Lenvatinib-pembrolizumab improves OS, PFS in advanced endometrial carcinoma regardless of DNA MMR status

The combination of lenvatinib and pembrolizumab improved progression-free survival (PFS) and overall survival (OS) compared with physician’s choice of treatment (TPC) among patients with advanced endometrial cancer with prior exposure to platinum-based therapy, regardless of DNA mismatch repair (MMR) status, according to results of a phase III study presented at IGCS 2021.

The multicentre, open-label Study 309/KEYNOTE-775 trial involved 827 patients with advanced endometrial cancer who had previously received platinum-based therapy*. They were randomized 1:1 to receive oral lenvatinib (20 mg QD) plus intravenous (IV) pembrolizumab (200 mg Q3W) or TPC (IV doxorubicin [60 mg/m² Q3W] or paclitaxel [80 mg/m² QW on a 3-weeks-on, 1-week-off schedule]). Of these, 697 and 130 were DNA MMR proficient (pMMR) and deficient (dMMR), respectively. Patients in the lenvatinib-pembrolizumab and TPC groups were followed up for a median 12.2 and 10.7 months, respectively.

PFS was significantly improved with lenvatinib-pembrolizumab vs TPC both in the overall population (median 7.2 vs 3.8 months; hazard ratio [HR], 0.56, 95 percent confidence interval [CI], 0.47–0.66) and among those who were pMMR (median 6.6 vs 3.8 months; HR, 0.60, 95 percent CI, 0.50–0.72; p<0.0001 for both). [IGCS 2021, abstract O008]

OS was also significantly improved with the lenvatinib-pembrolizumab vs TPC combination, both in the overall (median 18.3 vs 11.4 months; HR, 0.62, 95 percent CI, 0.51–0.75; p<0.0001) and the pMMR populations (median 17.4 vs 12.0 months; HR, 0.68, 95 percent CI, 0.56–0.84; p=0.0001).

Objective response rate (ORR) was also significantly better among patients in the lenvatinib-pembrolizumab compared with the TPC group (overall: 31.9 percent vs 14.7 percent; pMMR: 30.3 percent vs 15.1 percent; p<0.0001 for both). Median duration of response (DoR) was 14.4 vs 5.7 months for lenvatinib-pembrolizumab vs TPC in the overall population and 9.2 vs 5.7 months in the pMMR population.

Patients on lenvatinib-pembrolizumab and TPC received treatment for a median 231 and 104.5 days, respectively.

Any-grade treatment-emergent adverse event (TEAE) rates were comparable between lenvatinib-pembrolizumab and TPC recipients, with grade ≥3 TEAEs reported in 89 and 73 percent, respectively.

The most common TEAEs in the lenvatinib-pembrolizumab arm were hypertension (64 percent), hypothyroidism (57 percent), diarrhoea (54 percent), and nausea (50 percent). Among lenvatinib-pembrolizumab recipients, 30.8 percent discontinued lenvatinib, 18.7 percent pembrolizumab, and 14.0 percent both, due to TEAEs.

Findings evident in dMMR population

The 130 patients who were dMMR, 65 each in the lenvatinib-pembrolizumab and TPC groups, were followed up for a median 13.5 and 8.8 months, respectively.

PFS was significantly improved with lenvatinib-pembrolizumab vs TPC (median 10.7 vs 3.7 months; HR, 0.36, 95 percent CI, 0.23–0.57), as was OS (median not reached vs 8.6 months; HR, 0.37, 95 percent CI, 0.22–0.62; p<0.0001 for both). [IGCS 2021, abstract O002]

ORR was also greater with lenvatinib-pembrolizumab vs TPC (40.0 percent vs 12.3 percent; p=0.0002). Disease control rate was improved in the lenvatinib-pembrolizumab vs TPC group (73.8 percent vs 47.7 months). Among responders, DoR was longer with lenvatinib-pembrolizumab compared with TPC (median not reached vs 4.1 months).

Ninety-five and 73 percent of patients in the lenvatinib-pembrolizumab and TPC groups, respectively, experienced grade ≥3 TEAEs.

Benefits regardless of DNA MMR status

“Lenvatinib plus pembrolizumab demonstrated statistically significant and clinically meaningful improvements in PFS, OS, and ORR vs TPC in patients with advanced endometrial cancer … irrespective of MMR status,” said study author Dr Vicky Makker from Memorial Sloan Kettering Cancer Center, New York, US, and co-authors.

The OS and PFS benefits of lenvatinib-pembrolizumab were observed across all subgroups analysed including histology and number of prior therapies, and there were no between-group differences pertaining to health-related quality of life, she noted.