Lenvatinib plus pembrolizumab demonstrated promising antitumor activity among patients with previously treated advanced endometrial carcinoma, regardless of PD-L1 expression or microsatellite instability (MSI)/mismatch repair deficiency (dMMR) status, according to the final primary efficacy analysis of the KEYNOTE-146/Study 111 trial.

The current standard of care for advanced, recurrent endometrial cancer is paclitaxel plus carboplatin, except for a minority of patients whose tumors are MSI-high (MSI-H)/dMMR and who are therefore eligible for pembrolizumab monotherapy.

As monotherapies in endometrial cancer, both pembrolizumab and lenvatinib demonstrate low response rates of approximately 13% to 14%; however, preclinical studies suggest that their combination may be synergistic.

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The ongoing, open-label, single-arm phase Ib/II KEYNOTE-146/Study 111 trial enrolled patients with advanced solid tumors to receive treatment with lenvatinib plus pembrolizumab. The phase Ib portion established the dose as 20 mg lenvatinib given orally once daily and 200 mg of pembrolizumab administered intravenously every 3 weeks in 3-week cycles, with a maximum of 35 infusions. The primary endpoint was objective response rate (ORR) at 24 weeks (ORRWK24), and secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and disease control rate (DCR).

This analysis included 108 patients from the endometrial cancer cohort. Mean patient age was 65.1 years, most patients had endometroid or serous adenocarcinoma histology, and most patients also had received 1 or 2 prior treatments. PD-L1 expression was positive in 49.1% of patients, and 10.2% of patients had tumors that were MSI-H/dMMR.

During a median follow-up of 18.7 months, the ORRWK24 was 38% (95% CI, 28.8-47.8%) for the previously-treated endometrial cancer cohort, with an ORRWK24 of 63.6% (95% CI, 30.8%-89.1%) among those with MSI-H/dMMR tumors and 36.2% (95% CI, 26.5%-46.7%) among those with microsatellite stable (MSS)/MMR proficient (pMMR) tumors. The overall DCR was 84.3%, including 80.9% among the MSI-H/dMMR population and 84.0% among those with MSS/pMMR tumors. ORR was similar regardless of PD-L1 expressions status.

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The median OS was 16.7 months (95% CI, 15 months to not evaluable [NE]) and the median PFS was 7.4 months (95% CI, 5.3-8.7 months). The DOR was 21.2 months (95% CI, 7.6-NE).

Any-grade treatment-related adverse events (TRAEs) were common, and 66.9% of patients experienced grade 3 to grade 4 TRAEs. Treatment discontinuation occurred in 17.7% of patients due to TRAEs, with included 15.3% of patients who discontinued lenvatinib and 12.1% who discontinued pembrolizumab, and 8.9% who discontinued both drugs.

The authors concluded that these data “are encouraging and showed compelling efficacy and an acceptable safety profile in patients with advanced endometrial carcinoma.” The results of this study led to the US Food and Drug Administration approval of lenvatinib plus pembrolizumab for patients with previously treated advanced endometrial cancer that is MSI-H/pMMR. Phase 3 trials are ongoing.


Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer [published online March 13, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.02627.