Dr Westbrook on Clinical Trials That Have Shaped the Non-ccRCC Treatment Paradigm

“A lot of [oncologists] have experience using nivolumab plus cabozantinib in ccRCC. For many [oncologists who manage non-ccRCC], that combination might be their first choice, so it’s familiar. [However], in terms of the strength of the evidence, CA-209 9KU is a small study.”

Thomas Westbrook, MD, assistant professor, Department of Internal Medicine, Rush University, discusses the research in non–clear cell renal cell carcinoma (non-ccRCC) that informs his clinical practice.

The phase 2 CA-209 9KU trial (NCT03635892) was a single-center trial that enrolled 47 patients with non-ccRCC—a significantly smaller population number than those studied in trials such as the phase 2 KEYNOTE-B61 (NCT04704219) or SUNNIFORECAST (NCT03075423) studies, Westbrook begins. Although the combination investigated in CA-209 9KU, nivolumab (Opdivo) and cabozantinib (Cabometyx), is familiar to many oncologists and may be a first-line treatment choice for patients with ccRCC, the strength of evidence from CA-209 9KU is limited due to its noncomparative design and small sample size, he explains. This limitation is particularly evident in the data for rarer non-ccRCC subtypes, such as chromophobe RCC, he notes. Seven patients with chromophobe RCC were initially included in the trial, but data from this cohort were not consistently reported in subsequent updates, he says.

Despite these limitations, the CA-209 9KU regimen remains a viable treatment option, he reports. However, the KEYNOTE-B61 trial of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) has demonstrated more robust data than CA-209 9KU, according to Westbrook. This single-arm trial enrolled 158 patients with non-ccRCC, including chromophobe (n = 29), papillary (n = 93), and unclassified (n = 21) disease subtypes. The larger sample size and broader representation of histologic subtypes in KEYNOTE-B61 resulted in narrow confidence intervals and relatively reliable findings, he states. The trial reported a median PFS of 18 months (95% CI, 14-not reached), with insufficient follow-up data to determine the median overall survival, he explains.

Cross-trial comparisons between CA-209 9KU and KEYNOTE-B61 are unreliable due to differences in the trials’ baseline patient populations, Westbrook emphasizes. However, the KEYNOTE-B61 regimen has emerged as a preferred non-ccRCC treatment option for many oncologists, he says, although nivolumab plus cabozantinib may also be considered.

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Thomas Westbrook, MD, discusses the non–clear cell renal cell carcinoma research that informs his clinical practice.

Dr Westbrook on the Potential Use of ccRCC Therapies in Non-ccRCC

Thomas Westbrook, MD, assistant professor, Rush University Medical Center, discusses the investigation of approved treatment options for patients with clear cell renal cell carcinoma (ccRCC) treatments in the context of non-ccRCC treatment.

The adaptation of therapies from the ccRCC treatment arena to the non-ccRCC therapeutic landscape have become standard practice, though responses vary significantly across disease subtypes, Westbrook begins. Notably, certain non-ccRCC subtypes, such as collecting duct carcinomas and renal medullary carcinomas, are more responsive to chemotherapy than most other RCC subtypes, he says. Despite this, treatments originally studied and used in ccRCC, including mTOR inhibitors, TKIs, and immunotherapies, are frequently tested in non-ccRCC, he explains. Some clinical trials have included all RCC subtypes, yet the non-ccRCC cohorts are often small, creating barriers to drawing definitive conclusions for disease subtypes such as chromophobe RCC, he notes.

Over time, the kidney cancer treatment field has developed increasing awareness that non-ccRCC entities should not necessarily be treated identically to ccRCC or even to each other, given the unique biological drivers across all subtypes, he emphasizes. Although response variability remains across subtypes, there have been notable successes with ccRCC therapies in non-ccRCC cases, he reports. Many non-ccRCC tumors exhibit sensitivity to TKIs and immunotherapies that have demonstrated efficacy in ccRCC, Westbrook states. The broader applicability of these agents may stem from multi-targeted TKIs, which inhibit multiple pathways and may effectively address various non-ccRCC tumors, he says. Thus, although non-ccRCC tumors have diverse biological profiles, their responsiveness to some ccRCC-derived therapies highlights the therapeutic potential of these agents in these subtypes and underscores the need for further research to optimize treatments based on individual tumor characteristics, he notes.

Regarding the National Comprehensive Cancer Network guidelines for the treatment of patients with non-ccRCC, the first recommendation is clinical trial enrollment, Westbrook explains. Preferred frontline regimens include cabozantinib (Cabometyx) as monotherapy and in combination with nivolumab (Opdivo), as well as lenvatinib (Lenvima) plus pembrolizumab (Keytruda), he says. Everolimus plus lenvatinib is a strong second-line regimen for patients who have not received upfront lenvatinib plus pembrolizumab, he concludes.

Thomas Westbrook, MD, discusses the investigation of approved ccRCC treatments in patients with non-ccRCC.

Dr Westbrook on the Evolving Understanding of Non–Clear Cell RCC Subtypes

Thomas Westbrook, MD, hematologist/medical oncologist, assistant professor, Department of Internal Medicine, Rush University Medical Center, discusses the evolving understanding of non–clear cell renal cell carcinoma (nccRCC) and implications for clinical practice.

nccRCC represents a heterogeneous group of renal cancers, Westbrook begins. Non–clear cell indicates the absence of clear cell histology, but the category encompasses dozens of distinct subtypes. This classification does not denote a single disease, but rather a collection of diverse entities, he emphasizes.

Advancements in molecular pathology have been pivotal in distinguishing these subtypes, Westbrook explains. As molecular diagnostic tools improve, the ability to identify the unique characteristics of each renal carcinoma subtype has expanded. This deeper understanding is essential for tailoring therapeutic approaches to the individual patient, he adds. Westbrook also highlights that molecularly defined subtypes of renal cell carcinoma (RCC) are increasingly being recognized as separate entities, reflecting the growing importance of molecular pathology in the diagnostic process for suspected renal cancers.

Updates to the World Health Organization (WHO) 2022 classification of kidney tumors have further refined this evolving landscape, Westbrook notes. The major update to the WHO classification of renal tumors includes the distinction between clear cell RCC, papillary RCC, oncolytic and chromophobe RCC, collecting duct RCC, as well as the addition of other renal tumors and molecularly defined RCC as distinct subtypes. 

Westbrook concludes that nccRCC is not a single diagnosis but a spectrum of distinct subtypes, each with its own molecular characteristics. Continued research into defining these molecular subtypes will be useful for guiding future therapeutic decisions and improving outcomes for patients with this complex and difficult-to-treat disease.

Thomas Westbrook, MD, discusses the evolving understanding of non–clear cell renal cell carcinoma subtypes and implications for clinical practice.

Thomas Westbrook, MD

Articles

Dr Westbrook on Clinical Trials That Have Shaped the Non-ccRCC Treatment Paradigm

Dr Westbrook on the Potential Use of ccRCC Therapies in Non-ccRCC

Dr Westbrook on the Evolving Understanding of Non–Clear Cell RCC Subtypes