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Lenvatinib/Pembrolizumab Improves Survival in Advanced Endometrial Cancer


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In the first report from the pivotal phase III KEYNOTE-775/Study 309 trial, the combination of lenvatinib, a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3 kinases, and pembrolizumab significantly improved multiple outcomes compared with standard single-agent chemotherapy in patients with advanced, metastatic or recurrent endometrial cancer progressing after a prior platinum-based regimen.

The randomized study of 827 patients met the dual primary endpoints assessed by blinded independent central review—progression-free survival and overall survival—as compared with physician’s choice of treatment (doxorubicin or paclitaxel). It also met the secondary endpoint of objective response rate in the all-comer population (which included patients with mismatch repair–proficient [pMMR] and mismatch repair–deficient [dMMR] tumors) and in the pMMR subgroup, reported Vicky Makker, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, at the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer, held virtually.1

Vicky Makker, MD

Vicky Makker, MD

“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 endometrial cancer patients 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 with advanced endometrial carcinoma that is not dMMR or microsatellite instability–high (MSI-H), who have disease progression following systemic therapy and are not candidates for curative surgery or radiation therapy.

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); lenvatinib could be continued beyond this point if the patient was deriving benefit.
  • Chemotherapy of physician’s choice 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. 

Progression-free survival and overall survival were the primary endpoints. The statistical design called for progression-free survival to be tested first in the pMMR population, then in all comers, followed by overall survival and objective response rate for pMMR patients and then all comers. 

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 vs 3.8 months (hazard ratio [HR] = 0.56; P < .0001)
  • Median overall survival: 18.3 vs 11.4 months (HR = 0.63; P < .0001). 

Dr. Makker noted that the progression-free survival Kaplan-­Meier curves separated early, around the time of the first radiologic assessment. Similarly, the overall survival curves diverged by around 3 months, “despite informal crossover.” 

She further commented that the 38% reduction in risk of death regardless of MMR status in this population “is very encouraging, as this arm included an investigational patient population for whom more data have been sought by the gynecologic oncology community.” 

Lenvatinib/pembrolizumab led to a doubling in response rate: 31.9% vs 14.7% with physician’s choice of treatment (complete responses, 6.6% vs 2.6%; P < .0001). The median duration of response was 14.4 months vs 5.7 months, respectively.

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. The pMMR subgroup experienced a similar benefit as all comers with the combination vs standard therapy:

  • Median progression-free survival: 6.6 vs 3.8 months (HR = 0.60; P < .0001)
  • Median overall survival: 17.4 vs 12.0 months (HR = 0.68; P = .0001) 
  • Objective response rate: 30.3% (5.2% complete response rate) vs 15.1% (2.6% complete response rate; P < .0001) 
  • Median duration of response: 9.2 vs 5.7 months. 

The safety profile of the doublet was generally consistent with the established safety profiles of the individual monotherapies. Median treatment duration was doubled in the experimental arm: 231 vs 104 days with single-agent chemotherapy. 

In all comers, treatment-related adverse events leading to discontinuation of therapy were observed in 18.7% with pembrolizumab, 30.8% with lenvatinib, 14.0% with both, vs 8.0% with chemotherapy. Treatment-related grade ≥ 3 events were seen in 88.9% and 72.7%, respectively. Hypertension was, by far, the most common toxicity in patients receiving lenvatinib/pembrolizumab and was grade ≥ 3 in 37.9%. 

DISCLOSURE: Dr. Makker has received honoraria from Eisai, IBM Watson, Karyopharm Therapeutics, and Merck; has served as a consultant or advisor to ArQule, Eisai, GlaxoSmithKline, IBM Watson, Karyopharm, Merck, and Takeda; has received institutional research funding from AstraZeneca, Bristol Myers Squibb, Eisai, Karyopharm Therapeutics, Lilly, Merck, and Takeda; has been reimbursed for travel, accommodations, or other expenses by Eisai, Karyopharm Therapeutics, and Merck; and has held other relationships with IBM.

REFERENCE

1. Makker V , Colombo N, Casado Herráez A, et al: A multicenter, open-label, randomized phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: Study 309/KEYNOTE-775. Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer. Abstract 37/ID 11512. Presented March 19, 2021. 

 


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