Exploring New Horizons in Kidney Cancer Treatment: An Interview with Dr. Ilya Tsimafeyeu

Non-clear cell renal cell carcinoma (nccRCC) is a challenging kidney cancer subtype. Dr. Ilya Tsimafeyeu, Director of the Bureau for Cancer Research, recently presented promising results from a study on pembrolizumab and lenvatinib at the ASCO Breakthrough Meeting. In this interview, he discusses advancements in nccRCC treatment and the potential of personalized therapies.

On August 8, 2024, at the American Society of Clinical Oncology (ASCO Breakthrough) Meeting in Japan, you presented the results of a prospective phase 2 study on the efficacy and safety of pembrolizumab and lenvatinib in patients with papillary renal cell carcinoma (RCC).

As the Principal Investigator and Director of the Bureau for Cancer Research – BUCARE, can you tell me about non-clear cell kidney cancer?

Dr. Tsimafeyeu: Certainly. Non-clear cell renal cell carcinoma (nccRCC) refers to a diverse group of renal tumors that do not consist of at least 50% clear cells. Unlike clear cell RCC, these variants differ significantly in structure and biology, which impacts disease progression. Papillary RCC is the most common subtype within this heterogeneous group.

Are there any differences in the TNM classification between clear cell RCC and nccRCC?

Dr. Tsimafeyeu: The current TNM classification system does not differentiate between RCC subtypes, despite their distinct biological behaviors and treatment responses. As we gather more data and understand these differences better, creating subtype-specific classifications could potentially refine prognosis and treatment strategies. This approach, as seen in lung cancer or head and neck tumors, allows for more tailored treatment plans and could significantly impact patient outcomes. However, the feasibility and practicality of implementing such a system would require thorough research and consensus within the medical community.

Is nccRCC a significant issue in terms of incidence?

Dr. Tsimafeyeu: Certainly. Non-clear cell renal cell carcinoma accounts for roughly 15% of all kidney tumors. Given that approximately 400,000 new cases of RCC are diagnosed globally each year, this translates to about 60,000 cases of nccRCC annually. This is a significant number, indicating that nccRCC is not a rare occurrence.

However, the actual proportion of nccRCC cases is somewhat uncertain. The “15%” figure has been widely cited but is based on older data from past WHO pathological classifications. Our understanding of nccRCC has evolved, and improvements in pathomorphological diagnostics may affect the reported incidence.

Recognizing this, the Bureau for Cancer Research is currently conducting an epidemiological study to more accurately assess the prevalence of various nccRCC subtypes. To ensure the study’s representativeness, we plan to include over 1,000 patients from 10 different regions. This comprehensive approach should provide a clearer picture of nccRCC’s incidence in the population.

How often do you recommend immunohistochemical and molecular testing to detect non-clear cell variants of RCC?

Dr. Tsimafeyeu: We’ve been giving this a lot of thought. Alongside my colleague and best pathologist, Prof. Grigory Raskin, we’ve developed an algorithm for routine practice. We recommend immunohistochemical and molecular testing for all patients with grade 3 clear cell RCC, mixed tumors consisting of clear and papillary cells, as well as for any patients diagnosed with non-clear cell forms. This approach aims to ensure a precise assessment and better-informed treatment decisions. This initiative is currently a pilot project, so we’re eagerly awaiting the results to see its effectiveness.

Considering the complexities of nccRCC diagnosis, what challenges do you see in pathology, and how do you address them?

Dr. Tsimafeyeu: One significant challenge is that not all pathologists are familiar with the various forms of nccRCC, especially with the updates from the 2022 WHO classification. This can lead to inconsistencies in diagnosis and treatment planning. Another challenge we’re facing is the availability of resources. Not all laboratories of pathology are equipped with the necessary assays for these tests, which can limit the accessibility and consistency of these assessments.

To address this, in countries where there may be a lack of expertise or resources, I recommend organizing centralized testing in specialized laboratories of excellence. Centralized testing can ensure more accurate and consistent results, as these labs are equipped with the latest tools and staffed by experienced pathologists who are up-to-date with the latest classifications and diagnostic criteria.

Nonetheless, we’re optimistic that novel testing will improve diagnostic accuracy and patient outcomes as it becomes more widely adopted.

Let’s discuss treatment, starting with surgery. Are there specific considerations for nccRCC?

Dr. Tsimafeyeu: Surgical principles are generally consistent across RCC types. However, data suggest partial nephrectomy is more common in nccRCC patients with tumors up to stage T3a compared to clear cell RCC. For instance, radical nephrectomy is more frequent in cystic RCC cases despite the higher occurrence of smaller tumors. Conversely, for advanced cases like those with tumor thrombus, nccRCC has been associated with worse outcomes, underscoring its role as an adverse prognostic factor. Surgical treatment approaches for each nccRCC subtype should be studied, but this is not happening at this moment.

Given the higher recurrence risk in locally advanced nccRCC, what are the options for adjuvant therapy?

Dr. Tsimafeyeu: Unfortunately, there is no established adjuvant therapy for nccRCC post-surgery that reduces the risk of recurrence. While pembrolizumab is recommended for very high-risk clear cell RCC per the ESMO 2024 guidelines, clinical trials remain the primary options for nccRCC.

Your recent presentation at ASCO Breakthrough focused on systemic therapy for metastatic papillary RCC. Could you elaborate on the treatment approaches and your study?

Dr. Tsimafeyeu: Historically, options like sunitinib or mTOR inhibitors were used, with limited success. The phase 2 SWOG 1500 trial then established cabozantinib as a superior first-line treatment for papillary RCC. Recently, the success of checkpoint inhibitors and tyrosine kinase inhibitors in treating metastatic clear cell RCC inspired a similar exploration in nccRCC. Given the biological differences, it was logical to investigate whether these therapies could also benefit nccRCC patients, particularly since previous treatments showed limited efficacy.

The first significant exploration in this direction was the phase 2 KEYNOTE-427 study, which evaluated pembrolizumab monotherapy in 165 patients with nccRCC, primarily those with the papillary subtype.

The results were promising, with an objective response rate (ORR) of 26.7%, a median progression-free survival (PFS) of 4.2 months, and a median overall survival (OS) of 28.9 months. These outcomes were particularly noteworthy given the satisfactory tolerability profile of the treatment, marking a positive shift in the management of nccRCC.

Building on these findings, in 2021, we initiated a prospective phase 2 study focusing on the combination of pembrolizumab and lenvatinib, targeting patients with metastatic papillary RCC who had not undergone prior therapy. We adopted a two-stage Simon design for this study. In the first stage, we enrolled 5 patients, all of whom showed a positive response to the treatment—resulting in an unprecedented 100% ORR. This included one complete response and four partial responses.

These remarkable results prompted us to proceed to the second stage of the study.

However, just as we were preparing to expand the study, the 2023 ASCO Annual meeting presented findings from the KEYNOTE-B61 study, led by Chung-Han Lee and colleagues. This large prospective multicenter phase 2 trial included 158 patients treated with the pembrolizumab-lenvatinib combination. The study met its primary endpoint, reporting an ORR of 49.4%, a median PFS of 17.9 months, and a one-year OS rate of 82.2%. These were unprecedented results in the treatment of nccRCC, especially for the papillary subtype.

Given the strong positive outcomes from the KEYNOTE-B61 study, we decided to pause further patient recruitment in our study, as the pembrolizumab-lenvatinib regimen had already demonstrated considerable efficacy. This combination is now a viable treatment option in real-world clinical practice.

We continue to monitor our initial cohort: three patients remain on pembrolizumab and lenvatinib, one experienced disease progression after 14.3 months, and another was withdrawn due to uncontrolled grade 3 diarrhea. Encouragingly, all patients have survived beyond a year, highlighting the potential of this combination therapy to improve outcomes in nccRCC patients.

You are talking about the combination of pembrolizumab and lenvatinib. Has the combination of pembrolizumab and axitinib been explored in this context?

Dr. Tsimafeyeu: Yes, the Italian cohort study NEMESIA investigated this combination in 32 patients with metastatic papillary and chromophobe RCC, reporting a 43.7% objective response rate and a median PFS of 10.8 months. These findings demonstrate promising options for nccRCC treatment.

Thank you for sharing these insights, Dr. Tsimafeyeu.

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