Evolving Standards in Renal Cell Carcinoma: Practical Insights from ASCO GU

The treatment paradigm for RCC continues to evolve rapidly across localized and metastatic disease settings. At the 2026 ASCO Genitourinary Cancers Symposium (ASCO GU), a panel of experts discussed practical decision-making particularly relevant for community oncologists navigating real-world constraints.

Adjuvant Therapy: High Risk Today, Combination Tomorrow?

Adjuvant pembrolizumab remains the current standard for patients at high risk of recurrence following nephrectomy. Appropriate candidates include T2 grade 4 tumors, T3 or higher disease, and patients rendered with no evidence of disease after surgical resection of metastatic lesions, particularly if recurrence occurred within 1 year.

However, attention is now turning to LITESPARK-022, which evaluates pembrolizumab plus belzutifan versus pembrolizumab alone in the adjuvant setting. Given the size of the trial, even modest improvements in hazard ratios may reach statistical significance. Still, the panel emphasized that clinical relevance must guide adoption into practice. As one panelist noted, “If the hazard ratio is not low, is it clinically significant?”

For community oncologists, this distinction is critical. Expanding adjuvant therapy to combination regimens would require careful patient selection and thoughtful toxicity management in a population without measurable disease.

Oligometastatic Recurrence: Treat Locally, Stay Evidence-Based

The panel also addressed the common scenario of isolated recurrence during or after adjuvant therapy. The consensus approach favored local control radiation or surgery for solitary metastases while continuing the planned 1-year adjuvant course if still on treatment.

There was no support for extending adjuvant therapy beyond 1 year. Adhering to available data was emphasized as the safest course in the absence of evidence supporting prolonged treatment.

First-Line Metastatic RCC: The Most Important Decision

In metastatic disease, combination therapy with either dual immune checkpoint blockade or immuno-oncology (IO) plus tyrosine kinase inhibitor (TKI) remains standard. The key message was not whether to combine, but how to choose wisely.

A sobering point raised during the discussion: not all patients reach later lines of therapy. Roughly half of patients may never receive third-line treatment. As one panelist put it, “You really just have to use the best treatment … at that time.”

Sarcomatoid differentiation continues to favor nivolumab/ipilimumab based on durable survival data. For most other patients, IO/TKI combinations dominate frontline practice. Cabozantinib plus nivolumab is often selected for its tolerability at the 40 mg dose and broad kinase inhibition. Lenvatinib plus pembrolizumab offers high response rates but may be more difficult to manage in some patients. Axitinib-based combinations remain appropriate options, although selection varies by practice.

For community oncologists, tolerability and comorbidities frequently influence decision-making as much as efficacy metrics.

Sequencing After Progression and the Role of Belzutifan

Belzutifan continues to move into earlier lines of therapy. After progression on IO/TKI combinations, sequencing options include tivozanib, lenvatinib/everolimus, or belzutifan-based strategies.

Belzutifan introduces distinct toxicities, most notably anemia and hypoxia. Anemia is common and can reach grade 3–4 severity in a subset of patients. The panel reflected increasing comfort with erythropoiesis-stimulating agents when clinically appropriate, supported by emerging safety data.

Proactive dose adjustments and supportive care remain essential to maintain patients on effective therapy.

Immunotherapy Rechallenge: Generally Not Recommended

As immunotherapy moves earlier in treatment algorithms, questions about rechallenge inevitably arise. The panel was clear that rechallenge after confirmed progression is generally not supported. Mechanism switching remains the preferred strategy.

Exceptions may exist for patients who discontinued therapy because of toxicity rather than progression, but these situations are uncommon.

Cytoreductive Nephrectomy: A Narrower Role

The role of cytoreductive nephrectomy has narrowed significantly. Systemic therapy now takes priority in metastatic RCC. Surgery is reserved for symptomatic primary tumors such as pain, bleeding, or paraneoplastic syndromes, or in cases of clear discordance between primary and metastatic disease.

Overall, the session held during ASCO GU reinforced that while treatment options in RCC continue to expand, optimal care depends on thoughtful sequencing, evidence-based restraint, and careful toxicity management. As data from LITESPARK-022 and other trials mature, treatment algorithms may shift again but clinical judgment will remain central to delivering high-quality care in the community setting.