Emerging TKI/I-O Options in mRCC

Transcript:Chung-Han Lee, MD, PhD: Currently, there’s an active phase III clinical trial that’s a 3-arm study of lenvatinib plus pembrolizumab versus lenvatinib plus everolimus versus sunitinib in the first-line setting. That’s currently ongoing. However, we do have some preliminary evidence from the combined analysis of the phase Ib and phase II studies of lenvatinib plus pembrolizumab. Those results were initially presented at the ESMO 2017 Congress. It was shown that the combination had an objective response rate of 63%. With longer follow-up in the updates at the 2018 ASCO Annual Meeting, the authors were able to demonstrate an objective response rate by independent radiographic review of 67% by both RECIST 1.1 and irRECIST.

Furthermore, with longer follow-up, they were also able to demonstrate a progression-free survival of 18 months for this combination. This trial included patients who were treatment-naïve and patients who were pretreated. About 40% of patients were treatment-naïve, 60% of patients had received prior treatment, and clinical activity was seen within both groups.

Furthermore, they also looked at the role of PD-1 staining within that population. It demonstrated clinical activity within both the PD-L1—positive and the PL-1–negative populations. For this study, the safety and tolerability were quite good and consistent with monotherapy with either drug, for which no unexpected toxicities were identified.

Currently, the culmination of lenvatinib plus pembrolizumab has been granted FDA breakthrough status. Hopefully, that will accelerate the clinical development of this combination and provide this as a possible clinical option for more patients on an earlier basis.

Thomas E. Hutson, DO, PharmD: The ongoing CheckMate-9ER trial that combines cabozantinib with nivolumab, versus sunitinib, is a very interesting trial, and I’m pleased to have that open at my site. It is taking nivolumab and combining it with traditionally dosed cabozantinib or traditionally dosed sunitinib, hoping to see efficacy. Many people know that there used to be a third arm to that trial— ipilimumab/nivolumab plus cabozantinib. That arm was discontinued. We all believe this may be related to toxicity, although it’s not clear. But nivolumab/cabozantinib seems to be a combination that is tolerable, and it’s exciting to see how cabozantinib, such a powerful agent in the refractory setting, can combine with nivolumab and hopefully raise the bar for treatment. I think it will fare well compared with other VEGF/immunotherapy combinations.

Nizar M. Tannir, MD, FACP: The combinations of an immuno-oncology therapy plus an anti-VEGF therapy are here and are here to stay. An important, promising combination was recently published by Atkins et al in Lancet Oncology. In 52 patients, a response rate of 73% using the combination of the PD-1 antibody, pembrolizumab, in combination with axitinib, a VEGF receptor TKI, was shown. The adverse events were not trivial. Twenty-three percent of the patients had a high rate of adverse events—with hypertension, diarrhea, and fatigue—but the response rate was impressive in those 52 patients who received this therapy as first-line therapy—73% of the patients had a CR [complete response] or a PR [partial response]. The median progression-free survival was 20 months, so that’s impressive. This regimen is now being evaluated in a phase III trial versus sunitinib as a comparator. The study did complete its accrual last year, and we are waiting for results. We should have results early next year. We’ll see whether this combination shows better results than sunitinib. There are other combinations, similar to this one, that are now being tested in the phase III setting.

Transcript Edited for Clarity.