3: Traversing the Complexities of Non-Clear Cell Renal Cell Carcinoma

Oncology Decoded

This episode of Oncology Decoded tackled the challenging landscape of non-clear cell renal cell carcinoma (nccRCC), a heterogeneous group of tumors representing about 20% to 25% of all kidney cancers. The episode provided expert insights into the diagnosis and management of this complex disease.
Meet the panel discussants:

• Manojkumar Bupathi, MD, MS, executive co-chair of Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute; medical oncologist with Rocky Mountain Cancer Centers specializing in solid tumors and genitourinary cancers;
• Benjamin Garmezy, MD, associate director of Genitourinary Research and executive co-chair of Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI); medical oncologist at SCRI Oncology Partners specializing in genitourinary cancers;
• Stephanie A. Berg, DO, medical oncologist for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute.

The conversation centered around a case presentation: a 63-year-old female with papillary RCC, presenting with significant weight loss, cough, a large renal mass, and multiple pulmonary and bone metastases.
The panel emphasized the importance of accurate pathological diagnosis, highlighting the diverse subtypes within nccRCC, including papillary, chromophobe, translocation, and collecting duct carcinomas. They acknowledged the limitations of historical treatment approaches, which have yielded suboptimal response rates and progression-free survival (PFS).
The discussion then delved into the evolving treatment landscape, focusing on recent clinical trial data. The phase 2 PAPMET trial (NCT02761057) of cabozantinib (Cabometyx) vs sunitinib (Sutent) in patients with advanced RCC. The emergence of newer VEGF-selective TKIs, such as tivozanib (Fotivda), also showed promise in disease control.
The panel highlighted the growing role of immunotherapy (IO) in nccRCC, particularly the combination of cabozantinib and nivolumab (Opdivo), which showed encouraging response rates in non-chromophobe subtypes. Similarly, the combination of lenvatinib and pembrolizumab demonstrated significant PFS and overall response rates across various nccRCC subtypes, including chromophobe.
In the absence of clinical trials, the panel recommended a personalized approach to treatment, considering the patient's subtype, disease burden, and comorbidities. They generally favored IO-TKI combinations, such as lenvatinib plus pembrolizumab, for most patients with nccRCC, while acknowledging the potential role of ipilimumab (Yervoy) plus nivolumab (Opdivo) in select cases, particularly those with chromophobe histology and low disease burden.
The panel also addressed the role of radiation therapy in nccRCC, particularly for oligometastatic disease and oligoprogressive disease. They emphasized the importance of multidisciplinary collaboration with radiation oncologists to optimize treatment strategies.
Regarding molecular testing, the panel acknowledged its limited role in guiding treatment decisions at present but highlighted its potential to identify patients with specific genetic alterations, such as MET amplification or FH deficiency, who may benefit from targeted therapies or germline testing.
Finally, challenges of sequencing therapies in nccRCC were discussed, emphasizing the lack of definitive data and the need for individualized treatment decisions. They generally favored sequencing TKIs, such as tivozanib or sunitinib, after progression on IO-TKI combinations, but acknowledged the need for further research to optimize treatment sequencing.
Reference
Tripathi A, Tangen C, Li X, et al. Pathologic concordance rate and outcomes by histologic subtype in advanced papillary renal cell (pRCC) carcinoma: An analysis from the SWOG S1500 (PAPMET) trial. J Clin Oncol. 2023;41(suppl 16):4562. doi:10.1200/JCO.2023.41.16_suppl.4562
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