Lenvatinib + pembrolizumab improves survival in advanced endometrial cancer

In patients with advanced endometrial cancer with prior platinum chemotherapy exposure, a combination of lenvatinib + pembrolizumab improved survival compared with physician’s choice of treatment (TPC), results of the phase III Study 309/KEYNOTE-775 trial showed.

A total of 827 patients with advanced, metastatic, or recurrent endometrial cancer, prior exposure to platinum-based therapy*, and ECOG performance score 0–1 were randomized 1:1 to receive oral lenvatinib (20 mg QD) + intravenous (IV) pembrolizumab (200 mg Q3W for ≤35 doses) or TPC (IV paclitaxel 80 mg/m² QW [3-weeks-on, 1-week-off] or doxorubicin 60 mg/m² Q3W [maximum cumulative dose 500 mg/m²]). Of these, 697 and 130 were DNA mismatch repair-proficient (pMMR) and -deficient (dMMR), respectively.

Baseline characteristics (age, race, ECOG status, and prior pelvic radiation exposure) were comparable between groups. Endometrioid carcinoma was the most common histology (~60 percent), followed by serous carcinoma. 

Median follow-up for the lenvatinib + pembrolizumab group was 12.2 months, and 10.7 months for the TPC group.

Progression-free survival (PFS) was significantly longer with lenvatinib + pembrolizumab compared with TPC in both the pMMR (median 6.6 vs 3.8 months; hazard ratio [HR], 0.60, 95 percent confidence interval [CI], 0.50–0.72) and the overall population (median 7.2 vs 3.8 months; HR, 0.56, 95 percent CI, 0.47–0.66; p<0.0001 for both). [SGO 2021, abstract 11512]

There was also a significant improvement in overall survival (OS) with lenvatinib + pembrolizumab compared with TPC in both the pMMR (median 17.4 vs 12.0 months; HR, 0.68, 95 percent CI, 0.56–0.84; p=0.0001) and overall populations (median 18.3 vs 11.4 months; HR, 0.62, 95 percent CI, 0.51–0.75; p<0.0001).

The PFS and OS benefits with lenvatinib + pembrolizumab over TPC were consistent in various subgroups analysed including histology and number of prior treatments.

Objective response rate (ORR) was twofold in the lenvatinib + pembrolizumab vs TPC group in the pMMR (30.3 percent vs 15.1 percent) and overall population (31.9 percent vs 14.7 percent; p<0.0001 for both). Complete and partial response rates were also twofold in the lenvatinib + pembrolizumab vs TPC groups in both the pMMR and overall populations. Median duration of response was 9.2 vs 5.7 months (pMMR) and 14.4 vs 5.7 months (overall), while median time to response was 2.1 vs 3.5 months in the pMMR population and 2.1 months in both groups in the overall population.

Patients in the lenvatinib + pembrolizumab and TPC groups were treated for a median 231 and 104.5 days, respectively.

Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 88.9 and 72.7 percent of patients in the lenvatinib + pembrolizumab and TPC groups, respectively. TEAE-related dose reductions occurred in 66.5 and 12.9 percent, respectively, and discontinuations in 33.0 and 8.0 percent, respectively.

Among lenvatinib + pembrolizumab recipients, 30.8 percent of patients discontinued lenvatinib, 18.7 percent discontinued pembrolizumab, and 14.0 percent discontinued both drugs due to TEAEs. The most frequently occurring TEAEs (≥25 percent) in this group were hypertension, hypothyroidism, diarrhoea, and nausea (64.0, 57.4, 54.2, and 49.5 percent, respectively).

“Lenvatinib + pembrolizumab had a manageable safety profile that is generally consistent with the established safety profiles of the individual monotherapies,” said study author Dr Vicky Makker from Memorial Sloan Kettering Cancer Center, New York, New York, US, at SGO 2021.

“There continues to be a high unmet need for development of effective therapies to treat advanced/recurrent endometrial cancer and no standard second-line treatment as yet has been identified following platinum-based chemotherapy,” noted Makker.

“[In this trial,] lenvatinib + pembrolizumab showed statistically significant and clinically meaningful improvements in OS, PFS, and ORR versus TPC, regardless of MMR status in endometrial cancer following prior platinum-based chemotherapy,” she concluded.