A multicenter, open-label, randomized, phase III study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer

Abstract

<h3>Objectives:</h3> Results from a phase 1b/2 study showed lenvatinib (LEN) + pembrolizumab (pembro) has efficacy in patients (pts) with advanced endometrial carcinoma following prior treatment. Here, we describe the phase III study results of LEN + pembro vs treatment of physician's choice (TPC) following platinum-based therapy in pts with advanced endometrial cancer (aEC). <h3>Methods:</h3> Pts were randomized (1:1) to receive LEN 20 mg orally QD + pembro 200 mg IV Q3W or TPC (doxorubicin at 60 mg/m² IV Q3W or paclitaxel at 80 mg/m² IV QW [3 weeks on; 1 week off]). Eligible pts had aEC with 1 prior platinum-based chemotherapy regimen or up to 2 prior platinum-based chemotherapy regimens, if 1 was given in the neoadjuvant/adjuvant setting. Randomization was stratified by DNA mismatch repair (MMR) status (centrally determined); pts with proficient (p)MMR tumors were further stratified by ECOG PS, geographic region, and prior history of pelvic radiation. Primary endpoints were PFS by blinded independent central review per RECIST v1.1 and OS. Key secondary endpoints included objective response rate (ORR) and safety. A graphical approach for multiplicity to control for type 1 error was used to test PFS for pts with pMMR aEC, then pts irrespective of MMR tumor status (ie, all comers), followed by OS (pMMR aEC, then all comers) and ORR (pMMR aEC, then all comers). Efficacy analyses were conducted in randomized pts; safety analyses were conducted in pts who received treatment. <h3>Results:</h3> A total of 827 Pts (pMMR, n=697; dMMR, n=130) received LEN + pembro (n=411) or TPC (n=416). Median follow-up was 12.2 mo for pts randomized to LEN + pembro and 10.7 mo for pts randomized to TPC (data cutoff October 26, 2020). PFS was significantly improved with LEN + pembro vs TPC in pMMR aEC (median 6.6 vs 3.8 mo; HR 0.60) and in all-comers (median 7.2 vs 3.8 mo; HR 0.56). OS was significantly longer with LEN + pembro vs TPC in pMMR aEC (median 17.4 vs 12.0 mo; HR 0.68) and in all-comers (median 18.3 vs 11.4 mo; HR 0.62). ORR was significantly greater with LEN + pembro vs TPC in pMMR aEC (30.3% vs 15.1%) and in all-comers (31.9% vs 14.7%). Additional results are in the table. Median treatment duration was 231 days with LEN + pembro and 104.5 days with TPC. Overall, any-grade treatment-emergent adverse events (TEAEs) occurred at similar rates across treatment arms. Grade ≥3 TEAEs occurred in 89% of pts with LEN + pembro and 73% of pts with TPC. In the LEN + pembro arm, 30.8% pts discontinued LEN, 18.7% discontinued pembro, and 14.0% discontinued both study treatments due to a TEAE; the most common TEAEs were hypertension (64%), hypothyroidism (57%), diarrhea (54%) and nausea (50%). <h3>Conclusions:</h3> LEN + pembro demonstrated statistically significant and clinically meaningful improvements in PFS, OS, and ORR vs TPC both in pts with aEC that was pMMR and in pts with aEC irrespective of MMR status. The safety profile of LEN + pembro was manageable and consistent with previously reported studies.