According to a follow-up analysis of the phase 1b/2 study 111/KEYNOTE-146, lenvatinib/pembrolizumab continued to show tumor responses, overall survival, and progression-free survival benefits in endometrial cancer.
Deep and durable tumor responses were seen in patients with previously treated advanced endometrial cancer who received treatment with lenvatinib (Lenvima) plus pembrolizumab (Keytruda), according to a follow-up analysis of the phase 1b/2 study 111/KEYNOTE-146 trial (NCT02501096).
Regardless of histological subtype or mismatch repair (MMR) status, tumor responses were observed and the combination of lenvatinib and pembrolizumab continued to demonstrate benefit in progression-free survival (PFS) and overall survival (OS) compared with previous data. Moreover, the combination had a manageable safety profile which was generally comparable with established profiles of each agent alone.
In an open-label phase 1b/2 study (111/KEYNOTE-146; NCT02501096), 108 patients were enrolled who had received no more than 2 prior systemic therapies. Eligible patients were aged 18 years and older with histologically confirmed advanced endometrial cancer, an ECOG performance status of 0 or 1, and a life expectancy of 12 weeks or greater.
When enrolled, patients were given lenvatinib at a dose of 20 mg daily plus pembrolizumab at 200 mg every 3 weeks.Ninety-four patients in the trial had non- microsatillite instability (MSI)-high (H) and MMR proficient (pMMR) disease and 11 had MSI-H/MMR deficient (dMMR) disease.
For the primary analysis, investigators assessed the primary end point of overall response rate (ORR) at week 24, and secondary end points of ORR, duration of response (DOR), PFS, OS, disease control rate, and clinical benefit rate. For this follow-up analysis of the study, end points consisted of ORR, DOR, PFS, OS, and safety.
When looking at the primary analysis of the study, the investigator-assessed ORR on immune-related Response Evaluation Criteria in Solid Tumors criteria was 38.9% (95% CI, 29.7%-48.7%). The median DOR was 21.2 months (95% CI, 7.6- not estimable [NE] months), median PFS was 7.4 months (95% CI, 5.3-8.7 months), and median OS was 16.7 months (95% CI-15.0-NE months). Then, this follow-up analysis of 108 patients with endometrial cancer occurred after a median follow-up of 34.7 months (95% CI, 30.9-41.2 months).
Among the patients included at the updated data cutoff date, the mean age was 65.1, 86.1% of patients were White, 5.6% were Black, 4.6% were Asian, and the remaining 3.7% were of another Race. Fifty-five patients (50.9%) had an ECOG performance status 1 while 53 (49.1%) had an ECOG performance status of 0. For histological subtype, 55 (50.9%) patients had endometrioid adenocarcinoma, 35 (32.4%) had serous adenocarcinoma, 6 (5.6%) had clear cell adenocarcinoma, 1 (0.9%) had dedifferentiated carcinoma, 1 (0.9%) had adenocarcinoma, and 10 (9.3%) had other.
A total of 56 (51.9%) patients had 1 prior treatment regimen and 52 (48.1%) had received 2 or more prior treatments. Additionally, 32 (29.6%) patients were on study treatment or in survival follow-up and the other 76 (70.4%) patients discontinued the study as a result of death (n = 71), consent withdrawal (n = 4), or other reason (n = 1).
At the updated data cutoff date of August 18, 2020, the median study follow-up duration was 34.7 months (95% CI, 30.9-41.2). The ORR was 39.8% (95% CI, 30.5-49.7) with a total of 9 complete responses and 34 partial responses. The median DOR was 22.9 months (95% CI, 10.2-NE), the median PFS was 7.4 months (95% CI, 5.2-8.7), and OS was 17.7 months (95% CI, 15.5-25.8), respectively.
The ORR for patients with non–MSI-H/pMMR and MSI-H/dMMR tumors was 38.3% and 63.6%, respectively. For these patients, the median DOR was 23.0 months (95% CI, 8.5-NE) and 21.2 months (95% CI, 7.3-NE), and the upper ranges of DOR were ongoing at 4 years for both of these subgroups, respectively. The median PFS for patients with non–MSI-H/pMMR tumors was 7.4 months (95% CI, 4.4-7.6) while it was 26.4 months for patients with MSI-H/dMMR tumors (95% CI, 4.0-NE). For the median OS, rates were 17.2 months (95% CI, 15.0-25.8), and NE (95% CI, 7.4-NE).
Regarding safety, treatment-related treatment-emergent adverse events (TEAEs) of any grade were observed in 104 (96.3%) patients with the most common grade 3 or greater treatment-related TEAEs being hypertension (33.3%), elevated lipase (9.3%), fatigue (8.3%), and diarrhea (7.4%). Treatment-related TEAEs that resulted in discontinuation of at least 1 study drug occurred in 23 (21.3%) patients, discontinuation of both drugs were seen in 9 (8.3%) patients, lenvatinib dose reductions were observed in 73 (67.6%) patients, 80 (74.1%) patients had an interruption of 1 or both study drugs.
Moreover, the median dose intensity of lenvatinib was 13.84 mg once per day and the median number of pembrolizumab treatment cycles was 10. While there were 2 treatment-related deaths which occurred in the primary analysis of the study, no additional deaths related to treatment were seen in this follow-up.
Overall, these findings reveal the extended efficacy, safety, and tolerability of the combination of lenvatinib and pembrolizumab in this cohort of patients with previously treated advanced endometrial cancer.
“These results confirm the benefit of the combination in patients with previously treated advanced [endometrial cancer] when lenvatinib is initiated at the recommended starting dose of 20 mg orally once daily [in combination with pembrolizumab 200 mg intravenously once every 3 weeks] and the individualized patient approach of dose interruption/modification or discontinuation is implemented,” wrote study authors in findings published in the Journal of Clinical Oncology.