Optimizing Second-Line Therapy in Metastatic ccRCC

Treatment selection after progression on frontline immune checkpoint inhibitor (ICI)-based therapy remains a key challenge in metastatic clear cell renal cell carcinoma (ccRCC), with clinicians needing to carefully balance efficacy, tolerability, and quality of life when choosing second-line therapy. In a virtual Case-Based Roundtable event, Sumanta Pal, MD, FASCO, medical oncologist and co-director of the Kidney Cancer Program at City of Hope, led a discussion with oncologists in the Southwest, Rocky, and Pacific Regions on second-line treatment strategies, including treatment goals, the role of ICI rechallenge, and supporting clinical trial data.

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CASE SUMMARY

• 61-year-old man, married, father of 2 grown children and 5 grandchildren who live nearby, active lifestyle (daily walks, golfs regularly)
• History of low-volume, indolent metastatic ccRCC, status post left nephrectomy and adrenalectomy
  • Based on low-volume, indolent disease and patient preference: observation only
• 1.5 years postnephrectomy CT scan:
  • New paratracheal lymph node (2.0 x 1.5 cm) and > 10 pulmonary nodules on CT
    • Lung biopsy confirms metastatic ccRCC
• Labs: within normal limits
• ECOG performance status: 0
• The patient received first-line cabozantinib (Cabometyx) + nivolumab (Opdivo).
• Decrease or stabilization in metastatic lesions noted on follow up imaging
• He tolerated therapy well, with 1 interruption due to hypothyroidism on routine labs (treated with levothyroxine).
• 14 months after initiation of systemic therapy, the patient reported increasing back pain, mild nausea, weight loss, and new onset of persistent rib pain.
• Imaging confirms disease progression: growth of paratracheal lymph node (was 20 x 15 mm; now 25 x 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes and new lytic osseous lesions
• ECOG performance status: 1

DISCUSSION QUESTION

• What are the goals of therapy going into the second line?

Sumanta Pal, MD, FASCO: I know in the first-line setting, we're always talking about maximizing progression-free survival [PFS], response, and overall survival. As you're thinking about a patient who is going from first-line therapy to second-line therapy, do the priorities change a little bit? Are you thinking more about palliation there?

Jaspreet Chahal, MD: Yes, I think when you get to the second line and patients might be more symptomatic or have decreased performance status, I think it's more important to keep in mind balancing the quality of life. I think [the priorities are] checking in with them about their goals of care on a regular basis. We're not necessarily going to be so aggressive [with treatment]; therefore, balancing that toxicity and what's important to them [is a priority]. Maybe it's not coming in for infusions right now; that's not something that they want, so we're looking at more of an oral regimen.

DISCUSSION QUESTION

• Have you ever tried continuing/rechallenging with an ICI in a patient who had received a prior ICI?

Pal: This patient had progressed on cabozantinib-nivolumab. Would you ever think about using nivolumab-ipilimumab [Yervoy] or immunotherapy?

Brian Vicuna, MD: Not in the second line. Maybe fourth or fifth line down the road. But I'm done with all the tyrosine kinase inhibitors [TKIs]. Then maybe consider double immunotherapy [IO] if they haven't had it in the frontline setting.

Pal: I feel the exact same way as you do, Dr Vicuna, and we'll talk through some of the data associated with that.

EVENT RECAP

After discussing the case, the group reviewed efficacy and safety data supporting tivozanib (Fotivda) in the relapsed/refractory metastatic ccRCC setting, highlighting results from the phase 2 Study 218 (NCT03173560), phase 3 TIVO-3 (NCT02627963), and phase 3 TiNivo-2 (NCT04987203) trials.

Study 218 demonstrated encouraging clinical activity with tivozanib in patients whose disease had progressed after prior ICI therapy, supporting further investigation in the post-ICI setting.¹ In the pivotal phase 3 TIVO-3 trial, tivozanib significantly improved PFS compared with sorafenib (Nexavar) in patients who had received at least 2 prior systemic therapies while maintaining a favorable tolerability profile, leading to its FDA approval in this setting.²

More recently, the phase 3 TiNivo-2 trial evaluated tivozanib plus nivolumab vs tivozanib alone following progression on prior ICI therapy. Although the addition of nivolumab did not improve PFS, tivozanib monotherapy achieved a median PFS of 9.2 months in the second-line setting after prior ICI exposure, supporting its use as an effective and well-tolerated treatment option after frontline ICI-based combinations.³

DISCUSSION QUESTIONS

• What is your reaction to the efficacy data from the phase 3 TiNivo-2 study?
  • The combination arm?
  • The tivozanib monotherapy arm?
  • The 9.2-month median PFS of second-line tivozanib immediately following an ICI?
• Do you consider any of the results to be clinically meaningful, practice changing, or practice confirming?

Pal: I want to get reactions to the data… Any thoughts around tivozanib and where you might apply it on the basis of these data that we’ve just reviewed?

Shawn Shambaugh, MD: I haven't used [tivozanib] as of yet, but I am impressed by the data, so I am inclined to start thinking about using it a little bit more.

Pal: We'll go through the toxicity profile of this agent…we'll have a little discussion around relative merits of this agent vs others. But [Dr Sandhu], I'll ask you the same question. You've seen these data now from TiNivo-2 and the previous tivozanib studies. Any thoughts around its application?

Sonia Sandhu, MD: Certainly after IO-TKI, if I'm choosing the second line, I would be looking at one of the options with tivozanib. It’s well tolerated in patients who might be frail, and looking at the [adverse] effect profile, it may be one of the options I would be looking at for second line after that treatment.

Pal: I think that's a very fair perspective on it. Dr Montoya, how about you? Have you had a chance to use tivozanib in clinical practice yet?

Delmer Montoya, MD: Yes, I have used it in a couple of patients, and I think it's better tolerated. I had one particular patient who was reluctant to do anything else... She’s tolerated it really well. It’s been 7 months, and she's still on it and seems to be stable.

Praveena Solipuram, MD: [Dr Pal], did I hear you say that tivozanib is more likely to work after ipilimumab-nivolumab vs after axitinib [Inlyta]-pembrolizumab [Keytruda]?

Pal: I think that's maybe up for debate. I think that what we see with all the TKIs is that …if you look at any TKI, if you apply it in a TKI-naive setting, you're going to evoke a higher response rate and PFS. You see that with cabozantinib; you see that with tivozanib. So, I would say that there's still a role and rationale for using tivozanib after prior TKI-ICI. You think about that scenario that we discussed at the outset, right? The patient getting cabozantinib-nivolumab, and it seems reasonable to consider tivozanib here because the options that remain are, for instance, lenvatinib [Lenvima]-everolimus [Afinitor], which we discussed in the context of tolerability. So, I think there's the option of using tivozanib here. I wouldn't argue that it's better or worse in one particular setting. It's just different if you use it in a TKI-naive patient vs not.

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DISCLOSURES: Pal previously disclosed institutional research funding from Eisai, Genentech, Roche, Exelixis, Merck, Osel, Adicet Bio, ArsenalBio, Xencor, Miyarisan Pharmaceutical, Pfizer, CRISPR Therapeutics, and Allogene Therapeutics.

REFERENCES

1. Pal SK, Puente J, Heng DYC, et al. Phase II trial of lenvatinib (LEN) at two starting doses + everolimus (EVE) in patients (pts) with renal cell carcinoma (RCC): Results by independent imaging review (IIR) and prior immune checkpoint inhibition (ICI). J Clin Oncol. 2021;39(6_suppl):307-307. doi:10.1200/jco.2021.39.6_suppl.307

2. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2019;21(1):95-104. doi:10.1016/s1470-2045(19)30735-1

3. Chehrazi-Raffle A, Motzer RJ, Beckermann K, et al. Efficacy of second line (2L) treatment with tivozanib (Tivo) as monotherapy or with nivolumab (Nivo) in patients (pts) with metastatic renal cell carcinoma (mRCC) previously treated with an immune checkpoint inhibitor (ICI) combination of ipilimumab (Ipi)/Nivo or vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI)/ICI in the phase 3 TiNivo-2 study. J Clin Oncol. 2025;43(16_suppl):4540-4540. doi:10.1200/jco.2025.43.16_suppl.4540