The combination of pembrolizumab and lenvatinib had very promising results for the treatment of advanced endometrial cancer in a recent phase II trial. Importantly, activity was seen among patients with both high microsatellite instability/DNA mismatch repair (MSI-H/dMMR) and microsatellite stable (MSS) disease.
“Lenvatinib plus pembrolizumab showed compelling activity in patients with advanced endometrial cancer that has progressed following prior therapy, regardless of microsatellite instability status, PD-L1 status, or histology,” said lead author Vicky Makker, MD, of Memorial Sloan Kettering Cancer Center, New York, during a webinar produced by the Society for Gynecologic Oncology (SGO). The combination also showed “deep and durable responses” with a safety profile “similar to previously reported profiles for each monotherapy. The incidence of hypothyroidism, however, was higher in this study that in previous reports of each monotherapy.”
The findings were to be presented at the SGO 2020 annual meeting, planned to take place in Toronto, Canada from March 28-31. The conference was cancelled due to the COVID-19 pandemic, but a series of webinars presenting several studies intended to be presented at the conference were subsequently made available. Makker’s webinar was presented on April 23, 2020.
“At present, the standard frontline treatment for advanced endometrial cancer is comprised of paclitaxel and carboplatin chemotherapy,” said Makker. “However, treatment options beyond this frontline regimen are limited, especially for MSS endometrial cancers that comprise the significant majority of the recurrent disease space.”
“Pembrolizumab is a humanized monoclonal antibody against PD-1, and it is approved as monotherapy for MSI-H endometrial cancer following prior treatment failure,” she continued. “Lenvatinib is an oral multikinase inhibitor that targets VEGF receptors 1-3, FGFR receptors 1-4, PDGFRα, RET, and KIT and has established monotherapy in advanced endometrial cancer.” In vivo preclinical trials have shown that combining lenvatinib with PD-L1 signal inhibitors results in more potent anti-tumor activity than when either agent is used alone.
In this study, objective response rate (ORR), which included the combination of overall and partial responses, was 38.0% by investigator assessment and 40.7% by independent imaging review with use of the pembrolizumab plus lenvatinib combination. ORR was 63.6% among MSI-H patients and 36.2% among MSS patients by investigator assessment and 63.6% and 40.7%, respectively, by independent imaging review.
Histological analysis among patients with MSS adenocarcinoma-type tumors by independent imaging review revealed an ORR of 26.1% among the 46 patients with endometrioid tumors, 50.0% among the 24 with non-endometrioid tumors, 42.4% among the 14 with serous tumors, and 80% among the 4 with clear cell tumors.
“Responses in the MSS patients were deep, with 31% of patients experiencing tumor shrinkage of 50% or greater and 16% experiencing tumor shrinkage of 75% or greater,” said Makker. “Responses were seen across histologic subtypes and in patients who were PD-L1 positive and negative.”
Kaplan-Meier plots revealed an overall survival (OS) of 16.7 months (95% CI 15.0-NE), a duration of response (DOR) of 14.8 months (95% CI 7.2-NE) and a progression-free survival (PFS) of 7.5 months (95% CI 5.0-8.3). OS was 18.7 months (95% CI 13.1-20.3) and PFS was 18.9 months (95% CI 3.9-NE) among MSI-H patients and 16.4 months (95% CI 13.5-25.9) and 5.4 months (4.4-7.6), respectively, among MSS patients. Median DOR was not reached for either the MSI-H or MSS cohorts.
Almost all patients (97.2%) had a treatment-related adverse event, and 72.2% had an adverse event leading to drug interruption (67.6% for lenvatinib, 39.8% for pembrolizumab, and 27.8% for both). The most common grade 3 or 4 adverse events were hypertension (32.4%), fatigue (8.3%), and diarrhea (6.5%). Common immune-related adverse events were hypothyroidism (47.2%) and hyperthyroidism (6.5%).
The KEYNOTE-146/Study 111 was a phase II, open-label, single-arm study of patients aged 18 years or older with metastatic endometrial cancer who were recruited from 11 centers in the United States. All patients were unselected for microsatellite instability or PD-L1 status, had an Eastern Cooperative Oncology Group performance status of 0 or 1, received one or two previous systemic therapies, had measurable disease according to the immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and had a life expectancy of 12 weeks or longer.
In total, 108 patients, whose mean age was 65.1 years, received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Pembrolizumab could be continued for up to 35 cycles, and lenvatinib could be continued for as long as patients were benefitting, said Makker. Of these patients, 11 were MSI-H and 94 were MSS. The microsatellite stability status was not available for 3 patients.
Data cut-off occurred on Jan. 10, 2019, after there were ≥ 100 patients with histologically confirmed, previously treated endometrial cancer with sufficient follow-up to provide median overall follow-up of ≥ 12 months and ≥ 6 months of follow-up after initial objective response for all responders.
The primary endpoint was ORR by investigator review at week 24 by irRECIST. Secondary endpoints included overall ORR, DOR, PFS, and OS, as well as safety and tolerability. Pre-specified exploratory endpoints included independent imaging review per irRECIST v1.1 and antitumor activity by PD-L1 status.
“The findings from Dr. Makker’s study combining lenvatinib and pembrolizumab are transformational,” said commentator Melissa A. Gellar, MD, of the University of Minnesota, Minneapolis, during the same webinar. “Importantly, the serous tumors had a response rate of 42%, suggesting that the combination of pembrolizumab plus lenvatinib is moving cold tumors into a more immunogenic, hot tumor environment. This combination gives every patient the opportunity to get pembrolizumab now, regardless of the mismatch repair status… This combination is, however, not without toxicity.”
On Sept. 7, 2019, The United States Food and Drug Administration, Australian Therapeutic Goods Administration, and Health Canada all granted accelerated approval to lenvatinib plus pembrolizumab in advanced endometrial cancer that is not MSI-H among patients who have had disease progression following prior systemic therapy and who are not candidates for curative surgery or radiation.
A phase III trial comparing the benefits of this pembrolizumab/lenvatinib combination with doxorubicin or weekly paclitaxel in advanced endometrial cancer is currently underway.
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Lenvatinib plus pembrolizumab showed promising activity in advanced endometrial cancer among patients with both microsatellite stable and unstable disease.
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Toxicity was significant with the combination, but not higher than when each agent is used alone.
Alison Palkhivala, Contributing Writer, BreakingMED™
This study was funded by AstraZeneca, Eisai, Karyopharm, Lilly, Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co.), Takeda, and Genentech.
Makker reports being on advisory boards for and/or receiving honoraria/travel expenses from ArQule, Eisai, Karyopharm, Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co.), and IBM Watson.
Geller reports receiving clinical trial support from Morphotek, Tesaro, Fate Therapeutics, and Genentech.
Cat ID: 120
Topic ID: 78,120,730,120,445,935,191,357,192,356
