Future Directions in nccRCC: SAMETA, FORTUNE, and Second-Line Treatment

A roundtable discussion, moderated by Laurence Albiges, MD, PhD, discussed the risk stratification and management of metastatic non-clear cell renal cell carcinoma (nccRCC), along with recent advancements in targeted therapies and immuno-agents, treatment sequencing and combination approaches, and adjuvant therapy options. Dr. Albiges was joined by Renée Maria Saliby, MD, MSc; Tian Zhang, MD; and Shahla Bari, MD.

In the final segment of the roundtable series, the panel concludes with an overview of advancements and upcoming trials in the treatment of nccRCC, focusing on combination therapies and biomarker-driven approaches.

View previous segments of the roundtable discussion.

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Dr. Albiges: We are making progress. We have moved from single-agent to combination therapy, expanding progression-free survival and likely overall survival, although we need randomized data for the latter.

What are the next steps in terms of development? Dr. Saliby, can you comment on the CALYPSO trial and the current efforts in papillary RCC with the SUMMIT program?

Dr. Saliby: The future seems bright for nccRCC. We’re heading in the right direction with the SAMETA trial, a phase 3 randomized trial specifically designed for patients with MET-driven papillary RCC.

Dr. Albiges: We have discussed that about 33% of patients with papillary RCC have MET-driven disease. It is not just about mutations; it is about the ligand, amplification, or gain around chromosome 7. These used to be considered lower-grade papillary RCC, where the MET pathway plays a role. It is a biomarker-driven trial in a rare entity, making it very challenging, but it is a phase 3 study, so are we looking at combination therapy here?

Dr. Saliby: We are looking at a combination based on MET mutation amplification in papillary RCC. One treatment is durvalumab, an immune checkpoint inhibitor, combined with savolitinib, which directly targets MET. The other arms involve durvalumab and sunitinib as monotherapy. This trial is built on the success of CALYPSO, which showed promising results with savolitinib targeting MET in papillary RCC. I think this is the most exciting trial we have right now.

Dr. Albiges: That is a biomarker-driven trial in a rare entity.

Are there other trials we expect to read out? I have heard about SUNNIFORECAST, an academically-led German study enrolling across Europe. Why is this trial important?

Dr. Saliby: This trial is crucial, and the name reflects its positive outlook. We are evaluating nivolumab plus ipilimumab, which has had great success in clear cell RCC and in untreated patients with metastatic nccRCC. It is compared to the standard of care for these patients. We are excited about this trial’s readout.

Dr. Albiges: We had some results with nivolumab and ipilimumab in nccRCC, but this trial is randomized against standard care and includes various histologies. Hopefully, we will get results subtype-by-subtype, identifying who benefits from the doublet IO strategy.

Dr. Saliby: In the past, we had retrospective data and small cohorts in larger trials evaluating nivolumab and ipilimumab. Here, we are targeting non-clear cell with enough numbers to look at individual subtypes.

Dr. Albiges: Are there other trials we are awaiting?

Dr. Saliby: Yes, there is the FORTUNE trial, a phase 2 study evaluating tivozanib and nivolumab in patients with nccRCC. These patients may have had up to 1 line of systemic therapy before enrolling.

These are the main big 3 trials we are waiting for.

Dr. Albiges: We are waiting for randomized data, aiming for biomarker-based selection, targeting each subtype when feasible, especially papillary, which is the most common. Hopefully, we will also have trials for other rarer entities, highlighting the need for pathological review and referrals to tertiary centers for innovative treatments given the poor prognosis of these rare entities.

Dr. Bari: Yes, and global collaboration is essential due to the difficulty of agreement within 1 institution.

Dr. Zhang: Absolutely. Dr. Albiges, you mentioned the STELLAR program. We should discuss it. STELLAR-002 combines XL092 with nivolumab in various kidney cancer subtypes, including non-clear cell cohorts. It will be important to pay attention to each histology cohort and how XL092 with nivolumab performs as a combination.

Dr. Albiges: Exactly. It is early-stage phase 1 data, but hopefully progressing to more advanced stages.

We only discussed frontline. What is your strategy for patients who failed IO/TK regimens? How do you treat them in second-line?

Dr. Zhang: We have data on different TKIs. For example, if a patient with papillary kidney cancer had lenvatinib and pembrolizumab frontline, I would switch to cabozantinib second-line. Always consider trials, right? We have some enrolling in second-line and beyond. It is important to consider trials as patients move through treatment lines.

Dr. Albiges: Thank you very much. It was interesting to hear your perspectives. This field is rapidly evolving, so we need to stay up-to-date on new trials and ensure that patients with rare entities are referred to centers where they can access innovative treatments, including in the adjuvant setting and, hopefully, in later lines as well.