McGregor and Participants Discuss Impact of Drug Efficacy and Histology on nccRCC Care

Bradley McGregor, MD (MODERATOR)

Director of Clinical Research

Lank Center of Genitourinary Oncology

Dana-Farber Cancer Institute

Assistant Professor of Medicine

Harvard Medical School

Boston, MA

EVENT REGION Connecticut, Maine, Massachusetts, Ohio, Rhode Island

PARTICIPANT LIST Randall R. Ingham II, MD | Kamal Sahu, MD | Owen B. Pickus, DO | Madhavi Gorusu, MD | M. Sheila Donnelly, MD | Stephanie A. Berg, DO | Christi Kim, MD

McGregor: What do you feel is the prognosis for patients with advanced or metastatic nccRCC, and how does it compare with ccRCC? Do you feel these patients do the same, better, or worse than [those with] clear cell RCC?

Ingham: It’s been a while since I’ve treated a patient with nccRCC, so I have to look it up and refresh myself. I don’t know the answer to that.

McGregor: Does anyone have any thought about this overall, how they tend to act in the clinic compared with their counterparts [with ccRCC]?

Sahu: I think they do worse.

McGregor: That’s been my experience. That’s what the literature has shown us over time. Overall, these patients, especially when their disease is metastatic, can have a worse outcome than those with ccRCC.

Sahu: I don’t know if that’s related to the lower incidence, and then we’re not able to run big trials the way we are able to do on the clear cell variant. I’m unsure if that has something to do with our lack of knowledge and inability to have new drugs for them. I think we’re just trying to replicate, or copy, how we treat patients with clear cell disease to our patients with nccRCC as well.

McGregor: Do you think about all patients with nccRCC the same?

Sahu: What I know, basically, is those with sarcomatoid RCC don’t do well. That’s a broad understanding; whenever I see sarcomatoid RCC, I don’t like to see that in the pathology, so that’s certainly [something] I’m aware of. I don’t know if there are subtypes in nccRCC that have a different prognosis.

McGregor: So you’re saying any patient with RCC with sarcomatoid features, you’re worried how they’ll do overall, or specifically [those with] nccRCC with sarcomatoid features?

Sahu: I was thinking any sarcomatoid.

McGregor: Sarcomatoid features can accompany any histology overall. Yes, I would agree—historically [this shows] very poor outcomes. But more recently, at least in ccRCC, it seems to be predictive of response to immunotherapy [IO], specifically with nivolumab [Opdivo]/ipilimumab [Yervoy], where the complete response rate is higher with nivolumab/ ipilimumab if they have sarcomatoid features, than patients with nonsarcomatoid ccRCC.^1,2

Pickus: In addition, doesn’t the MET driver have something to do with the outcome and treatment of this particular histology?

McGregor: Historically, MET-driven histology is what used to be called a type 1 papillary, or just true papillary overall chromosome 7 alterations. There are a lot of efforts underway to go beyond this histology-directed therapy to molecular-driven therapy. The ongoing SAMETA trial [phase 3; NCT03091192] is open at Dana-Farber Cancer Institute looking at MET-driven RCC and randomly assigning patients to savolitinib with durvalumab [Imfinzi] vs sunitinib [Sutent]…to try to see whether an inhibitor with immunotherapy does better than sunitinib alone.

DISCUSSION QUESTIONS

• What data impress you related to efficacy and safety of combination regimens in nccRCC? Which are most impactful when choosing a treatment regimen?
• Do the data in this setting change your perspective on prescribing monotherapy vs a combination?
  

Sahu: I would give it a shot with the doublet agent.... One thing is patients with chromophobe histology don’t do well with cabozantinib [Cabometyx]/nivolumab, and they do well with pembrolizumab [Keytruda]/ lenvatinib [Lenvima].^3,4 I will use those kinds of cues to navigate my choice of one or the other. I will focus on safety, and next, I will look for the overall response rate.

Pickus: For me, it’s always progression-free survival that matters the most, because overall survival can be impacted by other factors that are not related to the malignancy itself. Duration of response is not a whole lot different in reality. Safety is important, of course, but that’s always in the back seat, unless it’s particularly severe, in which case the patient has to make a decision, such as when you use chimeric antigen receptor T-cell therapy or transplant. But I do believe that the combination of tyrosine kinase inhibitor [TKI] with immunotherapy, specifically—it looks like lenvatinib and pembrolizumab looked the best from the KEYNOTE-B61 data [phase 2; NCT04704219] over even the use of cabozantinib/nivolumab.⁴

McGregor: It’s exciting to have some phase 2 trials in this space that are [making us] start thinking about these overall.

Gorusu: In the NCCN [National Comprehensive Cancer Network] guidelines, we don’t have much single-agent immunotherapy as the first line.⁵ Were there negative trials in the metastatic setting that led to them not choosing the single agent in the metastatic category?

McGregor: Even in ccRCC, single-agent immunotherapy is not generally a frontline option. We have data from a trial with pembrolizumab monotherapy; response rates were around 26% in nccRCC.⁶ It was published by David McDermott, MD, in the Journal of Clinical Oncology a couple of years ago. Most of the papillary are unclassified, but I think now we see response rates close to 50% with IO/TKI. We have randomized data for single-agent cabozantinib vs sunitinib.⁷ I think that’s why you don’t see so much of pembrolizumab alone. That’s why [the NCCN recommends] other useful circumstances for single-agent nivolumab or pembrolizumab.⁵

As you see data for IO/TKI, how do you put that in perspective when you look at something like results of the PAPMET trial [phase 2; NCT02761057], which showed that cabozantinib is better than sunitinib?⁷ Are these single-agent trial response rates enough to say that IO/TKI should be a standard, or do you need more?

Donnelly: It seems like, across the board, if you add immunotherapy, you’re always going to be using a winner.

Berg: I agree with Dr Donnelly. I think it will be challenging to not offer IO in the frontline setting because these are pretty compelling data for papillary disease, at least right now. I know it has not been compared with monotherapy, because these are all phase 2 trials, but it’s tough not to offer it. We use it all the time, all of us do so. It’s tricky with how all of these pan out, in a lot of other diseases as well.

McGregor: You mentioned papillary, so do you think about the different histologies a bit differently?

Berg: I think it is different, even for papillary. You mentioned the SAMETA trial—we also know that there are some people who do well without TKI and just IO alone, so that’s why we have these other trials to compare…in papillary to help answer that question. But I think if they’re not going on trial,…as long as they could tolerate IO, I would be very hesitant to not give it to them unless it’s something really out of the box, where you’re using chemotherapy and things like that. But for all the other patients, I would be hard-pressed not to use it in the first line.

DISCUSSION QUESTIONS

• What factors influence your choice for treating with approved agents vs enrolling your patient in a clinical trial?
• How does your treatment approach vary based on histology?
  

Sahu: Isn’t papillary the most common nccRCC variant?

McGregor: Yes, papillary is about 80% of the divergent histologies, including all of the different types of papillary.

Sahu: That makes me more comfortable when I see papillary because we have a better understanding compared with the other histologies. That’s all I can comment, because they are so rare. But when I see papillary, I can find some treatment for this patient because we have the maximum data on this.

McGregor: Do the [combination] data change how you think about histologies? If you hadn’t thought about histology before, how do the data make you think about different histologies?

Kim: I think for patients with rare histology, I would prioritize a clinical trial enrollment…. For the most part, it’s a toxicity and tolerability issue as well, like cabozantinib/nivolumab vs lenvatinib/pembrolizumab. There are some major differences in terms of patient tolerability and toxicity. It’s hard to have a patient stay on lenvatinib at 20 mg, the prescribing dose in the guidelines. I think for the most part, for papillary histology, I prefer cabozantinib/ nivolumab. That has been my preferred option. But for other rare histology, clinical trials probably are the best approach.

Pickus: There’s been evidence in a trial that lenvatinib plus pembrolizumab was superior in translocation type. There was the KEYNOTE-B61 trial that demonstrated superior overall response rates in regard to a very small trial.⁸

McGregor: There were patients with translocation in KEYNOTE-B61, and they had comparable efficacy. The numbers were much smaller, but yes, I think we saw response rates that were maybe slightly higher than we saw with the entire patient population. There [are] obvious limitations with single-arm data. We’re looking forward to phase 3 trials.

There are randomized trials ongoing. SUNNIFORECAST [NCT03075423] is looking at nivolumab/ipilimumab vs sunitinib in diverse histologies; that’s a randomized phase 2 that’s completed accrual. Then we have another trial of zanzalintinib and nivolumab vs sunitinib in diverse histologies, which continues to enroll. Another trial looked at cabozantinib/atezolizumab [Tecentriq] vs cabozantinib, and that is also open.

I think we’re going to have randomized data in this space in the next couple of years to hopefully validate what we see in the single-arm trials…. If you start thinking about diverse histologies, there’s been a lot of movement forward…. Our pathologists are getting much better at telling us what we’re treating, so how do we treat patients differently? How do we use that? [My thought is to] start getting histology-based trials or molecular-based trials. I think that trials today have shown we can do it…. We now have SAMETA, which is nearing its accrual goal at the end of the year. There is a lot of excitement that we can continue to advance care, and I think eventually we’ll do a whole presentation just on the divergent histologies.

REFERENCES:

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2. Thouvenin J, Masson C, Boudier P, et al. Complete response in metastatic clear cell renal cell carcinoma patients treated with immune-checkpoint inhibitors: remission or healing? How to improve patients’ outcomes? Cancers (Basel). 2023;15(3):793. doi:10.3390/cancers15030793

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7. Pal SK, Tangen C, Thompson IM Jr, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet. 2021;397(10275):695-703. doi:10.1016/S0140-6736(21)00152-5

8. Voss MH, Gurney H, Atduev V, et al. First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): extended follow-up of the phase 2 KEYNOTE-B61 study. J Clin Oncol.2024;42(suppl 4):2. doi:10.1200/JCO.2024.42.4_suppl.2