Garmezy Highlights Ongoing and Future Research Directions Across RCC Subtypes

In an interview with OncLive^® regarding his presentation at an Institutional Perspectives in Cancer webinar on prostate cancer/renal cell carcinoma (RCC), Benjamin Garmezy, MD, provided an overview of recent data on immuno-oncology (IO)/TKI combination data in variant RCC, spotlighted potentially practice-changing research being conducted with novel TKIs and HIF-2α inhibitors, and emphasized the importance of sharing information from academic or research settings with community oncologists who can treat patients with RCC closer to home.

“Within the next 5 years, [I hope] we see an explosion of drugs with different mechanisms of action outside of immunotherapy, VEGF TKIs, or HIF-2α inhibition that we can leverage for patients who need it,” said Garmezy, who is a medical oncologist and the assistant director of Genitourinary Research at Sarah Cannon Research Institute, Tennessee Oncology in Nashville.

Garmezy further highlighted advances with frontline immunotherapy and TKI regimens in both clear cell and variant RCC in another article.

OncLive: Could you briefly discuss current data on the use of IO/TKI combinations in variant RCC?

Garmezy: We had recent triplet data with cabozantinib [Cabometyx], nivolumab [Opdivo], and ipilimumab [Yervoy], which was found to be toxic and is probably not where we need to move in variant RCC. We also have pembrolizumab [Keytruda] and lenvatinib [Lenvima], which is perhaps the most exciting option right now for variant RCC. [This combination] produced response rates [in the] 40% range for papillary disease, 28% for chromophobe disease, and between 50% and 60% for other unclassified disease. That looks good [in a setting] where previously we didn’t have good data.

We’ve seen early data fail [to be maintained] when [regimens] get to regulatory phase 3 trials, so we do need to keep pushing the field forward and run the studies, but that’s exciting. Responses with cabozantinib and nivolumab are in the 40% range as well, and we know from the single-agent efficacy that cabozantinib is a very good TKI for papillary disease. Perhaps some of that is the MET signaling [pathway that] cabozantinib can target in some of the papillary tumors, or perhaps it’s just a good VEGF TKI. We still need to complete that work. Those are the regimens I’m seeing. 

There’s an old dataset looking at lenvatinib plus everolimus [Afinitor] in chromophobe disease, which shows response rates in the 40% range. This is another reasonable option, though, I find myself gravitating more towards pembrolizumab and lenvatinib for those patients and then providing everolimus as a subsequent line of therapy in those patients who don’t achieve a response.

What ongoing research in this disease has the potential to change practice?

There are some other agents coming down the pike that could change the landscape. There’s the phase 2 PAPMET2 trial [NCT05411081] looking at cabozantinib plus atezolizumab [Tecentriq] vs a single-agent TKI [in papillary RCC]. If that [produces positive results], maybe we’ll have greater evidence for that [regimen] in papillary disease.

We have a trial looking at a new VEGF TKI called zanzalintinib [XL092] in combination with nivolumab vs sunitinib [Sutent] in variant disease. This could be a potential game changer, finally [providing us with] a regulatory phase 3 trial with level 1 evidence. We’ll follow that story as well. There’s a lot to be done, and more trials to be designed in this space. These aren’t the only 2 trials out there, and more are coming. Ultimately, the key thing is that we can’t leave these patients behind.

What have we seen thus far with HIF-2α inhibition in clear cell RCC, and what other future directions for research in RCC would you like to highlight?

The most exciting things happening in clear cell RCC right now revolve around HIF-2α inhibition. The phase 3 LITESPARK-005 trial [NCT04195750] presented at the 2023 ESMO Congress showed that belzutifan [(Welireg) was superior to] everolimus as far as progression-free survival [PFS]. The median PFS is similar [between arms], but there seems to be a tail of the curve, which means there’s a subset of patients where that HIF-2α inhibition can salvage and provide a durable response. A lot of investigators in the field are wondering about the best [role] for this mechanism of action, and we all think [that its use in] earlier lines might be better. There are trials right now in clear cell disease where HIF-2α inhibition would work best in combination with pembrolizumab and lenvatinib in the upfront setting vs many different investigational arms.

What about subsequent line settings? There were also data presented at the 2023 ASCO Annual Meeting suggesting that second- or third-line HIF-2α and VEGF TKI [combinations] could be a reasonable option to increase the response rates and perhaps allow HIF-2α [to produce durable responses]. There’s novel HIF-2α inhibitors out there that could fall into this space as well. Whether HIF-2α inhibitors end up in the frontline or the second line, I do expect that they will be moving up in the treatment paradigm over the next few years.

A lot of newer drugs [being currently evaluated] are potentially exciting. We have bispecific antibodies, CAR T cells, and antibody-drug conjugates all moving into RCC. Hopefully HIF-2α is the start of new mechanisms of action for our patients.

What is your main message for community oncologists based on your presentation?

It’s always great for community doctors to get together, whether it’s in person or virtually, and share data about specific tumor types. A lot of these doctors that we provide education for, they see all tumor types and that’s hard. This is a harder job than myself and my colleagues in the genitourinary research space have because they must know everything and be on top of their game. The providers who come to listen to us are really the boots on the ground, providing the care for the patients in their community. As investigators, we need to keep in mind that we [conduct research] to help the patients and help the providers who have access to those patients, so that those patients don’t have to travel far to get help from an academic institution. [Academic institutions] are great places, but a lot of those patients can’t travel. They need to be treated in their homes, in their communities, and it’s great that we have clinicians to provide that education so that they can serve the patients and achieve that mission.