The combination of pembrolizumab and lenvatinib improved progression-free and overall survival, as well as response rates, compared with chemotherapy in patients with advanced endometrial cancer who received prior platinum-based chemotherapy, irrespective of mismatch repair status, according to phase 3 findings of the Study-309/KEYNOTE-775 trial.
The combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) improved progression-free and overall survival (OS), as well as response rates, compared with chemotherapy in patients with advanced endometrial cancer who received prior platinum-based chemotherapy, irrespective of mismatch repair (MMR) status, according to phase 3 findings of the Study-309/KEYNOTE-775 trial (NCT03517449) that were presented during the 2021 SGO Virtual Annual Meeting on Women’s Cancer.
In patients with MMR-proficient (pMMR) disease, the median OS was 17.4 months with pembrolizumab/lenvatinib compared with 12.0 months with chemotherapy at a median follow-up of 11.4 months (HR, 0.68; 95% CI, 0.56-0.84; P <.0001). In all-comers, the median OS was 18.3 months and 11.4 months, respectively (HR, 0.62; 95% CI, 0.51-0.75; P <.0001).
Results showed that the median PFS in patients with pMMR status was 6.6 months and 3.8 months with pembrolizumab/lenvatinib and chemotherapy, respectively (HR, 0.60; 95% CI, 0.50-0.72; P <.0001). In all-comers, the median PFS was 7.2 months with pembrolizumab/lenvatinib and 3.8 months with chemotherapy (HR, 0.56; 95% CI, 0.47-0.66; P <.0001).
“Lenvatinib plus pembrolizumab showed statistically significant and clinically meaningful improvements in overall survival, progression-free survival [PFS], and objective response rate [ORR] versus treatment of physician’s choice, regardless of MMR status in endometrial cancer following prior platinum-based chemotherapy,” lead study author Vicky Makker, MD, medical oncologist of Memorial Sloan Kettering Cancer Center, said in a virtual presentation of the data. “Benefits of PFS and OS were observed across all analyzed subgroups, including histology and number of prior therapies.”
There continues to be a high unmet need for effective treatments for patients with advanced/recurrent endometrial cancer, said Makker, adding that there are no standard second-line regimens following platinum-based chemotherapy.
Previously, checkpoint inhibitors have shown a benefit in patients with microsatellite instability–high/mismatch repair deficient tumors.
In prior phase 2 data of the Study 111/KEYNOTE-146 trial, the combination of lenvatinib and pembrolizumab showed efficacy and a manageable safety profile in previously treated patients with advanced/recurrent endometrial carcinoma.
In the phase 3 Study-309/KEYNOTE-775 trial, investigators compared the efficacy and safety of pembrolizumab and lenvatinib with physician’s choice of doxorubicin or paclitaxel following platinum-based therapy in patients with advanced or recurrent endometrial cancer. Patients were randomized 1:1 to receive oral lenvatinib at 20 mg daily and pembrolizumab at 200 mg intravenously (IV) every 3 weeks (n = 411) or doxorubicin at 60 mg/m2 IV every 3 weeks or paclitaxel at 80 mg/m2 IV weekly on a 3-weeks-on/1-week-off schedule (n = 416). Treatment was given until disease progression or unacceptable toxicity.
To be eligible for enrollment, patients had to have advanced, metastatic, or recurrent endometrial cancer, have measurable disease by blinded independent central review (BICR), received 1 prior platinum-based chemotherapy, had an ECOG performance status of 0 or 1, and had tissue available for MMR testing.
Patients were stratified by MMR status, and also further stratification within pMMR by region (European, US, Canada, Australia, New Zealand, and Israel vs rest of the world), ECOG performance status (0 vs 1), and prior history of pelvic radiation (yes vs no).
The primary end points were PFS by BICR and OS; secondary end points were ORR, health-related quality of life, pharmacokinetics, and safety. Duration of response (DOR) was a key exploratory end point.
The data cutoff date for the final PFS and interim OS analysis was October 26, 2020, which was approximately 8.5 months after the last patient was randomized. PFS and OS were both evaluated using a stratified log-rank test.
The median age was 64.5 years, most patients (84.3%) had pMMR status, and 41.25% of patients had a prior history of pelvic radiation. A total 58.9% of patients had an ECOG performance status of 0, and 61.3% of patients were White. Histologies were broken down into high-grade endometrioid carcinoma (22.3%), low-grade (13.7%), or not specified (24.2%); serous carcinoma (26.4%); clear cell carcinoma (5.7%); and mixed (4.6%). Most patients (69.5%) had received 1 prior line of treatment; 77.5% had 1 prior line of platinum-based treatment and 57.4% received prior neoadjuvant and/or adjuvant treatment.
Additional findings showed that the PFS and OS benefit with pembrolizumab/lenvatinib was observed across prespecified patient subgroups, including age, race, region, MMR status, ECOG status, prior history of pelvic radiation, histology, and prior lines of therapy.
In the pMMR chort, the ORRs with pembrolizumab/lenvatinib and chemotherapy was 30.3% and 15.1%, respectively (P <.0001). In the pembrolizumab/lenvatinib arm, this comprised a complete response (CR) rate of 5.2%, and a partial response (PR) rate of 25.1%; these rates were 2.6% and 12.5%, respectively, with chemotherapy. Also, with pembrolizumab/lenvatinib, 48.6% of patients had stable disease (SD) and 15.6% of patients had progressive disease (PD); 0.6% and 4.9% of patients were not evaluable/assessed. In the chemotherapy arm, 2.0% and 12.5% of patients were not evaluable/assessed.
The median DOR was 9.2 months and 5.7 months with pembrolizumab/lenvatinib and chemotherapy, respectively, in the pMMR cohort. The median time to response was 2.1 months (range, 1.5-9.4) with pembrolizumab/lenvatinib and 3.5 months (range, 1.0-7.4) with chemotherapy.
In the all-comers population, the ORRs were 31.9% and 14.7% with pembrolizumab/lenvatinib and chemotherapy, respectively (P <.0001); the CR rates were 6.6% and 2.6%, respectively, and the PR rates were 25.3% and 12.0%, respectively. In the pembrolizumab/lenvatinib arm, 47.0% of patients had SD and 14.8% had PD; with chemotherapy, these rates were 40.1% and 29.6%, respectively. Finally, 1.2% and 5.1% of patients on pembrolizumab/lenvatinib were unevaluable/not assessed compared with 1.9% and 13.7% in the chemotherapy arm.
Here, the median DOR was 14.4 months with pembrolizumab/lenvatinib and 5.7 months with chemotherapy. The median time to response was 2.1 months in both arms.
The median duration of treatment was more than 50% longer with pembrolizumab/lenvatinib at 231 days (range, 1-817) compared with 104.5 days (range, 1-785) with chemotherapy. However, grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 88.9% of lenvatinib/pembrolizumab–treated patients and 72.7% of those on chemotherapy. A total 66.5% and 12.9% of patients on lenvatinib/pembrolizumab and chemotherapy, respectively, had TEAEs that led to dose reductions.
Any-grade TEAEs that led to dose interruptions occurred in 69.2% and 27.1% of those on pembrolizumab/lenvatinib and chemotherapy, respectively; 58.6% of patients discontinued lenvatinib alone, 50.0% discontinued pembrolizumab, and 30.8% of patients discontinued both drugs due to any-grade TEAEs.
The most common TEAEs (≥25%) in the all-comer population with pembrolizumab/lenvatinib were hypertension (64.0%), hypothyroidism (57.4%), diarrhea (54.2%), nausea (49.5%), and decreased appetite (44.8%). With chemotherapy, the most common TEAEs were anemia (48.7%), nausea (46.1%), and neutropenia (33.8%).
Grade 3 or higher TEAEs that were most commonly reported with pembrolizumab/lenvatinib (88.9%), were hypertension (37.9%), weight decrease (10.3%), decreased appetite (7.9%), and diarrhea (7.6%). In the chemotherapy arm, grade 3 or higher TEAEs occurred in 72.7% of patients, the most common of which was neutropenia (25.8%).
Regardless of causality, grade 5 AEs occurred in 5.7% of patients on pembrolizumab/lenvatinib, 21% of which were related to gastrointestinal disorders. The rate of grade 5 AEs was 4.9% in the chemotherapy arm, 30% of which were due to infections, Makker added.
“Lenvatinib plus pembrolizumab had a manageable safety profile that is generally consistent with the established safety profile that is generally consistent with the established safety profiles of the individual monotherapies,” Makker concluded.
Makker V, Colombo N, Herráez AC, et al. A multicenter, open-label, randomized, phase 3 sdtudy 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. Presented at: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 19-26, 2021; virtual.