Navigating the Treatment Landscape in Non–Clear Cell Renal Cell Carcinoma

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Although clear cell histology is the most common type of renal cell carcinoma (RCC), non–clear cell RCC (nccRCC) accounts for approximately 25% of RCC cases and comprises a broad group of variant histologies with heterogeneous clinical features, biologies, and treatment responses. nccRCC histologies include papillary RCC (15%), chromophobe RCC (5%), and other rare subsets such as collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), and translocation RCC, among others.¹ Collectively, nccRCC has an overall poor prognosis compared with the more common clear cell subtype. In recent years, the World Health Organization’s pathologic classification for kidney cancers has been updated with nomenclature changes and identification of new RCC entities with distinguishing molecular signatures. Thus, collaboration with expert pathologists is imperative for accurate nccRCC classification and optimal treatment decision-making.

There have been challenges with the optimal management of nccRCC. Patients with variant RCC have been historically excluded from RCC clinical trials, which mainly enrolled patients with clear cell RCC. Due to the rare frequency of nccRCC, prospective data for nccRCC have been limited to small, single-arm studies with a lack of high-quality randomized data to guide treatment selection. There is no currently accepted standard of care for nccRCC. Thus, it is critical for patients with newly diagnosed and refractory nccRCC to be referred for clinical trial opportunities at specialized academic centers.

Immunotherapy Combinations in nccRCC

Immune checkpoint inhibitors have revolutionized the treatment landscape in RCC. Recently, data from the SUNNIFORECAST study (NCT03075423) of ipilimumab (Yervoy) plus nivolumab (Opdivo) as frontline therapy for advanced nccRCC was reported.² In this German-led investigator-initiated randomized trial, patients with untreated metastatic nccRCC (mostly papillary RCC) were randomly assigned to combination ipilimumab and nivolumab vs the standard of care per investigator’s choice, which was mostly VEGF-targeted tyrosine kinase inhibitor (TKI) monotherapy with sunitinib (Sutent). The study met its unconventional primary end point of 12-month overall survival (OS) rate, which was 78% with ipilimumab and nivolumab and 68% with standard of care (P = .026).² However, there were no differences in median OS and other landmark OS rates at 6 and 18 months. The combination of ipilimumab and nivolumab had an objective response rate (ORR) of 33% compared with 19% with standard therapy. Enhanced ORR (70%) with the immunotherapy combination was also noted in the subset of nccRCC with sarcomatoid features, although this was a very small cohort of 10 patients. In addition to the primary end point selection, other limitations of this study included the heterogeneity of nccRCC subtypes enrolled and standard-of-care therapies in the control arm. Nonetheless, this study represented progress toward more randomized studies in nccRCC and continued to demonstrate the promising activity of immune checkpoint inhibitors in variant RCC subtypes.

Although the contribution of CTLA-4 inhibition with ipilimumab in nccRCC remains to be further investigated, the addition of TKI agents with immune checkpoint inhibitors remains a promising approach for nccRCC. Indeed, regimens such as cabozantinib (Cabometyx) plus nivolumab and lenvatinib (Lenvima) plus pembrolizumab (Keytruda) have demonstrated encouraging activity and raised the bar with ORRs near 50%.^3,4 Although these regimens are listed in the NCCN guidelines for nccRCC, it is important to note that data supporting these TKI combinations are still limited to single-arm phase 2 studies without robust randomized data. The majority of clinical trials for nccRCC have historically grouped together all the various nccRCC subtypes. Given the heterogeneity within nccRCC, evaluating the data by individual nccRCC histologies can be more impactful in guiding treatment selection.

Papillary RCC

As the most common nccRCC subtype, papillary RCC is characterized by MET alterations in up to 80% of cases, which represents a unique therapeutic target.^5-7 The PAPMET study (NCT02761057) was a pivotal study conducted through the SWOG Cancer Research Network that evaluated the role of MET inhibitors in papillary RCC.⁸ In this randomized, phase 2 study, patients with unselected papillary RCC who were previously treated with up to 1 line of therapy were randomly assigned to receive either MET inhibitors cabozantinib, crizotinib (Xalkori), or savolitinib (Orpathys in China) vs sunitinib. After an interim futility analysis, the savolitinib and crizotinib arms closed, which made the trial a 2-armed study of cabozantinib vs sunitinib. The study met the primary end point of progression-free survival favoring cabozantinib over sunitinib (9 months vs 6 months; HR, 0.6; 95% CI, 0.37-0.97; P = .019). While it did not demonstrate OS benefit, the PAPMET study was one of the largest randomized studies in nccRCC and demonstrated the promise of MET-directed approaches in papillary RCC.

Beyond cabozantinib monotherapy in papillary RCC, a single-arm, phase 2 study evaluated the combination of cabozantinib with nivolumab in patients with advanced nccRCC of several histologies who had up to 1 prior therapy.³ The ORR among the 32 patients with papillary RCC was 47%.⁹ Although lenvatinib does not target MET, a phase 2 study of lenvatinib plus pembrolizumab as first-line therapy for nccRCC demonstrated an ORR of 54% in papillary RCC.⁴ This may suggest that other pathways, beyond MET, are involved in papillary RCC.

Fumarate hydratase (FH)–deficient RCC is a hereditary form of kidney cancer in which germline FH inactivation leads to upregulation of hypoxia-inducible factors (HIFs) and increased HIF-mediated transcription of VEGF and EGFR, which may also be seen in sporadic papillary RCC.^10,11 A phase 2 study of bevacizumab (Avastin) and the EGFR inhibitor erlotinib (Tarceva) included a cohort of patients with FH-deficient RCC and a separate cohort with sporadic papillary RCC who had up to 2 prior therapies.¹² Although the ORR was 51% in all patients, the ORR in the papillary RCC cohort was 37%, demonstrating potential activity. Overall, cabozantinib monotherapy or in combination with nivolumab, as well as lenvatinib plus pembrolizumab and bevacizumab plus erlotinib, are standard options for papillary RCC.

Chromophobe RCC

Although chromophobe RCC is generally indolent, up to 10% of cases will metastasize, with a subset having sarcomatoid differentiation, which portends poor prognosis.¹³ Chromophobe RCC generally has poor response rates with limited data on treatment efficacy. However, there seems to be a potential role for lenvatinib-based combinations for chromophobe RCC. A single-arm, phase 2 study evaluated the combination of lenvatinib with everolimus in patients with newly diagnosed nccRCC.¹⁴ Among 9 patients with chromophobe RCC, the ORR was 44% with the combination. The lenvatinib/pembrolizumab study included a higher number of patients with chromophobe RCC (29 patients) in which the ORR within this subset was 28%.⁴

Collecting Duct Carcinoma and Renal Medullary Carcinoma

CDC and RMC are distinct nccRCC subtypes that should be approached differently than other RCC tumors. CDC is an exceptionally rare subtype that behaves similarly to urothelial carcinoma and responds to platinum-based chemotherapy. In a small, phase 2 study, the combination of gemcitabine with cisplatin (or carboplatin) resulted in an ORR of 26% among patients with CDC.¹⁵ Beyond platinum chemotherapy, CDC may also respond to cabozantinib, which had an ORR of 35% in this subtype.¹⁶

RMC is an aggressive subtype that is predominantly seen in young patients with sickle cell disease. Similar to CDC, RMC is responsive to platinum-based chemotherapy with an ORR of 29%.¹⁷ For refractory disease, other options for RMC include doxorubicin plus gemcitabine, as well as bevacizumab plus erlotinib.^18,19

Future Directions

Despite the recent focus on nccRCC, several challenges remain in the management of nccRCC. Additional research funding and focus are still needed to further elucidate the underlying biology and treatment strategies of rare subtypes. Specifically, more randomized and histology-specific studies are needed to generate high-quality evidence for nccRCC. Several randomized phase 3 studies, such as PAPMET2 (NCT05411081), STELLAR-304 (NCT05678673), and SAMETA (NCT05043090), are currently ongoing. Collaboration between community oncologists and academic centers to refer patients for participation in these important clinical trials will hopefully close the gap for this historically underrepresented group.

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