Comparing Treatment Approaches in Second-Line Metastatic ccRCC

Selecting subsequent-line therapy for metastatic clear cell renal cell carcinoma (ccRCC) after progression on an immune checkpoint inhibitor (ICI)-based combination requires consideration of treatment efficacy, prior tyrosine kinase inhibitor (TKI) exposure, adverse events, and quality of life.

During a virtual Case-Based Roundtable event for oncologists in Ohio, Pedro Barata, MD, MSc, of University Hospitals Seidman Cancer Center in Cleveland, Ohio, reviewed treatment evidence and moderated discussion of a patient whose disease progressed after first-line cabozantinib (Cabometyx) plus nivolumab (Opdivo).

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This article is part 1 of a 2-part series from a Case-Based Roundtable event.

CASE SUMMARY

Initial Presentation

• A 61-year-old man with indolent, low-volume metastatic ccRCC
• ECOG performance status: 0
• History of nephrectomy and adrenalectomy; initially managed with observation
• Small pulmonary nodules gradually increased in size.

Disease Progression

• Approximately 18 months later, imaging showed enlarging mediastinal lymph nodes and multiple pulmonary nodules.
• Lung nodule biopsy confirmed recurrent/progressive ccRCC.
• Laboratory results were unremarkable; International Metastatic RCC Database Consortium risk classification was favorable.

First-Line Treatment and Current Status

• He received cabozantinib plus nivolumab, achieving tumor shrinkage and stable disease.
• He developed treatment-related hypothyroidism, managed with medication.
• He experienced disease progression after approximately 14 months; ECOG performance status was 1.
• No clinical trial was available. Subsequent-line options included belzutifan (Welireg), lenvatinib (Lenvima) plus belzutifan, lenvatinib plus everolimus (Afinitor), tivozanib (Fotivda), ICI rechallenge, or another single-agent TKI.

EVENT RECAP

At the initial treatment poll, participants were evenly divided among lenvatinib plus belzutifan, lenvatinib plus everolimus, and tivozanib, each selected by 4 of 12 respondents (33.3%). No participants selected ICI rechallenge.

For Christopher Wee, MD, of Cleveland Clinic Taussig Cancer Center, the priority was maximizing treatment benefit. “Obviously [we want] overall survival [OS], but [also] durability of response in the second line [to] try to get as much mileage as we can,” he said. Wee favored lenvatinib plus everolimus while awaiting regulatory clarity on lenvatinib plus belzutifan, although he acknowledged the toxicity of lenvatinib.

Mark Knapp, MD, of Zangmeister Cancer Center, also considered efficacy but emphasized tolerability. He selected tivozanib, noting that he had used lenvatinib in some patients and had some issues with tolerability. He added that tivozanib appeared effective and well tolerated in the second-line setting.

Other participants favored different approaches. Joseph Attallah, MD, of MetroHealth, selected lenvatinib plus everolimus, citing its progression-free survival (PFS) results and the patient's good performance status and limited comorbidities. Ike Onwere, MD, of Blanchard Valley Hospital, favored lenvatinib plus belzutifan, pointing to clinical trial data supporting the combination.

Clinical Evidence Informs Treatment Selection

The phase 3 TIVO-3 trial (NCT02627963) compared tivozanib with sorafenib in patients with advanced RCC who had received 2 or 3 prior systemic therapies. Tivozanib improved median PFS vs sorafenib (5.6 vs 3.9 months; HR, 0.73; P = .016), although final OS results did not show a significant difference. The heavily pretreated population and comparator are important considerations when applying these findings to patients with disease progression after first-line therapy.¹

The phase 3 TiNivo-2 trial (NCT04987203) evaluated tivozanib alone or with nivolumab after prior ICI therapy. Adding nivolumab did not improve outcomes. In the second-line subgroup, median PFS was 9.2 months with tivozanib alone vs 5.9 months with the combination. These findings supported consideration of tivozanib monotherapy rather than ICI rechallenge.²

The phase 3 CONTACT-03 trial (NCT04338269) provided additional evidence against ICI rechallenge. Adding atezolizumab (Tecentriq) to cabozantinib after prior ICI progression did not improve PFS or OS compared with cabozantinib alone and increased toxicity.³ Barata noted that salvage nivolumab plus ipilimumab (Yervoy) may still be considered for selected patients who have not previously received ipilimumab, although its activity is limited.

In the phase 3 LITESPARK-005 trial (NCT04195750), belzutifan was compared with everolimus after prior ICI and antiangiogenic therapy. Median PFS was 5.6 months in both groups at the first interim analysis, although later PFS curves favored belzutifan. Objective response rates were 21.9% with belzutifan and 3.5% with everolimus; OS was not significantly different at the second interim analysis. Barata also reviewed anemia and hypoxia as important belzutifan-associated adverse events.⁴

Participants discussed how these toxicities could affect treatment decisions. Lingbin Meng, MD, of The Ohio State University Comprehensive Cancer Center, said the TiNivo-2 findings increased her confidence in using tivozanib monotherapy in the second-line setting. She also described tivozanib's adverse event profile as more manageable than that of lenvatinib plus everolimus in her clinical experience.

For lenvatinib plus everolimus, Barata reviewed the randomized phase 2 LenCabo trial (NCT05012371), which compared the combination with cabozantinib after prior ICI therapy. Median PFS was 15.7 months with lenvatinib plus everolimus vs 10.2 months with cabozantinib (HR, 0.51; P = .02); OS data were immature.⁵

Post-Discussion Polling Favors Tivozanib

After the evidence review, tivozanib was selected by 7 of 12 participants (58.3%) as their preferred second-line option in this case. Lenvatinib plus everolimus was selected by 3 (25%), while belzutifan and lenvatinib plus belzutifan each received 1 vote (8.3%). Ten participants (83.3%) said they were likely to use tivozanib in the second-line setting.

Regarding treatment sequencing, 8 participants (66.7%) selected tivozanib for second-line use, while 8 (66.7%) placed belzutifan in the third-line setting. The discussion highlighted how treatment sequencing is shaped by prior therapies, expected disease control, toxicity, and patient priorities.

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DISCLOSURES: Barata previously reported receiving personal fees from EMD Serono, Exelixis Inc, Pfizer Inc, Caris Life Sciences, UroToday, AstraZeneca, Myovant Sciences Ltd, Merck & Co Inc, Targeted Oncology, Bristol Myers Squibb, MJH Life Sciences, SeaGen Inc, Bayer AG, and Eisai Inc.

REFERENCES

1. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib vs sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21(1):95-104. doi:10.1016/S1470-2045(19)30735-1

2. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab vs tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 study. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6

3. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib vs cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4

4. Choueiri TK, Powles T, Peltola K, et al. Belzutifan vs everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906

5. Hahn AW, Chahoud J, Skelton WP, et al. A multicenter randomized phase II trial of lenvatinib plus everolimus vs 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