Novel Targeted Agents in Development, But Will Compete With Immunotherapy in RCC

Toni K. Choueiri, MD

Targeted therapies are continuing to evolve the landscape of renal cell carcinoma (RCC), but their maximum potential will likely be tested in combination with immunotherapy agents, according to Toni K. Choueiri, MD.

In a field that blossomed 3 FDA approvals over the last year—the PD-L1 inhibitor nivolumab (Opdivo), the MET/VEGF inhibitor cabozantinib (Cabometyx), and the combination of lenvatinib (Lenvima) and everolimus (Afinitor), the key strategy in RCC, he adds, will be combining them.

For instance, a multicenter, open-label, phase III randomized trial is investigating the combination of lenvatinib with either pembrolizumab (Keytruda) or everolimus versus sunitinib (Sutent) as a treatment for patients with advanced RCC (NCT02811861). The primary endpoint of the study is progression-free survival (PFS).

In the 5-arm, phase I CheckMate-106 trial, the safety of nivolumab is being explored in combination with sunitinib, pazopanib (Votrient), and ipilimumab (Yervoy) in patients with metastatic RCC (NCT01472081). The nivolumab/ipilimumab cohort will be studied at 3 doses: 1 mg nivolumab/3 mg ipilimumab, 3 mg nivolumab/3 mg ipilimumab, and 3 mg nivolumab/1 mg ipilimumab.

Other targeted agents are in development for another RCC population. Complete findings are anticipated from a phase II trial of the c-MET inhibitor volitinib (AZD6094) in patients with papillary RCC, a subset Choueiri says could be an interesting therapeutic option (NCT02127710). Phase I results showed that 3 patients achieved a partial response, and 1 patient experienced a best tumor response of 25% from baseline.¹

OncLive: Volitinib is a novel agent in development for RCC. What can you share about that research?

What are the plans for this agent in the future?

In an interview with OncLive during the 15th International Kidney Cancer Symposium in Miami, Florida, Choueiri, who is clinical director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, and a senior physician at the Dana-Farber Cancer Institute, dives into the ongoing research with volitinib, the competing yet complementary roles of targeted agents and immunotherapy, and the most important steps to take with biomarker research in the field of RCC.Choueiri: This is a specific MET inhibitor; it’s a very clean MET inhibitor. Early studies have shown activity in a rare form of RCC called papillary RCC. Some of these patients—not all of them—do harbor alterations in the MET gene or MET pathway. In these patients, volitinib can be a very interesting choice. In the early results, it seems the drug is well tolerated.The first is a complete analysis of a phase II trial. The phase II trial enrolled approximately 108 patients with papillary RCC who were treated with this drug. This was a single-arm study that looked at response rate across subgroups, PFS, and safety. It will be important to understand the safety of the drug.

We need to look at the data, and the data are evolving. We have built in a translational program inside this trial that looks specifically at patients with MET alternations; we have collected their blood samples. It will be interesting, and the results will be presented at a future medical meeting.

Though this MET inhibitor would be indicated for papillary RCC, could it potentially compete with the other MET inhibitors we have available in clear cell RCC?

We have witnessed several key advances and 3 recent drug approvals in RCC. What’s next?

Based on that, and if we see the level of activity—especially in the MET-positive population, we will see how we can develop this drug further. One of the reasons is, again, this is an unmet need. Unlike clear cell RCC, it seems that there is a subset of patients in papillary RCC that are driven by MET. This is genomic medicine, or precision medicine, at its best in RCC.Well, it is possible. Cabozantinib is another MET inhibitor though it has activity against other kinases, such as the VEGF receptor. That agent has been in trials mostly focused on patients with clear cell histology, and the VEGF inhibitor is a cornerstone in RCC clear cell biology. This is a bit different.Over the last 2 years—even perhaps less, when we thought that the field was stalling—we had 3 drugs approved: the combination of lenvatinib with everolimus, cabozantinib that targets the VEGF receptor, and nivolumab as an immune checkpoint inhibitor. This is a proof of concept. It’s almost like a snowball. We are going to have so many other trials. Actually, in frontline, there are many trials around checkpoint inhibitors, such as nivolumab, pembrolizumab, atezolizumab (Tecentriq), and others.

We do have trials in the second-line setting. The field is moving extremely fast to catch up.

When you have drugs like this, they not only get applied to the metastatic setting or to the clear cell setting but, suddenly, they move to a different unmet need of the disease. This is the non—clear cell setting, the adjuvant setting, and the perioperative setting, so we have several trials.

There is a very important trial, for example, in the perioperative, neoadjuvant, and adjuvant settings, led by Dr. Lauren Harshman. It is an ECOG study with nivolumab preoperatively followed by postoperative therapy versus placebo—trying to prime the immune response and continue it.

As you know, nivolumab is a very well-tolerated drug. Suddenly, we have new drugs being invested in the adjuvant setting. We have 1 study with sunitinib that is positive in the adjuvant setting for disease-free survival, and another larger one that is negative. Therefore, we are waiting.

Will we ever reach a point where immunotherapy agents will compete with the available targeted therapies?

At this point, my standard of care remains observation. However, we are waiting to see what’s going to happen. Is sunitinib going to be approved in the adjuvant setting? In a way, it’s very good news for patients. They have more options. There are a lot of unmet medical needs in RCC that are being addressed and, at the same time, it’s a crazy time for us physicians to keep up with everything that is going on in RCC.I think so. I think it is already competing, and immunotherapy may overtake targeted therapy. Despite that, VEGF TKIs are here to stay for a long time, but they are not curative. Immunotherapy may also offer this slim hope of a cure and the new immuno-oncology drugs seem to be well tolerated, though the best strategy will be combination.

We have to proceed carefully. We have some combinations such as nivolumab and cabozantinib in general genitourinary tumors, axitinib (Inlyta) with pembrolizumab, pembrolizumab with lenvatinib, and atezolizumab with bevacizumab (Avastin). These are VEGF-targeted agents versus PD-1/PD-L1 inhibitors. On paper and in single-arm studies, they seem to provide some synergy and enhanced efficacy compared with each agent alone. They seem to be tolerated well.

Is biomarker development an important next step to determine who may benefit from monotherapy versus combination regimens?

Earlier studies of full-dose sunitinib or pazopanib have shown that, on their own, patients need a lot of dose reduction from toxicity. But when they are combined with nivolumab, it was actually not the way to go. Perhaps we go with a lower dose—who knows. But now with [combinatorial options] such as bevacizumab, axitinib, even with cabozantinib at lower doses, it seems that you can get through this—but you need to be careful. You will have these very interesting and very intriguing responses. The field is probably going to go that way in RCC.Yes, we will try doing that. It will be ideal to have a blood test or, in retrospect, a biomarker on the tissue that can guide you certainly to [choose therapy]. Thus far, everything has not panned out. The reason is, even in biomarker-negative patients, we are seeing responders.

The biomarker field will advance and will answer questions. The question is, will that biomarker make sense enough to make it to clinical use, like estrogen receptor-positivity or HER2-positivity in breast cancer? Or, is it a biomarker that is just associated with a statistical difference that is actually not very clinically relevant? That will be the ultimate question.

1. Gan HK, Lickliter J, Millward M, et al. cMet: Results in papillary renal cell carcinoma of a phase I study of AZD6094/volitinib leading to a phase 2 clinical trial with AZD6094/volitinib in patients with advanced papillary renal cell cancer (PRCC). J Clin Oncol. 2015;33(suppl; abstr 487).

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