Outcomes for patients with advanced or metastatic non-clear cell renal cell carcinoma (nccRCC) are generally poorer compared to those with clear cell RCC (ccRCC), necessitating a more nuanced approach to treatment. Experts in genitourinary oncology are increasingly focusing on histology-directed and molecular-driven therapies to improve patient outcomes in this heterogeneous disease. A recent discussion among oncologists highlighted the impact of drug efficacy and histological subtypes on nccRCC care.
The Prognostic Challenge of nccRCC
Historically, nccRCC has been associated with worse outcomes, partly due to the lower incidence of these cancers and the resulting lack of large-scale clinical trials. According to Dr. Bradley McGregor, Director of Clinical Research at Dana-Farber Cancer Institute, "Overall, these patients, especially when their disease is metastatic, can have a worse outcome than those with ccRCC." This disparity underscores the urgent need for targeted therapies and improved treatment strategies.
Sarcomatoid features, present in various RCC histologies, have historically indicated poor prognosis. However, recent data suggest that in ccRCC, sarcomatoid differentiation may predict a better response to immunotherapy (IO) combinations like nivolumab/ipilimumab, with higher complete response rates observed in these patients.
Efficacy and Safety of Combination Regimens
The combination of tyrosine kinase inhibitors (TKIs) with immunotherapy is emerging as a preferred strategy in nccRCC. Phase 2 data from the KEYNOTE-B61 trial suggest that lenvatinib plus pembrolizumab may offer superior outcomes compared to other TKI/IO combinations, such as cabozantinib/nivolumab. Dr. Owen Pickus noted that progression-free survival is a critical endpoint, as overall survival can be influenced by factors unrelated to the malignancy itself.
Specific histological subtypes appear to respond differently to various treatments. For instance, chromophobe RCC may not respond well to cabozantinib/nivolumab but shows better outcomes with pembrolizumab/lenvatinib. These observations emphasize the importance of considering histology when selecting treatment regimens.
The Role of MET-Driven Therapy
MET-driven histology, historically referred to as type 1 papillary RCC, is another area of focus. The ongoing SAMETA trial (NCT03091192) at Dana-Farber Cancer Institute is evaluating savolitinib with durvalumab versus sunitinib in MET-driven RCC to determine if a MET inhibitor combined with immunotherapy can outperform sunitinib alone.
Clinical Trial Landscape and Future Directions
Several clinical trials are underway to validate the efficacy of IO/TKI combinations in nccRCC. The SUNNIFORECAST trial (NCT03075423) is comparing nivolumab/ipilimumab versus sunitinib in diverse histologies, while another trial is assessing zanzalintinib and nivolumab versus sunitinib. Additionally, a trial is investigating cabozantinib/atezolizumab versus cabozantinib alone.
Dr. McGregor emphasized the importance of histology-based and molecular-based trials to further refine treatment strategies. "Our pathologists are getting much better at telling us what we’re treating, so how do we treat patients differently? How do we use that? Start getting histology-based trials or molecular-based trials."
For patients with rare nccRCC histologies, clinical trial enrollment is often prioritized. However, treatment decisions are also influenced by toxicity and tolerability considerations. For papillary histology, cabozantinib/nivolumab is often preferred due to its favorable tolerability profile.
Data from the KEYNOTE-B61 trial indicated that lenvatinib plus pembrolizumab demonstrated superior overall response rates in patients with translocation-type nccRCC, although the sample size was small. These findings warrant further investigation in larger, randomized trials.
As diagnostic capabilities improve and more data emerge from ongoing clinical trials, the treatment landscape for nccRCC is expected to evolve, leading to more personalized and effective therapies for this challenging group of cancers.
