Improving Outcomes in Patients With Chromophobe, Papillary RCC

A roundtable discussion, moderated by Katy Beckermann, MD, PhD, discussed the treatment sequencing, management, and future directions of advanced or metastatic kidney cancer, as well as relevant clinical trial data from the 2024 American Society of Clinical Oncology Annual Meeting. Dr. Beckermann was joined by Yousef Zakharia, MD; Pavlos Msaouel, MD, PhD; Benjamin Maughan, MD, PharmD; and David McDermott, MD.

In the fifth segment of the roundtable series, the panel explores the latest research to improve treatments for rare subtypes of kidney cancer, emphasizing the need for biology-driven trials, patient selection, and the importance of both broad randomized trials and targeted studies for advancing understanding and therapies.

View the next segment on Refractory RCC: Third-Line Treatment Considerations.

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Dr. Beckermann: I wanted to express my appreciation for the rapid oral abstract that you co-authored, Dr. Msaouel, aimed at retrospectively identifying effective treatments for chromophobe kidney cancer, involving over 100 patients. Could you provide some insights on that?

Dr. Msaouel: Approaching a hundred patients now, yes. What is exciting is the growing realization that therapies designed for clear cell renal cell carcinoma (RCC) may not be as effective for other subtypes, such as renal medullary carcinoma. In some cases, they may even exacerbate the condition. This underscores the importance of biology-driven research to enhance patient outcomes, recognizing that randomized trials are just 1 aspect of the solution. Advocates from the chromophobe community rightly emphasize the need for specific trials tailored to chromophobe RCC, similar to efforts underway for other rare subtypes like FH-deficient and translocation RCC.

The initial step involves collaboration among multiple institutions. This cannot be undertaken by 1 individual alone. First, we need robust clinical data to discern patterns and observations that can inform our research direction. Without comprehensive clinical insights, guiding fundamental research becomes challenging.

Early findings suggest that employing combination therapies in chromophobe kidney cancer, although not originally developed for this subtype, may offer superior outcomes compared to single agents like sunitinib. However, it is important to note that immunotherapy, including current immune checkpoint inhibitors, may not be as effective in chromophobe, either alone or in combination with TKIs developed for clear cell RCC.

These insights are valuable for guiding future research efforts. While collaborations continue to yield promising data, it is crucial not to prematurely conclude that we have all the answers. We must prioritize biology-driven trials for chromophobe and other subtypes such as FH-deficient and translocation RCC. This approach holds tremendous potential to advance our understanding and treatment of RCC and other cancers.

Dr. Beckermann: So in that data, based on initial clinical observations using drugs designed for the most common clear cell type, it seemed about 50% of patients benefited from an IO. Moving forward with our drug development and technological advancements, do you think the next step is to subtype them, explore gene expression, or conduct GNA whole exome sequencing? What do you see as the most achievable goal here?

Dr. Msaouel: That is a great question. We were eager to hear what insights people had. One consistent inquiry was about the subtypes, particularly regarding sarcomatoid chromophobe, which tends to show more P53 mutations. What are the findings in these cases? These are crucial patterns to investigate and biology to unravel. As you mentioned, we have even published the trial design; it is primed and ready. The statistics are set.

If you have a strategy to potentially activate a cold tumor—like chromophobe, compared to the hotter response in, say, renal medullary carcinoma, which does not respond well to standard immune checkpoint therapy—here is a strategy you can consider adding to a nivo/ipi backbone. You would not need hundreds of patients; realistically, 20 to 30 metastatic chromophobe patients could suffice. This approach allows for correlatives and advances in science. Even if the trial outcome is not positive, the correlatives will yield invaluable insights.

Dr. Beckermann: I find that approach fascinating. Shifting to non-clear cell types and the emerging data, you mentioned FH variants. Does anyone here have a particular interest in other non-clear cell types and ideas on how we should treat those patients? For instance, papillary, with the recent trials like PAPMET2.

Dr. Maughan: Absolutely, PAPMET2 is on the horizon. It is exciting to see the evolving mindset from lumping together all non-clear cell cancers to recognizing their biological distinctions. This shift is crucial for making real progress. Papillary, for instance, has garnered the most substantial data among non-clear cell types. Yet, there is much to uncover. Recent retrospective studies, similar to Dr. Msaouel’s work with chromophobe, have generated conflicting findings across different treatment approaches. Some suggest upfront combination therapies are superior, while others show no added benefit over sequential single-agent therapy. Clearly, there is still much to understand.

Currently, we are adapting therapies developed for clear cell to treat papillary, driven by their high response rates. But to truly advance, we need next-generation trials tailored specifically to papillary’s biological underpinnings. Historically, this was challenging due to papillary’s diverse nature. However, with updated WHO criteria distinguishing subtypes like FH-deficient or translocation, we are poised for progress. While we have effective tools in hand, ongoing clinical trials aim to optimize these treatments for papillary patients.

Dr. Beckermann: It is really exciting to see these ongoing randomized phase 3 trials specifically tailored for papillary in the non-clear cell setting.

Dr. Maughan: Absolutely, I am particularly enthusiastic about PAPMET2, which stands out as one of the most promising trials. It underscores our collective commitment to treating each disease distinctly and comprehensively. Trials like PAXIPEM in Europe and the international STELLAR trial, with significant US participation, reflect this global effort. While these trials do not yet focus on therapies tailored to papillary’s unique biology, they aim to optimize existing tools. It is a step forward, not the largest leap, but significant nonetheless. Moreover, the tissue databanks being amassed alongside these trials promise to propel the field forward.

Dr. Beckermann: Indeed, these trials mark our initial foray into prospective validation, offering invaluable insights into clinical responses and underlying biology. This foundational understanding will ideally pave the way for targeted drug development. Yet, the challenge remains in repurposing existing drugs or generating new excitement among our industry partners for rare subtypes like papillary. I am eager for PAPMET2’s outcomes and hopeful that our collaborative efforts will yield breakthroughs not just for papillary, but across rare tumors like chromophobe and renal medullary carcinoma. Hopefully, in 5 years, we will be discussing their underlying biology and novel therapies.

Dr. Maughan: You raise an excellent point about collaboration with institutions and industry partners. These trials illustrate not only our eagerness to advance knowledge but also the broader support from industry and governmental bodies to facilitate such trials, whether randomized or otherwise.

Dr. Zakharia: We are beginning to see a wealth of biomarker data emerge for non-clear cell carcinomas. At this meeting, for instance, we are presenting findings from a study on papillary RCC, involving comprehensive genetic analyses of 102 patients. We have identified genes like YTHDF-II and seq-XXI, showing significant implications for survival. Collaborative efforts like Caris’ POA are similarly crucial for understanding rare tumors.

Dr. Msaouel: I want to caution against what Dr. Monty Pal has aptly described as the “lumpers versus splitters” debate, analogous to the trade-off between robustness and relevance in data science and laboratory settings. While robustness ensures consistent inferences across varying conditions, relevance to individual patients demands deeper, nuanced approaches. It is crucial not to be dogmatic on either extreme but rather to apply methods that best suit the specific clinical scenario. This nuanced approach includes both robust randomized trials like PAPMET and exploratory, subtype-focused investigations.