Following a prior announcement that the phase 3 KEYNOTE-775 trial met both primary end points of progression-free and overall survival benefit, data for the pembrolizumab/lenvatinib combination were presented at the Society of Gynecologic Oncology 2021 Annual Meeting on Women’s Cancer.
Patients with advanced, metastatic, or recurrent endometrial cancer who had previously received1 prior platinum-based regimen in any setting who were treated with pembrolizumab (Keytruda) plus lenvatinib (Lenvima) on the phase 3 KEYNOTE-775/Study 309 trial (NCT03517449) experienced improved progression-free (PFS) and overall survival (OS) versus those treated with physician’s choice therapy, according to a press release from Merck and Eisai, the companies responsible for developing the 2 agents.1
Previously reported results of the trial initially supported FDA accelerated approval of the combination in 2019 for the treatment of patients with advanced endometrial cancer that is not deemed to be microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy, and are not candidates for curative surgery or radiation.2 In December, the companies announced that both primary end points were met. Updated data have been made available as part of a plenary session at the virtual Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer.
“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,” Vicky Makker, MD, Principal Investigator and Medical Oncologist at Memorial Sloan Kettering Cancer Center, said in a press release. “With a 38% reduction in risk of death regardless of mismatch repair status, [pembrolizumab plus lenvatinib] significantly improved overall survival compared with chemotherapy in the all-comer group of patients with advanced, metastatic or recurrent endometrial carcinoma, which is very encouraging, as this arm included an investigational patient population for which more data have been sought after by the gynecologic oncology community.”
The dual primary end points of the trial, PFS and OS, were statistically significantly greater in the experimental arm (n = 411) compared with the control arm (n = 416). In the all-comer population, the median PFS was 7.2 months (95% CI, 5.7-7.6) with pembrolizumab/lenvatinib versus 3.8 month (95% CI, 3.6-4.2), leading to a 44% reduction in the risk of disease progression or death (HR, 0.56; 95% CI, 0.47-0.66; P <.0001). The corresponding median OS in either group was 18.3 months (95% CI, 15.2-20.5) versus 11.4 months (95% CI, 10.5-12.9), for a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.51-0.75; P <.0001).
The objective response rate (ORR), a key secondary end point, was also improved with pembrolizumab/lenvatinib at 31.9% (95% CI, 27.4-36.6) versus 14.7% (95% CI, 11.4-18.4) with physicians’ choice therapy. Rates of complete or partial response were 6.6% and 25.3%, respectively, for the experimental combination compared with 2.6% and 12.0% with the control arm. The median duration of response was 14.4 months (range, 1.6-23.7) versus 5.7 months (range, 0.0-24.2), respectively.
In patients with mismatch repair deficiency, results were similar to those observed in all comers. Statistically significant and clinically meaningful benefits to PFS were observed (HR, 0.60; 95% CI, 0.50-0.72; P <.0001), with medians of 6.6 months (95% CI, 5.6-7.4) and 3.8 months (95% CI, 3.6-5.0) with pembrolizumab/lenvatinib and control therapy, respectively. The median OS was 7.4 months (95% CI, 14.2-19.9) with the immunotherapy/TKI combination versus 12.0 months (95% CI, 10.8-13.3) with chemotherapy (HR, 0.68; 95% CI, 0.56-0.84; P = .0001). The ORR was also improved with pembrolizumab/lenvatinib at 30.3% (95% CI, 25.5%-35.5%), comprised of 5.2% complete responses and 25.1% partial responses, compared with 15.1% (95% CI, 11.5%-19.3%), made up of 2.6% complete responses and 12.5% partial responses. The median duration of response was 9.2 months (range, 1.6-23.7) versus 5.7 months (range, 0.0-24.2), respectively.
Discontinuations due to treatment-emergent adverse events (TEAEs) in the all-comer population occurred at a rate of 18.7% for pembrolizumab, 30.8% for lenvatinib, and 14.0% for both agents. In the physician’s choice arm, discontinuation of chemotherapy due to TEAEs occurred in 8.0%. Grade 5 TEAEs occurred in 5.7% of those treated with pembrolizumab/lenvatinib and in 4.9% of those treated with chemotherapy. The most common any-grade AEs in the experimental group occurring in more than 30% of patients were 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%), and arthralgia (30.5%).
“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,” Takashi Owa, MD, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai, said in a press release. “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. We are grateful to the patients and healthcare providers whose participation and persistence amid a global pandemic have made this milestone possible.”
1. 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. News release. Merck. March 19, 2021. Accessed March 19, 2021. https://www.businesswire.com/news/home/20210319005069/en/
2. Simultaneous review decisions for pembrolizumab plus lenvatinib in Australia, Canada and US. FDA. September 17, 201. Accessed March 19, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/simultaneous-review-decisions-pembrolizumab-plus-lenvatinib-australia-canada-and-us