The combination of lenvatinib plus pembrolizumab induced durable responses with a manageable safety profile in adults with previously treated, advanced endometrial cancer, according to a long-term follow-up analysis of a phase 1b/2 study (NCT02501096).
The combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) induced durable responses with a manageable safety profile in adults with previously treated, advanced endometrial cancer, according to a long-term follow-up analysis of a phase 1b/2 study (NCT02501096) presented by Vicky Makker, MD, during the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting.1
“With extended follow-up, this updated analysis continued to show durable responses, as well as [survival] benefits in patients with challenging to treat, advanced endometrial cancer who received lenvatinib plus pembrolizumab,” said Makker, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. “The safety profile [for the combination] was generally consistent with that of the individual monotherapies.”
At the August 18, 2020, data cutoff, the total population of the analysis included 108 patients. The objective response rate (ORR) was 39.8% (95% CI, 30.5%-49.7%), including 9 (8.3%) complete responses (CRs). The median progression-free survival (PFS) was 7.4 months (95% CI, 5.2-8.7) and the median overall survival (OS) was 17.7 months (95% CI, 15.5-25.8). The median duration of response (DOR) was 22.9 months (95% CI, 10.2-not evaluable [NE]).
To be eligible for the open-label, single-arm trial, patients needed to have histologically confirmed and metastatic endometrial carcinoma measurable by immune-related RECIST. A maximum of 2 prior systemic therapies were permitted and patients needed to have an ECOG performance status of 1 or less. The study required patients have a minimum life expectancy of at least 12 weeks.
Investigators administered oral lenvatinib at a dose of 20 mg per day; 200 mg pembrolizumab was administered intravenously every 3 weeks. Pembrolizumab could be given for a maximum of 35 cycles and lenvatinib could continue beyond this point as long as benefit was observed. The primary end point of the trial was ORR at week 24. Key secondary end points included overall ORR, disease control rate (DCR), DOR, and progression-free survival (PFS).
The mean age of the total population was 65.1. Most patients (50.9%) had an endometroid carcinoma and 32.4% had a serous adenocarcinoma. The vast majority of the population (98.1%) had previously been treated for endometrial cancer with a platinum plus taxane combination and 49.1% of patients were PD-L1 positive.
The end points of the follow-up analysis included ORR, PFS, DOR, OS, and safety. The median follow-up duration was 34.7 months (95% CI, 30.9-41.2). The analysis population included 94 patients who were MMR proficient (pMMR) and 11 patients who were MMR deficient (dMMR).
In the pMMR cohort, the mean age was 65.4 and 48.9% of patients were PD-L1-positive. An even number (50%) of patients received 1 or 2 prior treatments for endometrial cancer. Common histological subtypes included endometrioid adenocarcinoma (48.9%), serous adenocarcinoma (35.1%), and clear cell adenocarcinoma (5.3%). Nearly all (98.1%) had been previously treated for endometrial cancer with a platinum plus taxane combination.
In the dMMR group, the mean age was 62.4 and most patients were PD-L1-positive (63.6%). All patients had been previously treated for endometrial cancer with a platinum plus taxane combination and 36.4% had undergone 2 prior treatment regimens. The most common histological subtype was endometrioid carcinoma (72.7%), of which 36.4% of patients were FIGO grade 2.
Among the patients who were pMMR, the ORR was 38.3% (95% CI, 28.5%-48.9%) and 8 patients achieved a CR. The median DOR was 25.0 months (95% CI, 8.5-NE) and the mean time to response was 3.2 months. The median PFS was 7.4 months (95% CI, 4.4-7.6) and the median OS was 17.2 months (95% CI, 15.0-28.5).
In the dMMR cohort, the ORR was 63.6% (95% CI, 30.8%-89.1%). The median DOR was 21.2 months (95% CI, 7.33-NE). Notably, the median OS was NE (95% CI, 7.4-NE) and the median PFS was 26.4 months (95% CI, 4.0-NE).
In terms of safety, 96.3% of the total population experienced any treatment-related treatment-emergent adverse events (TEAEs). Most patients (74.1%) experienced a TEAE that lead to study-drug interruption and 21.3% had a TEAE that lead to study-drug discontinuation. TEAEs of grade 3 or higher were reported in 71.3% of patients.
Common TEAEs of any grade included hypertension (60.2%), diarrhea, fatigue (both 53.7%), decreased appetite (50%), and hypothyroidism (46.3%). Grade 3 or higher TEAEs included hypertension (33.3%), fatigue (8.3%), and diarrhea (7.4%).
“Study 309/KEYNOTE-775 (NCT03517449), a confirmatory study of lenvatinib plus pembrolizumab vs treatment of physician’s choice in advanced endometrial cancer, further supports the lasting clinical benefits observed in this follow-up study,” concluded Makker.
On July 21, 2021, the FDA granted a full approval to lenvatinib plus pembrolizumab for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high or dMMR, who have disease progression after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation based on data from the KEYNOTE-775 trial.2