Pembrolizumab Plus Lenvatinib Demonstrates Improved Overall Survival in Treatment of Advanced Endometrial Cancer

Results from the phase 3 KEYNOTE-775/study 309 trial (NCT03517449) found that pembrolizumab (Keytruda; Merck) plus lenvatinib (Lenvima; Eisai) reduced risk of death by 38%, with a median overall survival (OS) of 18.3 months versus 11.4 months for treatment with chemotherapy, regardless of mismatch repair status. The trial results were presented during an oral plenary session at the Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer.

The trial assessed the combination treatment of the anti-PD-1 therapy pembrolizumab with the orally available multiple receptor tyrosine kinase inhibitor lenvatinib for the treatment of advanced, metastatic, or recurrent endometrial cancer following 1 prior platinum-based regimen in any setting.

The dual primary endpoints were progression-free survival (PFS) and OS, which the study was able to meet. PFS and OS were assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additionally, the trial’s secondary efficacy endpoint was objective response rate (ORR), which was also assessed by BICR per RECIST v1.1, in the all-comer population, which included mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR]) subgroups.

For both the all-comer population and the pMMR subgroup, the investigators conducted a median follow-up over a period of 11.4 months. The PFS demonstrated pembrolizumab plus lenvatinib (n=411) reduced the risk of disease progression or death by 44% in the all-comer population (HR=0.56 [95% CI: 0.47-0.66]; p<0.0001).

Among this population, the investigators observed a median PFS of 7.2 months (95% CI: 5.7-7.6; number of events=281) versus 3.8 months for chemotherapy (n=416; 95% CI: 3.6-4.2; number of events=286), which was the given as the treatment of the physician’s choice (TPC) of either doxorubicin or paclitaxel.

In the analysis of OS among the all-comer population, pembrolizumab plus lenvatinib was found to reduce the risk of death by 38% (HR=0.62 [95% CI: 0.51-0.75]; p<0.0001), with a median OS of 18.3 months (95% CI: 15.2-20.5; number of events=188) versus 11.4 months for TPC (95% CI: 10.5-12.9; number of events=245). Additionally, the investigators observed that the safety profile of pembrolizumab plus lenvatinib was consistent with the individual monotherapies’ previously established safety profiles.

“Patients diagnosed with endometrial cancer, the most common type of gynecologic cancer in the US, face low survival rates when diagnosed at an advanced stage or at recurrence, especially once the disease progresses after prior platinum-based therapy and is not amenable to curative surgery or radiation,” said Vicky Makker, MD, principal investigator and medical oncologist, Memorial Sloan Kettering Cancer Center, in a prepared statement.

Makker explained further that the significant improvement in OS for patients treated with pembrolizumab plus lenvatinib compared with chemotherapy in the all-comer group of patients was very encouraging.

“This arm included an investigational patient population for which more data have been sought after by the gynecologic oncology community,” Makker said.

In the all-comer population arm, ORR for patients treated with pembrolizumab plus lenvatinib was 31.9% (95% CI: 27.4-36.6), with a complete response (CR) rate of 6.6%, and a partial response (PR) rate of 25.3%, versus 14.7% (95% CI: 11.4-18.4) with a CR rate of 2.6%, and a PR rate of 12.0% for patients who received TPC (p<0.0001).

Additionally, the median duration of response (DOR) for patients who received pembrolizumab plus lenvatinib was 14.4 months (range: 1.6-23.7) versus 5.7 months (range: 0.0-24.2) for patients treated with TPC.

“The positive results seen in KEYNOTE-775/Study 309 help confirm the currently approved use of the [pembrolizumab plus lenvatinib] combination in certain patients with advanced endometrial carcinoma,” said Takashi Owa, PhD, chief medicine creation officer and chief discovery officer, oncology business group at Eisai, in a prepared statement. “As this stage of disease has been notoriously difficult to treat, Eisai and Merck remain committed to addressing the unmet need of advanced endometrial carcinoma.”

The investigators additionally noted that the positive results found from treatment with pembrolizumab plus lenvatinib in the all-comer population were similar in the pMMR subgroup. In this subgroup, pembrolizumab plus lenvatinib was found to reduce the risk of disease progression or death by 40% (HR=0.60 [95% CI: 0.50-0.72]; p<0.0001), with a median PFS of 6.6 months (95% CI: 5.6-7.4; number of events=247) versus 3.8 months for TPC (95% CI: 3.6-5.0; number of events=238).

In relation to the combination treatment’s impact on the risk of death, pembrolizumab plus lenvatinib was found to reduce this risk by 32% (HR=0.68 [95% CI: 0.56-0.84]; p=0.0001), with a median OS of 17.4 months (95% CI: 14.2-19.9; number of events=165) versus 12.0 months for TPC (95% CI: 10.8-13.3; number of events=203).

In the pMMR subgroup, ORR for patients who received pembrolizumab plus lenvatinib was 30.3% (95% CI: 25.5-35.5), with a CR rate of 5.2% and a PR rate of 25.1%, versus 15.1% (95% CI: 11.5-19.3), with a CR rate of 2.6% and a PR rate of 12.5%, for TPC (p<0.0001). Additionally, among those patients who responded to treatment, the median DOR was 9.2 months for pembrolizumab plus lenvatinib (range: 1.6-23.7) versus 5.7 months for TPC (range: 0.0-24.2).

In the all-comer population, treatment-emergent adverse events (TEAEs) of any grade from treatment with pembrolizumab plus lenvatinib led to the discontinuation of pembrolizumab in 18.7% of patients and of lenvatinib in 30.8% of patients, with the discontinuation of both occurring in 14.0% of patients. Additionally, the investigators found that grade 5 TEAEs occurred in 5.7% of patients, while grade ≥3 TEAEs occurred in 88.9% of patients treated with pembrolizumab plus lenvatinib.

The most common TEAEs to emerge in at least 25% of patients during treatment with pembrolizumab plus lenvatinib of any grade were hypertension (64.0%), hypothyroidism (57.4%), diarrhea (54.2%), nausea (49.5%), decreased appetite (44.8%), vomiting (36.7%), weight decrease (34.0%), fatigue (33.0%), arthralgia (30.5%), proteinuria (28.8%), anemia (26.1%), constipation (25.9%), and urinary tract infection (25.6%).

In 2019, the FDA cited the positive results from the KEYNOTE-146/Study 111 assessing pembrolizumab plus lenvatinib for the accelerated approval of the treatment for patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. KEYNOTE-775/Study 309 is the confirmatory trial for the prior KEYNOTE-146/Study 111, which provided further data on the combination treatment in these population groups.

REFERENCE

KEYTRUDA® (pembrolizumab) Plus LENVIMA® (lenvatinib) Significantly Improved Progression-Free Survival and Overall Survival Versus Chemotherapy in Patients With Advanced Endometrial Cancer Following Prior Platinum-Based Chemotherapy in Phase 3 Study. Kenilworth, NJ: Merck; March 19, 2021. Accessed March 23, 2021. https://www.businesswire.com/news/home/20210319005069/en