Lenvatinib Plus Pembrolizumab Promising in Advanced Endometrial Cancer

Treatment options for patients with advanced endometrial cancer are limited and chemotherapy, which is the current standard, is associated with low response rates and poor  outcome. While immunotherapy with PD-1 and PD-L1 inhibitors has been highly effective in patients with high microsatellite instability (MSI-H), the majority of advanced endometrial cancers are microsatellite stable (MSS), and results with single-agent checkpoint inhibitors in these patients have been disappointing. Angiogenesis plays an essential role for growth and metastasis of endometrial cancer. Angiogenesis inhibitors, including lenvatinib, which targets VEGFR1–3, FGFR1–4, PDGFRα, and the oncogenes RET and KIT, showed modest activity as monotherapy in previously treated patients with endometrial cancer. However, co-inhibition of the VEGF-mediated immunosuppressive microenvironment and anti-PD-1 signaling with lenvatinib and the PD-1 inhibitor pembrolizumab appears to increase antitumor immune responses in preclinical models. A multicenter phase II trial evaluated this combination in 53 patients with advanced, previously treated endometrial cancer and results of an interim analysis were recently published in Lancet Oncology. The most common histological subtypes of disease were endometriod adenocarcinoma and serous carcinoma, and 85% of patients had MSS disease.

At 24 weeks, the combination of lenvatinib and pembrolizumab resulted in an objective response rate (ORR) of 39.6% per investigator assessment (45.3% per independent review), an outcome that is much higher than is seen with current cytotoxic therapies and in studies of pembrolizumab or angiogenesis inhibitor monotherapy. Responses were seen irrespective of MSI status or PD-L1 expression. Of 49 patients with evaluable tumor assessments, 88% had a decrease in tumor size from baseline. The median duration of response was not reached. At 6 months, 83.0% of patients continued to have a response, and 64.5% of responses were ongoing at 12 months. The median progression-free survival (PFS) was 7.4 months.

The adverse events (AEs) seen in this study were, in general, consistent with the known safety profile of this combination. Overall, the most frequently reported any-grade treatment-related AEs were hypertension (58%), fatigue (55%), diarrhea (51%), and hypothyroidism (47%). Serious treatment-related AEs occurred in 30% of patients, and 9% discontinued due to AEs. The most common grade 3 treatment-related AEs were hypertension (34%) and diarrhea (8%). There were no grade 4 AEs, but one treatment-related death due to intracranial hemorrhage.

The investigators concluded that promising findings from this study supports investigation of lenvatinib plus pembrolizumab in the ongoing phase III clinical KEYNOTE-775 trial comparing this combination to current standard chemotherapy in patients with advanced endometrial cancer. In an accompanying commentary, Gottfried Konecny, MD (University of California, Los Angeles, California, United States), highlighted the increasing incidence of advanced endometrial cancer and the high need for more effective therapies. He agrees that the efficacy from the interim analysis of this study are quite impressive, but cautioned that the toxicity is considerable and may impact use of this combination. Phase III data are necessary to see if these results will translate to meaningful outcomes with an acceptable toxicity profile compared to current chemotherapy standards.

Lancet Oncol. 2019 March 25. [Epub ahead of print.]

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