Discussing Immunotherapy Options in Advanced Non–Clear Cell RCC

Meet the experts

As part of a Satellite Sessions program focused on Memorial Sloan Kettering Cancer Center (MSK) and surrounding institutions, CancerNetwork hosted a panel discussion on variant histologies of renal cell carcinoma (RCC). The program was brought together to discuss immunotherapy (IO) options for non–clear cell RCC in light of emerging clinical trial data and National Comprehensive Cancer Network (NCCN) guidelines. The panel also discussed patient guidance for undergoing IO for non–clear cell RCC and parameters that are monitored.

The panel was led by Martin H. Voss, MD, clinical director of Genitourinary Medical Oncology at MSK. Panelists included Jarett Feldman, MD, a hematologist at White Plains Hospital; Benjamin A. Gartrell, MD, director of the Genitourinary Malignancy Program at Montefiore Einstein and assistant professor of oncology and urology at Albert Einstein College of Medicine; Jennifer Wu, MD, associate professor in the Department of Medicine at NYU Grossman School of Medicine, section chief of Hematology and Medical Oncology, and director at Bellevue Cancer Center; Lan Mo, MD, attending physician at Maimonides Medical Center; and Xinhua Zhu, MD, assistant investigator at the Institute of Health System Science, Feinstein Institutes for Medical Research, attending physician at RJ Zuckerberg Cancer Center, Northwell Health, and associate professor of Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.

Voss / Are you familiar with the [phase 3 KEYNOTE-B61 (NCT04704219)] data? If so, did it change your practice?¹ Are you using lenvatinib [Lenvima]/pembrolizumab [Keytruda] for the non–clear cells much, or are you not?

Wu / Yes, before the data came out, we used cabozantinib [Cabometyx] and then maybe nivolumab [Opdivo]. [Lenvatinib/pembrolizumab] is quite impressive, especially [because] it is a whole number of patients in all different subgroups. Chromophobes usually were not known to respond to any IO. I felt this was standard care.

Voss / Is it the standard of care for all non–clear cell variants, or do you pick out a winner?

Wu / For all non–clear cell.

Voss / For a while, we put every patient with non–clear cell RCC on [the phase 2 PAPMET2 trial (NCT05411081)], so automatically, we defaulted to this [regimen of cabozantinib with or without atezolizumab (Tecentriq)].² Then once the [phase 2 cabozantinib/nivolumab] study was published and updated, that was my go-to regimen for non–clear cell RCC because it was prospective, limited data.³ I have switched to lenvatinib/pembrolizumab since the data came out, not necessarily because I know it is the better regimen but because it is the more robust data set. It has more patients to lean on, and…I like to think of cabozantinib as my second-line option that I still have as a single agent in my pocket. I like that sequence, especially for non–clear [cell RCC].

The chromophobes are tricky, and I have been very interested in chromophobes. I have worked a ton with the immunologists at MSK, and we have projects where we have looked into it. Maybe a little unfairly, I have been very averse to using [IO] with chromophobes based on the work that I have done there. What do you do for chromophobes early on?

Zhu / I have been using pembrolizumab and lenvatinib.

Voss / What is your experience?

Zhu / I have seen 1 response in the 6 patients who I have treated.

Vos / Maybe there is a lesser proportion of chromophobes that have a [favorable] response to immune-based therapy. That is what the ipilimumab [Yervoy]/nivolumab German data say…20% [of patients] respond to pure IO.

The phase 2 KEYNOTE-B61 trial and the phase 2 cabozantinib/nivolumab trial bring home the same point; they see that you have high fidelity with an IO tyrosine kinase inhibitor–based regimen. They took a long time to make it onto the NCCN recommendation because they are single-arm phase 2 studies. They are not randomized trials, which is what the NCCN panel of experts loves.

The one thing I would be curious to hear…based on the data, [is whether] it matters if the NCCN now says to…do this or not. Dr Feldman, is it easier for you to get it approved to feel better about it?

Feldman / My practice is primarily following NCCN guidelines. If it is in the NCCN, I feel comfortable using it. If it is not, it is harder to use.

Voss / Because it is hard for you to keep up with all the data?

Feldman / It is hard to keep up to date and to get it approved.

Voss / What do you do, then?

Feldman / Typically, what I feel comfortable using in other histologies and adverse effect profiles. I feel like [I prefer] cabozantinib vs lenvatinib, if I am looking at adverse effects.

Voss / It is fair to use either. Most people will feel better about lenvatinib/pembrolizumab because [there are] bigger data, more patients, and it is not just 1 institution. Ultimately, they are similar in what they say, that if you love cabozantinib/nivolumab, what is not to like about it? In these 2 immune checkpoint inhibitor trials, lenvatinib/pembrolizumab, cabozantinib/nivolumab, toxicity also is comparable, and it is tricky to look at these for toxicity guidance because they are small data sets.

What guidance do you provide to patients when starting therapies, and what parameters do [you] monitor?

Mo / We always present a [handout]…to patients.

Voss / You print it off UpToDate, or how do you do it?

Mo / Yes, you can print it. We have our own program. We can even print different versions, [such as in] Chinese, English, and Russian.

Gartrell / We often give the patient handout from UpToDate, as well, but the most important thing is that we have [an in-depth] conversation, and we treat enough patients that we anticipate a lot of what is going to happen. We want to make sure the patient understands what is likely to occur. The last thing you want is for a patient [to have] a bad initial week or 2 of therapy and become disillusioned and not want to do it anymore. Usually, [I tell] them something [like], “Hey, we are going to give you the full dose.” Many patients require dose reductions.

These are the typical toxicities; they are generally reversible with a brief break and a dose reduction. That is…one of the most important parts of the conversation. We use Beacon order sets through Epic, and we build in the standard laboratory results that we check––the standard stuff. We check the thyroids, and we generally check a [urinalysis] or a protein and creatinine each time we see the patient. We are concerned about hypertension, particularly if we are going to start lenvatinib. Those are some of the things that we do.

References

1. Albiges L, Gurney H, Atduev V, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2023;24(8):881-891. doi:10.1016/S1470-2045(23)00276-0
2. Maughan BL, Plets M, Pal SK, et al. SWOG S2200 (PAPMET2): a phase II randomized trial of cabozantinib with or without atezolizumab in patients with advanced papillary renal cell carcinoma (PRCC). J Clin Oncol. 2024;42(suppl 4):TPS493 doi:10.1200/JCO.2024.42.4_suppl.TPS493
3. Fitzgerald KN, Lee, CH, Voss MH, et al. Cabozantinib plus nivolumab in patients with non–clear cell renal cell carcinoma: updated results from a phase 2 trial. Eur Urol. 2024;86(2):90-94. doi:10.1016/j.eururo.2024.04.025