regimen. Patients could have received two regimens if one was given in the neoadjuvant or adjuvant setting.
Of the 827 patients, 697 patients had tumors that were pMMR, and 130 patients had tumors that were dMMR. Patients were randomly assigned 1:1 to receive either:
- Pembrolizumab at 200 mg intravenously every 3 weeks for up to 35 cycles in combination with lenvatinib at 20 mg orally once daily
- Chemotherapy treatment of physician’s choice consisting of either doxorubicin at 60 mg/m2 every 3 weeks up to a maximum cumulative dose of 500 mg/m2, or paclitaxel at 80 mg/m2 on a 28-day cycle.
Dual Primary Endpoints Met
At a median follow-up of 11.4 months, in the all-comer population, lenvatinib plus pembrolizumab reduced the risk of disease progression or death by 44% (P < .0001) and the risk of death by 38%, based on the following outcomes in the experimental vs standard arms:
- Median progression-free survival: 7.2 months vs 3.8 months (hazard ratio [HR] = 0.56, P < .0001)
- Median overall survival: 18.3 months vs 11.4 months (HR = 0.63, P < .0001).
Dr. Makker commented that the 38% reduction in risk of death regardless of MMR status in all comers with advanced, metastatic, or recurrent endometrial carcinoma “is very encouraging, as this arm included an investigational patient population for which more data have been sought by the gynecologic oncology community.”
Objective response rates among all comers were 31.9% with lenvatinib/pembrolizumab vs 14.7% with physician’s choice of treatment; complete responses were observed in 6.6% and 2.6%, respectively (P < .0001), and median duration of response was 14.4 months vs 5.7 months.
Within the all-comer subgroups, comparable benefits in progression-free and overall survival were observed by age, race, region, MMR status, history of pelvic radiation, histology, and prior lines of therapy.
Lenvatinib/pembrolizumab showed a statistically significant and clinically meaningful improvement in overall survival, progression-free survival, and objective response rate vs treatment by physician’s choice, regardless of MMR status, in patients with endometrial cancer progressing after prior platinum-based therapy.— Vicky Makker, MD
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A similar benefit was seen in the analysis of the pMMR population, where the combination reduced the risk of disease progression or death by 40% (P < .0001) and death by 32% (P < .0001), she added.
No New Safety Signals
The safety profile of the doublet was generally consistent with the established safety profiles of the individual monotherapies. Treatment-related grade ≥ 3 events were observed in 88.9% of the combination arm and 72.7% of the chemotherapy arm. Hypertension was, by far, the most common toxicity reported in patients on lenvatinib/pembrolizumab and was grade ≥ 3 in 37.9%.
Median treatment duration was 231 days with the combination and 104.5 days with chemotherapy.
Disclosure: Dr. Makker disclosed financial relationships with Merck, Eisai, Karyopharm, AstraZeneca, Clovis, Mereo, Takeda, Zymeworks, and Genentech.
