The KEYNOTE-146 Trial

Transcript:Vicky Makker, MD: Next, I’ll go on to discuss KEYNOTE-146, which was a phase Ib/2 trial in advanced cancers, and I’ll speak to the endometrial cancer cohort. Before I launch into the clinical trial and its results, I think it is important to speak a little bit about lenvatinib and pembrolizumab, which were the 2 agents that were evaluated in this trial.

So lenvatinib is an oral multi—tyrosine kinase inhibitor that inhibits VEGF receptors 1 through 3; fTfR [olive flounder transferrin] receptors 1 through 4; PDGFR [platelet-derived growth factor receptor] alpha, RET, and KIT. This agent has been evaluated in advanced endometrial cancers of the monotherapy in patients that were previously treated. And in that trial on central independent radiology reviewed the objective response rate with a modest 14.3%.

Pembrolizumab has also been evaluated in previously treated endometrial cancer patients that were PD-L1 [programmed death-ligand 1] positive and were enrolled regardless of microsatellite instability MSI status. And on that trial the objective response rate again was a modest 13%. There is preclinical in vivo data that have shown that lenvatinib has immunomodulatory effects, and that it can decrease the tumor-associated macrophage population. Additionally, preclinical work in the in vivo setting has shown that when lenvatinib is combined with anti—PD-1 [programmed cell death protein 1] therapy, that they can act by the interferon signaling pathway, and that the combination of the 2 agents can have higher effect than either agent alone. With that background, this phase Ib/2 trial was launched across multiple cohorts, including endometrial cancers.

For the endometrial cancer cohort, eligible patients were those who had measurable disease by ir-RECIST [immune-related response evaluation criteria in solid tumors]. They had to be 18 or older. Patients had to have an ECOG [Eastern Cooperative Oncology Group Performance Status] of 0 or 1. For the phase 2 portion of the study, patients had 2 or fewer prior lines of therapy. Patients had to have adequately controlled blood pressure and had to have adequate organ function. Patients could not have received anti-cancer therapy within 28 days of initiating treatment. They also could not have received prior therapy with lenvatinib or a prior anti—PD-1, PD-L1, or PD-L2 agent. So those were the primary eligibility criteria.

The primary objective of the study was objective response rate at week 24 by ir-RECIST on investigator review. Secondary objectives of the study included assessment of safety and tolerability, overall objective response rate, progression-free survival, overall survival, and duration of response all by ir-RECIST.

On the study patients received treatment with lenvatinib at 20 mg orally daily, and pembrolizumab was dosed intravenously at 200 mg IV q3 every 3 weeks. Each treatment cycle was 21 days in duration, and patients received treatment until they developed progression of disease or intolerable toxicity. Pembrolizumab could be dosed on study for a maximum of 2 years.

With regards to the patient demographics and efficacy data, patients were enrolled on study between September 10, 2015, and December 15, 2017. We had 54 patients who were administered at least 1 dose of treatment. However, 1 patient had a protocol deviation, and so for the final study set 53 patients were included. The vast majority of patients were of ECOG 1 and equal numbers received 1 or 2 prior lines of therapy, and that was 43%. The median age of patients on our study was 64. With regards to the histologic subtypes, 30% of patients had low-grade endometrioid adeno carcinomas, so those are the 501 or 502 endometrioid adenocarcinomas. Eleven percent were grade 3 endometrioids, and 38% of patients were serous or serous-like.

On the study, 8% of patients were microsatellite instability high, and 85% of patients were microsatellite stable [MSS]. Twenty-five percent of patients were PD-L1 positive, 21% were PD-L1 negative, and the status in the remaining patients was unknown at the time that the study was presented at ASCO 2018 [American Society of Clinical Oncology Annual Meeting].

With regards to the efficacy endpoints, the objective response rate at week 24 by ir-RECIST done on investigator review was approximately 40%, which was equal to the overall objective response rate by investigator review by ir-RECIST. On independent radiology review the objective response rate at week 24 was 45%, and the overall objective response rate was 47% on independent radiology review.

Encouragingly, of the patients that responded, an impressive 83% had a duration of response that was 6 months or greater, and 65% of patients had a duration of response that was 12 months or greater. With regards to responses among the MSS patients vs the MSI-high patients, responses were comparable. With regards to treatment-related adverse events, 70% of patients had grade 3 adverse events; we had no grade 4 adverse events. Of the adverse events that were seen regardless of grade, the most common were hypertension, fatigue, diarrhea, and hyperthyroidism.

We found that adverse effects, toxicities, adverse events were manageable on study with dose holds, dose reductions, and dose discontinuations. Only 9% of patients required a dose discontinuation, which again was encouraging. And no new safety signals were identified in this study. Based on these encouraging data, the Food and Drug Administration did grant breakthrough therapy designation to the combination of lenvatinib and pembrolizumab for patients with microsatellite stable previously treated endometrial cancers. This study is now ongoing. Accrual has completed, and we are in a follow-up phase of this trial.

Educational support for this activity provided by Eisai.​​​​​​​

Transcript Edited for Clarity.