Lenvatinib/Pembrolizumab Efficacy Data Holds Up in Updated KEYNOTE-146 Analysis for Advanced Endometrial Carcinoma


Updated findings from the KEYNOTE-146 trial support the use of lenvatinib/pembrolizumab in advanced endometrial cancer.

Vicky Makker, MD

Vicky Makker, MD

Updated data from the phase 1b/2 Study 111/KEYNOTE-146 trial (NCT02501096) demonstrated deep and durable tumor responses in patients with previously treated advanced endometrial carcinoma who received lenvatinib (Lenvima) plus pembrolizumab (Keytruda). Findings from the analysis were published in the Journal of Clinical Oncology.

At a median follow-up of 34.7 months (95% CI, 30.9-41.2) with a data cutoff of August 18, 2020, patients (n = 108) achieved a median progression-free survival (PFS) with the combination of 7.4 months (95% CI, 5.2-8.7) while overall survival (OS) was 17.7 months (95% CI, 15.5-25.8). The mean time to response was 3.2 months (3.41) and all previously treated patients from the primary data cutoff analysis were included in the updated analysis.

Patients experienced an objective response rate (ORR) of 39.8% (95% CI, 30.5-49.7) with 8.3% achieving a CR (n = 9), 31.5% achieving a partial response (PR; n = 24), and 42.6% achieving stable disease (SD) status (n = 46). The durable SD rate was 16.7% (n = 18).

In addition, the median duration of response (DOR) was 22.9 months (95% CI, 10.2- not estimable [NE]) with the combination and the clinical benefit rate was 56.5% (95% CI; 46.6-66.0). The disease control rate was 84.3% (95% CI; 73.9-89.1).

Moreover, a total of 104 patients (96.3%) experienced an adverse event (AE) with treatment. The most common grade 3 or worse treatment-related adverse events (TRAEs) included hypertension, elevated lipase, fatigue, and diarrhea, all of which occurred at rates of 33.3%, 9.3%, 8.3%, and 7.4% respectively.

“This follow-up analysis showed deep and durable tumor responses in patients with previously treated advanced EC who received lenvatinib plus pembrolizumab,” Vicky Makker, MD, a medical oncologist with Memorial Sloan Kettering, and co-investigators, wrote in the study.

“The combination continued to show compelling PFS and OS benefits in comparison with what would be expected on the basis of historical data for this treatment setting.”

In September of 2019, the FDA granted lenvatinib plus pembrolizumab accelerated approval for patients with advanced endometrial cancer based on data suggesting that the combination was linked to improved responses in this patient population.2 Shortly thereafter, the phase 3 Study 309/KEYNOTE-755 study was launched and demonstrated that the combination bested physician’s choice of chemotherapy in both PFS and OS data.3

The data most recently published from Study 111/KEYNOTE-146 provides a long-term follow-up to those findings previously reported with the regimen, and according to investigators, is consistent with the findings from the Study 309/KEYNOTE-755 study trial.1

Patients in the study were aged 18 years or older with an ECOG score of 1 or less and a life expectancy of 12 weeks or greater. Lenvatinib was given orally once daily at a dose of 20 mg and pembrolizumab was given intravenously once every 3 weeks in 3-week cycles at 200 mg. The median dose intensity of lenvatinib was 13.84 mg once daily and the median number of pembrolizumab treatment cycles was 10.1

Tumors were to be evaluated at baseline, every 6 weeks for the first 24 weeks, and every 9 weeks following immune-related RECIST criteria. The primary end point was ORR at week 24 with ORR, DOR, PFS, OS, and safety serving as secondary end points.

Overall, the mean age was 65.1 years and patients had a PD-L1 status of positive (49.1%), negative (39.8%), and not available (11.1%). ECOG performance scores were 0 (49.1%) and 1 (50.9%) and 51.9% of patients received one prior treatment regimen while 48.1% received 2 or more. Histological subtypes were endometrioid adenocarcinoma (50.9%), serous adenocarcinoma (32.4%), clear cell adenocarcinoma (5.6%), dedifferentiated/undifferentiated carcinoma (0.9%), and adenocarcinoma not otherwise specified (0.9).

Additionally, in the updated analysis 29.6% (n = 32) of the original patient population remained on treatment or were in survival follow-up, 5.6% remained on either the combination or lenvatinib monotherapy. Data showed that 76 patients had discontinued the study

Investigators noted that patients experienced tumor responses regardless of histological subtype or MMR status.

In the updated cutoff data, patients were stratified by non–microsatellite instability-high (MSI-H)/mismatch repair–proficient (pMMR; n = 94) tumors and MSI-H/deficient mismatch repair (dMMR; n = 11) tumors. Between the 2 groups, median PFS was 7.4 months (95% CI, 4.4-7.6) and 26.4 months (95% CI, 4.0-NE), respectively, while ORR was 38.3% (n = 36) and 63.6%, (n = 7) respectively. The median OS was 17.2 months (95% CI, 15.0-25.8) in patients with non–MSI-H/pMMR tumors and NE (95% CI, 7.4- NE) in those with MSI-H/dMMR tumors.

Moreover, patients with non–MSI-H/pMMR tumors experienced a median DOR of 23.0 months (95% CI, 8.5-NE) while median DOR for those with MSI-H/dMMR tumors was 21.2 months (95% CI, 7.3-NE). Investigators noted that upper ranges of DOR were ongoing at 4 years for both subgroups.

Patients experienced grade 3 or higher TEAEs at a rate of 87.0% while grade 4 or high events occurred at a rate of 9.3%. Serious treatment emergent adverse events (TEAEs) were reported in 32.4% of patients and 2 deaths due to treatment occurred in the primary analysis. TEAEs led to discontinuation in 21.3% of patients, with 8.3% discontinuing both agents, 17.6 lenvatinib, and 15.7% pembrolizumab.

Dose reduction due to TEAEs occurred in 67.6% of patients and dose interruption occurred in 74.1% of patients (combination, 31.5%; lenvatinib, 71.3%; pembrolizumab, 43.5%). Hypertension, elevated lipase, fatigue, and diarrhea, were the most common grade 3 or higher TEAEs. The most common any-grade AEs included hypertension (60.2%), diarrhea (53.7%), fatigue (53.7%), decreased appetite (50.0%), hypothyroidism (46.3%), and nausea (43.5%).

“Lenvatinib plus pembrolizumab had a manageable safety profile that was generally comparable with established profiles of the in- dividual monotherapies,” wrote study authors.

Study author concluded by noting that, although the Study 11/KEYNOTE-146 trial was limited in the sense that it was a single-arm study, with small enrollment, the results were consistent with the phase 3 global Study 309/KEYNOTE-775 study, both in terms of efficacy and safety.

“These results confirm the benefit of the combination in patients with previously treated advanced EC when lenvatinib is initiated at the recommended starting dose of 20 mg orally once daily and the individualized patient approach of dose interruption/modification or discontinuation is implemented,” they concluded.


  1. Makker V, Aghajanian C, Cohn AL, et al. A phase Ib/II study of lenvatinib and pembrolizumab in advanced endometrial carcinoma (study 111/KEYNOTE-146): long-term efficacy and safety update. J Clin Oncol. 2023;41(5):974-979. doi:10.1200/JCO.22.01021
  2. FDA takes first action under new international collaboration with Australia and Canada designed to provide a framework for concurrent review of cancer therapies, approving treatment for patients with endometrial carcinoma. FDA. Published September 17, 2019. https://bit.ly/2kqmAGq. Accessed February 16, 2023.
  3. Makker V, Colombo N, Casado Herráez A. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022 Feb 3;386(5):437-448. doi: 10.1056/NEJMoa2108330.
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