Optimizing Therapeutic Strategies Across Treatment Lines in Advanced RCC

As part of a recent Training Academy segment hosted by CancerNetwork^®, a panel of experts in genitourinary oncology convened to discuss considerations for optimally selecting and sequencing different lines of therapy for patients with advanced renal cell carcinoma (RCC). These experts highlighted different therapeutic strategies and broke down the efficacy and toxicity profiles of various key regimens in the context of 2 patient cases involving initial disease progression on frontline therapy.

The panel was moderated by Moshe Ornstein, MD, MA, a genitourinary medical oncologist focusing on RCC at Cleveland Clinic. He was joined by Adam E. Singer, MD, PhD, an assistant clinical professor of Medicine and division lead for kidney cancer in the Division of Hematology/Oncology at University of California, Los Angeles Health; and Terence Friedlander, MD, chief of Hematology-Oncology at Zuckerberg San Francisco General (ZSFG), associate director for Cancer Research at ZSFG of Helen Diller Family Comprehensive Cancer Center, and associate clinical professor in the Division of Hematology/Oncology at the University of California, San Francisco.

Here are their key takeaways from the discussion:

Factors for Determining First-Line RCC Treatment Strategies

• Immune checkpoint inhibitors plus VEGF-targeted agents have become a standard of care in frontline metastatic RCC.
  • Immunotherapy plus tyrosine kinase inhibitors (TKIs) may be more likely to elicit responses and work faster vs immunotherapy doublet options.
  • Lenvatinib (Lenvima) plus pembrolizumab (Keytruda) may have the “best” data based on findings from the phase 3 CLEAR trial (NCT02811861).¹
    • The 20-mg dose of lenvatinib may be difficult for some patients to tolerate.
• Educating patients about toxicities that may be associated with upfront TKIs or small molecule inhibitors is critical.
  • Patients should know when to call providers based on the incidence of adverse effects (AEs) like rash, oral mucositis, and high blood pressure.
  • Statistically, dose reductions may be necessary to maintain patients on treatment.
  • Frequent check-ins and monitoring of urine tests, thyroid functioning, and other parameters can help with keeping patients on treatment as needed.

Navigating Treatment Decision-Making in the Second Line and Beyond

• The rate of disease progression and extent of AEs associated with frontline therapy may help influence treatment strategies in the second line.
  • For example, HIF-2α inhibitors like belzutifan (Welireg) may not be suitable for patients in the relapsed setting if they have rapid progression or excessive bone disease.
  • Sequencing PD-1 inhibitors after prior PD-1 inhibition may not provide additional benefit; decision-making may come down to sequencing different TKIs.
• International Metastatic RCC Database Consortium (IMDC) risk and how aggressive a patient’s disease is may determine suitable therapeutic choices following progression on frontline therapy.
  • Aggressive disease with bone or brain metastases may warrant more intensive second-line regimens like lenvatinib plus everolimus (Afinitor).
  • TKI monotherapy may still produce enduring responses with fewer AEs.
  • Axitinib (Inlyta) may only be suitable for patients who are frailer.
• Balancing potential toxicity and benefit is critical for deciding on the use of second-line therapy.
  • Clarifying patient goals may impact treatment decisions.
    • Therapeutic options may depend on whether patients are more focused on quality of life or extending survival by any means necessary.

Patient Case 1: Progression Following Frontline Immunotherapy

• A 62-year-old patient with intermediate-risk metastatic clear cell RCC achieved an initial partial response on nivolumab (Opdivo) plus ipilimumab (Yervoy) before radiographic progression after 14 months of treatment.
  • The patient had good performance status and adequate organ function.
• Lenvatinib plus everolimus may be a suitable option for a patient like this based on current evidence.
  • Phase 2 LenCabo study (NCT05012371) showed improvements in progression-free survival (PFS) with lenvatinib/everolimus vs cabozantinib (Cabometyx) monotherapy (HR, 0.51; 95% CI, 0.29-0.89; P = .02).²
    • However, more patients discontinued treatment with the lenvatinib combination (20%) vs those who received cabozantinib (10.9%), which may add nuance to treatment decision-making.
• Data from the phase 3 LITESPARK-011 study (NCT04586231) may position belzutifan plus lenvatinib as a potential therapeutic option for similar patient cases.³
  • The belzutifan combination improved PFS and responses vs cabozantinib alone among those with advanced RCC after prior anti–PD-(L)1 therapy.
    • However, additional follow-up and more mature overall survival data may be needed to “seal the deal” for lenvatinib/belzutifan as an option.
  • If approved, this therapeutic regimen may cause the second-line therapy discussion to evolve even further.

Patient Case 2: Progression After Immunotherapy and Targeted Agents

• A 70-year-old patient with metastatic clear cell RCC and multiple metastatic sites experienced disease progression after 8 months of frontline therapy with an immune checkpoint inhibitor and VEGF-targeted agent.
  • Patient had an ECOG performance status of 1 and mild treatment-related fatigue and hypertension.
• If a patient like this is committed to such a treatment course, administering a doublet therapy may be ideal.
  • Selection of lenvatinib/belzutifan or lenvatinib/everolimus may be dependent on factors like cost, patient preference, and individual toxicity profiles.
    • Everolimus may elicit more toxicities, although belzutifan carries its own risks of hypoxia and other AEs.
• Brain metastases may be underdiagnosed for this patient population, and TKIs don’t appear to be as effective in this space.
  • Asymptomatic brain metastases may need to be managed via radiotherapy or other alternative approaches.

References

1. Motzer RJ, Porta C, Eto M, et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. J Clin Oncol. 2024;42(11):1222-1228. doi:10.1200/JCO.23.01569
2. Hahn AW, Chahoud J, Skelton WP, et al. A multicenter randomized phase II trial of lenvatinib plus everolimus versus cabozantinib in patients with metastatic clear-cell RCC that progressed on PD-1 immune checkpoint inhibition (LenCabo). Ann Oncol. 2026;37(2):241-249. doi:10.1016/j.annonc.2025.10.009.
3. Motzer RJ, Park SH, McDermott RS, et al. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti–PD-(L)1 therapy: open-label phase 3 LITESPARK-011 study. J Clin Oncol. 2026;44(suppl 7):LBA417. doi:10.1200/JCO.2026.44.7_suppl.LBA417