Joseph Vento, MD, is an assistant professor in the Department of Internal Medicine at the University of Texas Southwestern Medical Center in Dallas. 

Vento

“[NGS] helps develop precision medicine approaches and would [help us find abnormalities that] we’re not frequently finding—like 

Joseph Vento, MD, an assistant professor in the Department of Internal Medicine at the University of Texas Southwestern Medical Center; as well as a medical oncologist at the Harold C. Simmons Comprehensive Cancer Center, discussed the clinical significance of using somatic next-generation sequencing (NGS) to guide treatment decisions for patients with non–clear cell renal cell carcinoma (non-ccRCC).

Given the heterogeneity of non–clear cell subtypes—including papillary, chromophobe, and unclassified histologies—Vento emphasized the importance of precision oncology approaches to improve outcomes in this population. In his practice, Vento routinely orders somatic NGS for patients with advanced or metastatic non-ccRCC to identify actionable genomic alterations that could inform treatment selection. Although targetable findings, such as 

 fusions, are uncommon, their detection can be clinically meaningful, offering additional therapeutic opportunities and potentially life-prolonging benefits with ALK-directed agents. He highlighted a case series demonstrating the value of this approach and noted that even infrequent discoveries across the field can substantially affect individual patient care.

Beyond rare gene fusions, Vento explained that NGS provides broader insights into tumor biology and may uncover other actionable pathways, such as 

-driven papillary RCC. These findings could support the use of targeted agents in select patients, he emphasized. Additionally, as tumor-agnostic drug approvals expand, identifying genomic alterations with relevance across tumor types has become increasingly important, he stated. Accumulating molecular data from NGS testing also contributes to a growing evidence base that can refine future therapeutic strategies for non-ccRCC and beyond, he noted. According to Vento, incorporating somatic NGS into routine care is most relevant for patients with advanced or metastatic disease, who represent most of the cases managed at tertiary cancer centers.

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Joseph Vento, MD, discusses the importance of using somatic NGS to guide treatment decision-making for patients with non–clear cell RCC.

Dr Vento on the Clinical Significance of Somatic NGS in Guiding Treatment Decisions for Non–Clear Cell RCC

“Having more molecularly driven subtypes is very helpful for studying these very unique non–clear cell subtypes. A lot of times we throw around this term of non-ccRCC, as if we’re referring to one disease, but we’re really referring to a lot of different diseases, and they’re all very different.”

Joseph Vento, MD, an assistant professor in the Department of Internal Medicine at The University of Texas Southwestern Medical Center, underscored the importance of refining the classification of non–clear cell renal cell carcinoma (non-ccRCC) to improve stratification of the disease's molecular heterogeneity.

Although commonly grouped under a single category, non-ccRCC encompasses a range of biologically distinct malignancies, each with unique clinical behaviors and therapeutic implications, according to Vento. Traditionally, treatment strategies for non-ccRCC have often been extrapolated from studies conducted in ccRCC, Vento explained. However, this approach overlooks the distinct biology that characterizes subtypes like papillary, chromophobe, collecting duct, translocation-associated, and medullary RCC, he noted. He emphasized that improved characterization of the molecular features and drivers underlying these entities is critical for designing more effective therapeutic strategies.

Translational research has begun to illuminate how mutational landscapes, signaling pathways, and tumor immune microenvironments differ across non–clear cell subtypes, he said. Vento noted that these insights are reshaping the understanding of disease mechanisms and informing the rationale for developing subtype-specific therapies. By correlating molecular features with clinical presentation and treatment response, investigators are moving closer to a precision medicine framework in which therapy is tailored to the underlying biology of each subtype rather than applied uniformly across all non–clear cell disease, he highlighted.

At the clinical trial level, Vento pointed to the growing importance of incorporating molecular stratification into study design. Historically, non-ccRCC has been underrepresented in prospective studies, limiting evidence-based treatment options for these rare populations, he stated. Subtype-directed trials, informed by genomic and transcriptomic data, clarify therapeutic sensitivity and aid in identifying predictive biomarkers for immunotherapy and targeted agents, he emphasized. This, he explained, represents a critical shift away from the “one-size-fits-all” approach that has long characterized the field.

Joseph Vento, MD, discusses the importance of refining RCC classification standards to improve the field’s understanding of the disease’s heterogeneity.

Dr Vento on the Importance of Refining the Classification of RCC to Better Account for Molecular Heterogeneity

Joseph Vento, MD, highlights the role of IO/TKI combinations for the treatment of patients with non–clear cell renal cell carcinoma. 

Dr Vento on the Role of IO/TKI Combos in Non–Clear Cell RCC

“For specific subtypes, such as papillary RCC, this notion of unclassified RCC or RCC not otherwise specified, and maybe even [in] chromophobe RCC and translocation RCC, this IO/TKI approach is a reasonable frontline treatment in the current setting.”

Joseph Vento, MD, an assistant professor in the Department of Internal Medicine at University of Texas Southwestern Medical Center, discussed the role of immuno-oncology (IO) plus TKI combinations as a treatment option for patients with non–clear cell renal cell carcinoma (RCC).

Currently, there are 2 large ongoing studies evaluating IO/TKI combinations, including a phase 2 trial (NCT03635892) examining cabozantinib (Cabometyx) plus nivolumab (Opdivo) in non–clear cell RCC, and the phase 2 KEYNOTE-B61 trial (NCT04704219) investigating pembrolizumab (Keytruda) plus lenvatinib (Lenvima) for the same patient population, Vento began. He noted that in both studies, patients have experienced promising overall response rates (ORRs) across a variety of non–clear cell RCC subtypes. Specifically, in patients with papillary RCC, unclassified RCC, RCC not otherwise specified (NOS), chromophobe RCC, and translocation RCC, IO/TKI combinations could be a reasonable treatment in the frontline setting, he explained. However, with more studies assessing molecular drivers in non–clear cell RCC, Vento added that it’s important to consider more specific factors in respective subtypes, such as 

-driven papillary RCC. With this consideration, utilizing MET inhibitors to target certain subgroups that would demonstrate responses could be a next step, he said.

Furthermore, in the chromophobe RCC space, Vento explained that there has been more translational research regarding pathways involved and whether targeting pathways involved with IL-15 for apoptosis. Nevertheless, he emphasized that it’s important to have reasonable frontline treatment for at least some subtypes of non–clear cell RCC with cabozantinib/nivolumab and pembrolizumab/lenvatinib that have produced higher ORRs. Still, additional work needs to be done in this space to investigate other approaches beyond IO/IO and IO/TKI combination, including other clear cell RCC regimens as options for patients with non–clear cell RCC, he concluded.

Joseph Vento, MD

Articles

Dr Vento on the Clinical Significance of Somatic NGS in Guiding Treatment Decisions for Non–Clear Cell RCC

Dr Vento on the Importance of Refining the Classification of RCC to Better Account for Molecular Heterogeneity

Dr Vento on the Role of IO/TKI Combos in Non–Clear Cell RCC