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

Gina Columbus @ginacolumbusonc
Published: Friday, Nov 04, 2016

Toni K. Choueiri, MD

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

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.

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

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.

What are the plans for this agent in the future?

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.

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.

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?

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.

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

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.

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