FDA grants regular approval to Keytruda-Lenvima combination for endometrial carcinoma
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The FDA granted regular approval to the combination of pembrolizumab and lenvatinib for certain women with advanced endometrial carcinoma that is not microsatellite instability-high or mismatch repair deficient.
The approval applies to use of the agent by women whose disease progressed after systemic therapy in any setting and who are not candidates for curative surgery or radiation.
The agency had granted accelerated approval to the combination for this indication in September 2019. Continued approval was contingent upon verification and description of clinical benefit.
The FDA based the approval on results of the randomized phase 3 KEYNOTE-775/Study 309 trial, which included 697 women with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen who had disease that was not microsatellite instability-high or mismatch repair deficient.
Researchers randomly assigned 346 women to the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) dosed at 200 mg via IV every 3 weeks plus lenvatinib (Lenvima, Eisai) — a multiple receptor tyrosine kinase inhibitor — dosed at 20 mg orally once daily. The other 351 women received investigator’s choice of doxorubicin dosed at 60 mg/m2 every 3 weeks (n = 254) or paclitaxel dosed at 80 mg/m2 weekly in a 3-weeks-on, 1-week-off schedule (n = 97).
OS and PFS as assessed by blinded independent central review served as major efficacy outcomes.
Patients assigned the pembrolizumab-lenvatinib combination achieved significantly longer PFS (HR = 0.6; 95% CI, 0.5-0.72) and OS (HR = 0.68; 95% CI, 0.56-0.84) compared with investigator’s choice of chemotherapy. The combination also induced a higher objective response rate (30% vs. 15%).
“With a 5-year survival rate of just 17%, women with advanced endometrial cancer who are not candidates for curative therapy — particularly those with disease progression following prior systemic therapy — have limited treatment options,” researcher Vicky Makker, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, said in a Merck-issued press release. “This approval is an important step forward in helping patients fight this difficult-to-treat malignancy, as physicians can now provide an option that may improve survival outcomes.”
Fatal adverse reactions occurred among 4.7% of women assigned the pembrolizumab-lenvatinib combination. These included two cases of pneumonia and one case each of acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism and right ventricular dysfunction.
Fifty percent of women assigned the combination experienced serious adverse reactions. These included hypertension (4.4%) and urinary tract infections (3.2%).
The most common adverse events among women assigned the combination included hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%) and urinary tract infection (31%).
Fifteen percent of women discontinued pembrolizumab due to an adverse event and 26% discontinued lenvatinib for the same reason.
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