TKIs After Upfront Immunotherapy in Metastatic RCC: A Practical Review

With immune checkpoint inhibitor (ICI)–based regimens now firmly established as the standard of care in both the adjuvant and first-line metastatic settings for clear cell renal cell carcinoma (RCC),^1-4 an expanding population of patients experiences progression or recurrence after prior ICI. Sequencing subsequent therapy—particularly tyrosine kinase inhibitors (TKIs) targeting VEGF—has become one of the most common and least well-defined decisions in genitourinary oncology. Randomized data specifically guiding this choice remain sparse. National Comprehensive Cancer Network guidelines list cabozantinib, axitinib, lenvatinib plus everolimus, tivozanib, and the HIF-2α inhibitor belzutifan (the latter following both a PD-1/PD-L1 inhibitor and a VEGF-TKI) as other recommended subsequent options after prior ICI, with no agent designated as preferred.⁵ This review summarizes trial and cohort evidence across three clinical scenarios that medical oncologists commonly encounter post-ICI.

A Foundational Principle: ICI Rechallenge Does Not Add Benefit

Before turning to sequencing specifics, one pivotal finding should anchor decision-making: reintroducing PD-1/PD-L1 blockade after prior ICI exposure does not improve outcomes and adds toxicity. Two randomized phase 3 trials have now tested this question. In CONTACT-03, patients with ICI-pretreated RCC were randomized to cabozantinib with or without atezolizumab, with no difference in progression-free survival (PFS, 10.6 months vs 10.8 months; HR, 1.03) or overall survival (OS).⁶ TiNivo-2 subsequently randomized 343 post-ICI patients to tivozanib with or without nivolumab and likewise showed no PFS benefit from ICI rechallenge (median PFS, 5.7 months vs 7.4 months; HR, 1.10; P = .49), with numerically shorter PFS in the combination arm.⁷ Outside of a clinical trial—and particularly outside the specific scenario of a long treatment-free interval, which was not well represented in either trial—the post–immuno-oncology (IO) setting is therefore a TKI-dominant and in select cases a belzutifan-eligible one.

Scenario 1: Progression After First-Line Ipilimumab Plus Nivolumab

This scenario offers a favorable context for VEGF-TKI, as patients remain VEGF-TKI-naïve. The prospective phase 2 CaboPoint study showed in an ipilimumab/nivolumab-pretreated cohort, second-line cabozantinib produced an overall response rate (ORR) of 40.5%, a median PFS of 10.9 months, and a median OS of 24.3 months.⁸ Supporting real-world data from the GUARDIANS consortium (n=356) identified cabozantinib as both the most commonly selected subsequent therapy (63.4%) and the one associated with superior OS and PFS.⁹ An International Metastatic RCC Database Consortium target trial emulation comparing second-line cabozantinib with sunitinib after first-line ipilimumab/nivolumab demonstrated significantly better outcomes with cabozantinib—ORR 27% versus 20%, time to treatment failure 8.5 months versus 4.5 months, and OS 21.4 months versus 10.1 months (adjusted HR, 0.44).¹⁰ 

The recently reported phase 2 LenCabo trial—the first head-to-head randomized comparison of contemporary second-line options after ICI—further informs this decision: among 86 patients (~70% with prior ipilimumab/nivolumab), lenvatinib/everolimus prolonged PFS over cabozantinib (15.7 months vs 10.2 months; HR, 0.51; P = .02) with numerically higher ORR (53% vs 39%), although toxicity-related discontinuation was more common (20% vs 11%, predominantly from proteinuria).¹¹ These data position lenvatinib/everolimus as an option for patients fit enough for combination therapy, with single-agent VEGF-TKI like cabozantinib or axitinib as alternatives when toxicity or logistical factors favor monotherapy. 

In addition, recent findings from the phase 3 LITESPARK-011 study showed that in patients previously treated with PD-1/PD-L1-based regimens, belzutifan plus lenvatinib improved PFS compared to cabozantinib with a median PFS of 14.6 months versus 10.6 months (HR, 0.74), although with increased hypoxia and anemia.¹² These findings, still under FDA review, may make belzutifan/lenvatinib an option for fit post-IO patients in the future.

Scenario 2: Progression After First-Line PD-1 Inhibitor Plus VEGF-TKI

Decisions are more nuanced after first-line IO–TKI combinations because patients have already received a VEGF inhibitor. In the CaboPoint IO–TKI cohort, cabozantinib produced a somewhat lower ORR of 27.5% and a median PFS of 8.3 months, although median OS remained similar at 24.1 months.⁸ A post hoc subgroup analysis of CONTACT-03 reported comparable second-line cabozantinib activity between patients previously treated with first-line IO–IO and those treated with first-line IO–TKI (ORR, 38% vs 31%; median PFS, ~10 months in both subgroups), with a pooled median PFS of 10.3 months and an ORR of 36% across the overall first-line IO-pretreated population.¹³ The TiNivo-2 population, although tested in a trial asking a different question, independently corroborates the activity of a different VEGF-TKI in this setting: among patients who received ICI as their most recent prior therapy, tivozanib monotherapy yielded a median PFS of 9.2 months.⁷ The LenCabo trial of lenvatinib/everolimus also enrolled some patients with prior IO–TKI exposure (~30% of its population).¹¹

For patients who have already received both a PD-1/PD-L1 inhibitor and a VEGF-TKI, belzutifan—a first-in-class HIF-2α inhibitor—offers a mechanistically distinct option. In the phase 3 LITESPARK-005 trial, belzutifan improved PFS over everolimus (HR, 0.75; 12-month PFS, 33.7% vs 17.6%) and ORR (22.7% vs 3.5%); OS did not reach significance (HR, 0.92; P = .18).^14,15 Whether belzutifan should be preferred over a second VEGF-TKI in this setting is unresolved in the absence of head-to-head comparisons. Whether belzutifan/lenvatinib will also become a standard option based on LITESPARK-011 will depend on ongoing FDA review.¹²

Scenario 3: Recurrence After Adjuvant Pembrolizumab

KEYNOTE-564 established adjuvant pembrolizumab as a standard option for high-risk resected clear cell RCC, with significant improvements in both disease-free survival (HR, 0.72) and OS (48-month OS, 91.2% vs 86.0%; HR for death, 0.62).^2,16 As this regimen has been adopted, a growing cohort of patients is now recurring after ICI exposure in the adjuvant setting. Randomized data to guide subsequent treatment are lacking. In a retrospective international multicenter study of 94 patients with recurrent RCC following adjuvant IO, 76 patients treated with first-line systemic therapy had 18-month PFS and OS of 45% and 85%, respectively.¹⁷ Outcomes were broadly comparable across regimens (18-month PFS, 47% IO–IO, 38% IO plus VEGF-targeted therapy, 48% VEGF-targeted monotherapy). 

Decision-making in this scenario therefore hinges increasingly on the interval between adjuvant therapy completion and recurrence. A European Delphi study defined ICI-refractory disease as relapse within 6 months of adjuvant therapy, with 87% of experts supporting targeted therapy or clinical trial enrollment for such patients.¹⁸ In the absence of randomized data, a common clinical approach is to treat patients relapsing within 1 year of adjuvant pembrolizumab with VEGF-TKI–based therapy rather than ICI rechallenge, and to consider standard first-line IO-based combinations for those with later relapse.¹⁹

Future Directions in Post-IO RCC

Across all three scenarios, VEGF-TKI–based therapy remains the best-supported subsequent option after upfront IO exposure, with the strongest prospective evidence in the post-ipilimumab/nivolumab setting. The phase 2 LenCabo trial positions lenvatinib plus everolimus as an option for fit patients and cabozantinib or other single agents as appropriate alternatives.¹¹ Two phase 3 trials (CONTACT-03 and TiNivo-2)^6,7 argue against routine ICI rechallenge outside of clinical trials. Belzutifan provides a mechanistically distinct option after prior ICI and VEGF-TKI.¹⁴ Clinical practice post-IO will continue to evolve in light of recent and ongoing trials, such as the LITESPARK-011 trial, which showed improved PFS with lenvatinib/belzutifan compared with cabozantinib.¹² In all cases, treatment selection should be individualized based on prior regimen, interval to progression, disease burden, comorbidity, and patient preference, and clinical trial enrollment should be considered wherever feasible.

References

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