Invited discussant Ursula A. Matulonis, MD, Chief of the Division of Gynecologic Oncology at Dana-Farber Cancer Institute, Boston, applauded the improved outcomes favoring lenvatinib/pembrolizumab in the confirmatory KEYNOTE-775 trial. “This represents the start of a new era in endometrial cancer drug development and improved patient outcomes,” she said.

Questions Remain

However, Dr. Matulonis thoughtit was important to question whether single-agent nonplatinum chemotherapy was the best control arm and whether 20 mg was an appropriate dose for lenvatinib. “It’s interesting that previous phase III trials have shown higher single-agent response rates with either doxorubicin or paclitaxel. There seemed to be lower response rates in the control arm of this study,” she said.

Ursula A. Matulonis, MD

Alternative options for the control arm could have included, for example, endocrine therapy for estrogen receptor–positive tumors, single-agent pembrolizumab for mismatch repair–deficient tumors, and reuse of platinum. There are emerging targeted agents such as inhibitors of cyclin-D kinases 4/6 for estrogen receptor–positive tumors and agents such as adavosertib, a tyrosine kinase inhibitor targeting WEE1, for uterine serous carcinomas that may serve as important treatment options in the future. She suggested that future clinical trials consider molecularly targeted agents that are appropriate for specific histologic and genetic features of the tumor.

Dosing Concerns

Commenting on the dosing of lenvatinib, Dr. Matulonis pointed out that 24 mg was found to be intolerable in a previous phase Ib trial, but doses less than 20 mg/d were not explored. In KEYNOTE-775, 66% of patients required dose reductions from 20 mg/d, 59% had doses held or interrupted, and 31% discontinued lenvatinib.

“The toxicity of this combination is significant, and I strongly recommend studying lenvatinib dosing based on factors such as weight, performance status, and comorbidities,” Dr. Matulonis said. “We need objective criteria for selecting the appropriate starting doses, to safely and effectively treat patients.” 

DISCLOSURE: Dr. Matulonis has received honoraria from Advaxis; has served as a consultant or advisor to Merck, NextCure, and Novartis; has received research funding from Fujifilm, ImmunoGen, Leap Therapeutics, Merck, Mersana, Novartis, SQZ Biotechnologies, Syndax, and Tesaro; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca.