Choueiri Discusses Avelumab/Axitinib, Other Novel RCC Combos

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).

In the phase Ib JAVELIN Renal 100 trial, the combination induced an overall response rate of 58.2%, including complete response rate of 5.5% and a partial response rate of 52.7%. The disease control rate was 78.2%.

OncLive: Can you give an overview of this study?

In an interview with OncLive 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.Choueiri: 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.

The first one I want to talk about is the axitinib (Inlyta) plus avelumab (Bavencio) study. Axitinib is a potent VEGF receptor antagonist and is a standard second-line therapy. It is approved in the second-line, not first-line, but nevertheless has a good response rate in first-line—around 30%. So, based on that, axitinib was combined with avelumab, which is a PD-L1 inhibitor already approved in more than 1 solid tumor. It is approved in Merkel cell carcinoma and advanced refractory bladder cancer, and it has activity and a safe track record in many malignancies, including RCC.

These 2 drugs were combined and there are some toxicities, but overall, we did not have dose-limiting toxicities (DLTs), so we proceeded and had an expansion phase. We had some toxicities that were mostly related to axitinib or to avelumab—autoimmune toxicities versus toxicity related to class-effect of axitinib—hypertension, diarrhea, fatigue. What is interesting is this high response rate—around 60%. If you think about axitinib frontline at 30%, certainly there is a signal here of added activity and synergy, justifying the ongoing phase III trial of sunitinib (Sutent) versus the combination of axitinib and avelumab—that is accruing well so far.

With this avelumab/axitinib combination, we looked at PD-L1, like everyone else. There was almost double the response rate from the combination if the PD-L1 on the immune cell, by immunohistochemistry, was positive at 1% or more. This will also be looked at in the phase III trial, so this is promising.

Please discuss the potential synergy of the combination.

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.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.

What is the status of the axitinib plus avelumab phase III study in RCC?

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. 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.

The question is, in the next 5 to 10 years, if these trials are positive against a control—sunitinib let’s say—how do you proceed in the clinic with a first-line treatment? Are we going to have a biomarker where we can say, “This is the combination for that biomarker”? I hope so, but I don’t know. Or are we going to say, “Well look, that study showed PFS, but that other combination, for whatever reason, is showing PFS and OS.” Or is it going to be activity with toxicity? So, we are going to have a lot of discussion.

In addition to the ones mentioned, do you think we are going to see more combinations like this?

Certainly, the most important thing is that there are going to be more options for patients, and at the end of the day, that is what is important. Regarding what is first and what is second, leave that on us.Absolutely, there is a promising phase III trial combining axitinib with pembrolizumab (Keytruda). The preliminary data from the phase I showed a very high response rate of 71%. You also have a combination of lenvatinib (Lenvima) plus pembrolizumab—the phase I study showed very exciting activity—that is also going to a phase III comparing that combination with lenvatinib/everolimus (Afinitor), which is an approved combination.

Finally, just recently, there has been data from the phase I study that matured from Dr Andrea Apolo, who really led the task of combining cabozantinib (Cabometyx) with other immune checkpoint blockers. Dr Apolo combined cabozantinib with nivolumab and with ipilimumab (Yervoy) in another cohort. No DLTs were found, there were some toxicities of course, but she established the doses of the drugs, which involved a lower dose of cabozantinib and ipilimumab.

She has seen very good response rates with very hard-to-treat GU malignancies. For non-urothelial bladder, pure squamous cell tumors of the bladder, metastatic germ cell tumors that are highly refractory, urachal adenocarcinoma—she has seen around a 30% response rate in these rare tumors. Based on the safety of that combination, this has led to a phase III trial that was just recently announced, comparing sunitinib with a combination of cabozantinib plus nivolumab versus cabozantinib plus nivolumab plus ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (CheckMate 9ER; NCT03141177).

Of course, we still need to proceed extremely carefully, watching autoimmune side effects, VEGF side effects, and sometimes it is really hard—especially if both drugs give diarrhea and fatigue—but at least it is exciting. It gives some important primary endpoints of PFS and OS, which, if met, some patients could be cured, and you start seeing that shape of the curve plateauing and responses being durable on therapy or even better, off therapy.

Choueiri TK, Larkin JMG, Mototsugu O, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial. J Clin Oncol 35, 2017 (suppl; abstr 4504).