Toni K. Choueiri, MD
Results from a phase Ib trial presented at the 2017 ASCO Annual Meeting showed strong activity with the combination of the PD-L1 inhibitor avelumab (Bavencio) and the VEGF inhibitor axitinib (Inlyta) in patients with advanced renal cell carcinoma (RCC).
during ASCO, the study’s lead author, Toni Choueiri, MD, senior physician and director of the Kidney Cancer Center at Dana-Farber Cancer Institute, reflected on the avelumab/axitinib results and other emerging combos in RCC.
OncLive: Can you give an overview of this study?
Drugs that target the VEGF or its receptor have been the cornerstone of treatment for 10 years now, and we were looking for a combination with another active drug for a long time. Then the PD-1/PD-L1 inhibitors came and generated this data, with phase I and up to phase III trials in this disease. Based on that, now you have 3 abstracts selected for oral presentation that deal with combining a VEGF inhibitor and a PD-1/PD-L1 inhibitor.
You will also see that another [anti–PD-L1/VEGF] combination—atezolizumab (Tecentriq) plus bevacizumab (Avastin) in a randomized phase II study that Dr Atkins will present—is safe and there is activity. Finally, there is a combination using [the PD-1 inhibitor pembrolizumab and] pazopanib (Votrient)…though in this situation the combination was not well tolerated due to many reasons. So, this combination is not proceeding.
Please discuss the potential synergy of the combination.
First, without thinking too deep in it, the simple thing is VEGF inhibitors have activity on their own and a certain mechanism of action. PD-1 inhibitors also show activity and proof of concept—we have a drug as of today—nivolumab (Opdivo) in the second line—that shows survival benefit…But also, PD-1 and PD-L1 inhibitors have been relatively safe with few side effects. You could sometimes see immune-related adverse events, but usually, when you have low side effects as a single agent and a good track record of safety, that is good to combine.
The second thing is that you know VEGF receptor inhibition may lead to an immune-tolerant milieu, so the combination does make sense. A lot of the inhibition of VEGF receptor leads to downregulation to Treg and those inhibitory cells, so having PD-1 inhibition onboard may really make sense. And potentially, this is why sometimes rather than added activity, we are seeing synergy—more than you expect even if you add [to the] response of [the] single agent. Perhaps there is a reason behind that. And there is preclinical data to back that up.
What is the status of the axitinib plus avelumab phase III study in RCC?
Based on the encouraging activity with the phase Ib, there is a phase III now accruing—so untreated patients with good performance status. They will be randomized to standard sunitinib versus the combination of axitinib plus avelumab, looking at progression-free survival (PFS) as a primary endpoint and overall survival (OS) as a secondary endpoint. We will also be looking at PD-L1 expression and its correlation to outcome. The trial is actively enrolling patients.
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