Clinical and Logistical Factors Determine Treatment Choice for nccRCC

Treating advanced non-clear cell renal cell carcinoma (nccRCC) poses challenges due to differing outcomes by histology and limited trial data. In a virtual Case-Based Roundtable event for oncologists in Illinois, Indiana, and Missouri, moderator Randy F. Sweis, MD, assistant professor of medicine at University of Chicago Medicine, asked participants how they would choose to use a tyrosine kinase inhibitor (TKI) or immunotherapy (IO) in their regimen. In addition to the unresolved questions from trial data, participants raised practical issues like out-of-pocket costs for oral therapies and logistical difficulties getting access to clinical trials.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

DISCUSSION QUESTIONS

• Thinking about the most recent data for nccRCC trials:​
• Do the data change your perspective on prescribing monotherapy vs a combination? IO/TKI vs IO/IO?

Melhem Jabbour, MD: Sometimes for ccRCC we do monotherapy, if they’re older. We do nivolumab [Opdivo] only because they cannot tolerate a combination. Is it OK to do that in nccRCC?

Randy F. Sweis, MD: PD-1 monotherapy is on the NCCN guidelines as other recommended treatment.¹ Do you ever do PD-1 alone, especially if you’re worried about somebody who might be frail with TKI toxicity…? I will say I like that approach, in a sense.

One of the problems is, we had data with cabozantinib [Cabometyx] in papillary RCC. It’s the only randomized data in papillary…the PAPMET trial [NCT02761057] that showed cabozantinib seemed to have a better progression-free survival [PFS] than sunitinib.¹ Cabozantinib became the de facto standard of care for papillary in particular, and then everybody just moved to cabozantinib/nivolumab. We now have data for cabozantinib/nivolumab, but it’s never been randomized to compare cabozantinib/nivolumab vs cabozantinib alone.²

There is a trial, PAPMET2 [NCT05411081], that’s looking at that question, but a lot of people say, “I don’t want to accrue to it, because why would I just give cabozantinib if I can give cabozantinib/nivolumab?” The important question is, if you give cabozantinib followed by nivolumab, is that the same or even better than if you give cabozantinib/nivolumab together? Conversely, to the point that was raised, what if you just give PD-1 alone, and then give cabozantinib if they don’t respond?

We don’t have data for that, but these are good questions. I like thinking about IO first, because unless they have rapidly growing [disease] or high burden of disease, if you have a window where you can afford some tumor growth if you’re wrong. If it’s a chance at a durable remission, IO seems preferable to try first, and then you may never need TKI if it’s one of these lucky patients who has an incredible response. It’s less common with nccRCC than ccRCC, so I don’t use that rationale too loosely, but it’s a good point.

So, do the data I just shared change your views for either TKI/IO vs IO/IO?

Allen Greenberg, MD: I still think I am probably going to use more IO/IO…. If I feel a patient can’t tolerate dual checkpoint inhibitors, [I would] probably [use] IO/TKI. The data are more impressive with the lenvatinib arm, but I don’t know what to make of [the cabozantinib/nivolumab] study that only had 40 patients.^2,3

Sweis: Yes, and only the IO/IO was randomized, albeit with a control arm that may not be what most people are doing in current practice in the US. Any other thoughts on that?

Lisa Baddi, MD: It’s also good because for a lot of these people, they can’t afford it. They’re often older, and the oral [TKI] can be a significant out-of-pocket cost. With an IO/IO combination, there’s no out-of-pocket cost because they’re both intravenous infusions. Particularly if you have somebody who isn’t going to be able to afford the out-of-pocket cost of the TKI, then you have the all-intravenous option for those patients.

Sweis: That’s an important consideration, and not to mention drug-drug interactions and polypharmacy with patients managing lots of pills. It’s one less pill. To some extent, that’s easier. Have you had a lot of challenges with copays or issues with these TKI drugs?

Baddi: It is difficult for the Medicare patients. Sometimes they have high out-of-pocket costs. It’s always there, but none of them are prepared to pay it. That is an issue, and you can’t get assistance for the Medicare patients. If they’re younger, you can get assistance through the companies, but if they’re older, you cannot, and some of them just simply don’t have the money to pay for that.

DISCUSSION QUESTIONS

• What factors influence your choice for treating with approved agents vs enrolling your patient in a clinical trial?​

Sweis: Do you refer patients when you see nccRCC, or do you treat with these treatment paradigms we just talked about first and then refer [upon progression]? What’s the referral pattern for clinical trials?

Jabbour: I [have] a friend in a tertiary center, which is good. [I can ask], “Hey, should I do this? Should I send it to you? Do you prefer a clinical trial?” It’s good to have connections. It really helped, because he does more trials. I don’t do any trials where I practice. I try to take his opinions, because they do trials for genitourinary [cancers] all the time. He said to go ahead and start cabozantinib/nivolumab, for example. He said there was no need to bring him there. I believe it’s always good to ask a colleague.

Sweis: Good point. There may not be trials for nccRCC, which is pretty rare. We have one open, not for the front line, but with a novel mechanism of action drug that’s pretty exciting. But that’s few and far between, other than phase 1 trials, but those are not typically going to be first line or even second line.

Baddi: I think in the first line, we have some reasonable options. We’re in the Chicago metro area, but with the horrific construction that there is everywhere, going from one side of the city to the other for a clinical trial can sometimes take 2 and a half hours one way [even if] it’s only 20 miles away. You have to have a really motivated patient. You’d be surprised how many people that live on the north side will refuse to ever go on the highway. We do have some reasonable first-line options, so we would definitely consider a second line.

Sweis: Definitely, that’s a big issue that we think about all the time, and we’re trying to address by trying to get trials out in our other sites, but it is a real problem.

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DISCLOSURES: Sweis previously reported consulting fees from Eisai; institutional research support from ALX Oncology, Ascendis, Astellas, AstraZeneca, Bayer, Bristol‐Myers Squibb, CytomX, Eisai, Genentech/Roche, Gilead, Immunocore, Jounce, Lilly, Loxo, Merck, Mirati, Moderna, Novartis, Pfizer, Pionyr, Pyxis, QED Therapeutics, and Scholar Rock; and a patent: neoantigens in cancer, PCT/US2020/031357.

REFERENCES

1. Barata P, Tangen C, Plets M, et al. Final overall survival analysis of S1500: a randomized, phase II study comparing sunitinib with cabozantinib, crizotinib, and savolitinib in advanced papillary renal cell carcinoma. J Clin Oncol. 2024;42(33):3911-3916. doi:10.1200/JCO.24.00767

2. 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

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