Dr Xu on Changes in Systemic Therapy in RCC

Wenxin (Vincent) Xu, MD, physician, Dana-Farber Cancer Institute, and assistant professor of medicine, Harvard Medical School,provides insights into the rapid evolution of systemic therapy for patients with renal cell carcinoma (RCC), marked by significant developments and emerging treatment modalities.

The emergence of various systemic therapies has quickly altered the RCC treatment paradigm, Xu begins, noting that the most recent change came in December 2023, when 

 for the treatment of patients with advanced RCC following a PD-1 or PD-L1 inhibitor and a VEGF TKI, making it the first HIF2A inhibitor approved for patients with refractory kidney cancer. This introduction of a novel therapeutic class offers promise in addressing unmet needs in the treatment of RCC, Xu says.

Furthermore, Xu notes the significance of pembrolizumab (Keytruda) demonstrating efficacy in the adjuvant setting, with the first overall survival benefit demonstrated in this patient population, underscoring a shift in the standard of care, Xu explains.

In the realm of first-line metastatic RCC, ongoing trials evaluating doublet therapies continue to yield promising data, he continues. Recent findings suggest sustained benefits for the various approved combinations over single-agent TKIs, presenting opportunities for optimizing treatment strategies and improving patient outcomes, Xu notes.

Xu highlights the imperative need for biomarkers in guiding treatment decisions for RCC. Although the field has made progress through the combination of highly active agents, results from the phase 3 COSMIC-313 trial (NCT03937219), which evaluated the triplet of cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy), revealed potential limitations associated with indiscriminate combination therapy. Despite improved progression-free survival observed with the triplet in this study, significant toxicity underscores the necessity for more refined combination strategies tailored to individual patient profiles, Xu says.

Several trials are of interest in exploring biomarkers for predicting treatment response in RCC, he continues. One such trial focuses on mRNA gene expression signatures derived from prior phase 3 trials, aiming to differentiate patients more likely to respond to anti-VEGF therapy vs immunotherapy. Additionally, investigational biomarkers, including circulating biomarkers, hold the potential for informing treatment decisions and optimizing therapeutic outcomes, Xu says.

Xu emphasizes the importance of advancing precision medicine in RCC management through the integration of biomarkers into treatment algorithms. Continued research efforts are warranted to elucidate the utility of biomarkers in guiding treatment selection and optimizing therapeutic efficacy for patients with RCC, he concludes.

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Wenxin (Vincent) Xu, MD, on evolving systemic therapy and the utilization of biomarkers in the treatment of renal cell carcinoma.



Wenxin (Vincent) Xu, MD, discusses the factors he takes into account when sequencing treatment options for patients with metastatic renal cell carcinoma.

Dr Xu on Treatment Sequencing Considerations in Metastatic Renal Cell Carcinoma

Wenxin (Vincent) Xu, MD, physician, Dana-Farber Cancer Institute, and assistant professor of medicine, Harvard Medical School, discusses the factors he takes into account when sequencing treatment options for patients with metastatic renal cell carcinoma (RCC).

Every patient is unique and comes with their own set of considerations, with a key difference between patients being the severity of treatment-related toxicities in the frontline setting, Xu begins. In the second line, some patients who were initially treated with an immunotherapy plus TKI regimen may be worn down by TKI toxicity, Xu continues. For these patients, belzutifan (Welireg) is an option, allowing the patient to take a break from the rigors of TKI toxicity, Xu says.

In the phase 3 LITESPARK-005 trial (NCT04195750), patients with previously treated, advanced RCC who received belzutifan experienced a prolonged time to deterioration (TTD) by FKSI-DRS, QLQ-C30 GHS/QoL, and QLQ-C30 PF scores compared with those who were treated with the kinase inhibitor everolimus (Afinitor). At a median follow-up of 25.7 months (range, 16.8-39.1), the median TTD was not reached vs 11.99 months with belzutifan and everolimus, respectively, by FKSI-DRS (HR, 0.53; 95% CI, 0.41-0.69; 

 < .0001), 19.35 months vs 10.19 months, respectively, by QLQ-C30 GHS/QoL (HR, 0.75; 95% CI, 0.58-0.96; 

 = .019), and 19.32 months vs 13.83 months, respectively, by QLQ-C30 PF (HR, 0.93; 95% CI, 0.72-1.20; 

Conversely, patients who can tolerate TKI toxicities can receive a TKI in the second or even third line, Xu says. Options in later lines include cabozantinib (Cabometyx) or lenvatinib (Lenvima) plus everolimus; these regimens are still highly active in this setting, Xu explains. The goal is to sequence treatments in a manner that gives patients the best chance at a great response without compromising their safety or quality of life, Xu concludes.

Wenxin Xu, MD, physician, Dana-Farber Cancer Institute, instructor, medicine, Harvard Medical School, discusses future considerations for the treatment of patients with kidney cancer. 

The kidney cancer field is moving quickly, with several drugs gaining FDA approval for metastatic or adjuvant kidney cancer, Xu says. Going forward, determining the best combinations of therapies will be important, as, with several classes of medications to choose from, combination therapies need to have synergistic efficacy without excessive toxicity, Xu explains.

Additionally, these new classes of agents will need to be integrated into the treatment paradigm, Xu emphasizes. For instance, belzutifan (Welireg), which targets HIF-2α, is being compared with everolimus (Afinitor) in the refractory setting in the phase 3 MK-6482-005 trial (NCT04195750), which, if positive, may lead to the approval of belzutifan as a second- or third-line therapy, Xu says. Belzutifan may also demonstrate a benefit in the first-line setting, and additional ongoing trials with this agent and others will inform the future of kidney cancer care, Xu concludes.

Wenxin Xu, MD, discusses future considerations for the treatment of patients with kidney cancer. 

Wenxin Xu, MD

Articles

Dr Xu on Changes in Systemic Therapy in RCC

Dr Xu on Treatment Sequencing Considerations in Metastatic Renal Cell Carcinoma

Dr. Xu on Future Developments in Kidney Cancer