Tivozanib Explored in Second-Line ccRCC

In patients with clear cell renal cell carcinoma (ccRCC), there are a number of second-line options to consider. Sumanta K. Pal, MD, FASCO, professor, Department of Medical Oncology & Therapeutics Research, and codirector of the kidney cancer program at City of Hope in San Francisco, California, and participants at a virtual Case-Based Roundtable event explored challenges when making these clinical decisions including the limitations of second-line options, weighing toxicities of current standards vs newer therapies, and the need for subtype-specific strategies.

DISCUSSION QUESTIONS

1. What are the goals of therapy going into the second line?
2. What do you find most challenging about disease management in the second-line setting for patients who have received a prior immune checkpoint inhibitor (ICI)?
3. What are the evidence/knowledge gaps and unmet needs? How do the following factors influence your second-line regimen selection?
4. Have you ever tried continuing / rechallenging with an ICI in a patient who had received a prior ICI?

Sumanta K. Pal, MD: The patient has received a combination of cabozantinib [Cabometyx] and nivolumab [Opdivo] upfront. You’re weighing second-line options. What are you thinking of treating with and why?

Yu-Wei Chen, MD, MS: I would want to aim for efficacy but at the same time I also want to [consider] their functional status. Is the patient robust? Usually, you pick one of the TKI [tyrosine kinase inhibitor] options that you’re most familiar treating with, including its adverse events. So I would consider the patient’s functional status and a TKI not offered in the first-line setting.

Helen Moon, MD: I was thinking exactly what [Dr Chen] was saying. I’ve personally prescribed tivozanib [Fotivda] monotherapy. This decision is influenced in part by the trial data, and I would not continue combination immunotherapy. We have 2 definitive randomized trials showing that continuing IO [immuno-oncology] beyond progression likely does not provide additional benefit for these patients.

My primary consideration here is the need for a rapid response, especially given the patient's increasing symptoms. I’ve leaned towards lenvatinib [Lenvima], however, it can be somewhat toxic.

If we were thinking about altering the mechanism of action, then that would be an approach that I find compelling. Tivozanib also has strong single-agent data, including as a second-line therapy following prior IO-TKI combination in TiNivo-2 [NCT04987203]. This strategy could potentially allow us to reserve a drug such as belzutifan [Welireg] for use later in the treatment sequence.

Pal: How do you feel about tivozanib monotherapy vs in combination based on the efficacy data from the phase 3 TiNivo-2 study [NCT04987203]?

Gigi Chen, MD: I think these data are good. Certainly, it’s an unmet need for patients who have progressed to later line therapy. I have a couple of patients who I’m thinking about right now who I’ll probably switch over to this regimen. I think some of the questions I have focus on sequencing, particularly tivozanib vs belzutifan, and also the impact of prior therapies.

Karo Arzoo, MD: I think these data are strong. I would use tivozanib [in the] second line plus nivolumab. I think both are acceptable. I think longer data are needed to see if there is a difference between them, particularly further efficacy of tivozanib in renal cell carcinoma. I’m just not sure if monotherapy is any worse than combination therapy.

Lulu Zhang, MD: I haven’t prescribed this to many patients. I just recently started 1 patient on tivozanib in the third line but that person had upfront doublet immunotherapy, and then progressed on cabozantinib.

Progression-free survival [PFS] is one thing, but what about the overall survival [OS]? Does the sequence really matter? I do struggle when I choose between tivozanib vs lenvatinib plus everolimus. Do I give the patient a harder tolerated regimen when they have better performance status?

James Coggan, MD: I haven’t had the opportunity to use tivozanib yet, but my thoughts echo others. It looks like good data but I am curious about the differences for second-line vs third-line therapy. I need more reflection on that. These patients are heavily pretreated and I’m curious about those patients who were treated with ipilimumab [Yervoy] and nivolumab in the first line or those [whose disease] recurred after adjuvant pembrolizumab [Keytruda].

Is tivozanib preferred? Is cabozantinib preferred as the second line and how do we sequence that? Or does it truly matter? I know the PFS wasn’t all that different in the third line after prior TKI so it’s still a little unclear.

Pal: There was no difference in OS in the phase 3 TIVO-3 trial (NCT02627963), which is a later-line trial evaluating tivozanib.¹ There was no difference in OS for the TiNivo-2 trial. It’s rare in the late salvage setting to see an OS advantage. OS is a tough bar to achieve, and we haven’t seen it demanded for regulatory approval.

Let’s talk a little bit about the TIVO-3 and TiNivo-2 studies. When you look at the safety for tivozanib monotherapy, we saw the rate of discontinuation was lower compared with lenvatinib and everolimus, for example. What has been your experience with tivozanib today? Does it mirror the trial data?

Yu-Wei Chen: Yes, I think so. I have seen better tolerability in terms of the adverse event profile. Generally speaking, in the refractory setting with a patient who has been on more than 2 lines of therapy, tivozanib seems to be better tolerated in the patient population.

Li Zhang, MD: In my experience, it has been pretty well-tolerated. Hypertension can be an issue and [there can be] some fatigue and a little loss of appetite. I have a patient who is morbidly obese and he is tolerating tivozanib pretty well. I have a few patients who demonstrated a sustained response.

Thomas Spillane, MD: I’ve used it in 1 patient and they used it for 2 to 3 months and it was well tolerated. They had progressive disease, which was probably the main reason we discontinued it, but in terms of tolerability, it’s very doable.

Arati Chand, MD: Does tivozanib have any central nervous system [CNS] effect? Does it penetrate the blood-brain barrier?

Pal: I’ve had disease control in patients with CNS metastasis. In my practice, I irradiate CNS metastasis and then initiate systemic therapy. Having said that, I’ve seen stability in CNS metastasis while the patient is on tivozanib for a protracted period of time.

DISCLOSURES:

Sumanta K. Pal reports being a member of the speakers’ bureau of IntrinsiQ, MJH Life Sciences, and Peerview; support for travel, accommodations, and expenses from CRISPR Therapeutics, Exelixis, and Ipsen.

Helen Moon has served in consulting or advisory roles for Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany; and has received funding for travel, accommodation, and expenses from Bayer. J.B. Aragon-Ching has served in consulting or advisory roles for Algeta/Bayer, Amgen, AstraZeneca, AstraZeneca/MedImmune, AVEO, Bayer, Dendreon, Exelixis, Immunomedics, Janssen Biotech, Merck & Co., Rahway, NJ, Pfizer, Pfizer/Myovant, Sanofi, Seagen, and the healthcare business of Merck KGaA, Darmstadt, Germany; reports speakers services for Astellas Pharma, Bristol Myers Squibb, Janssen-Ortho, and Seagen/Astellas Pharma; has received travel and accommodation expenses from Algeta/Bayer, Astellas Pharma, Bristol Myers Squibb, Dendreon, and the healthcare business of Merck KGaA, Darmstadt, Germany; and has received honoraria from Astellas Scientific and Medical Affairs Inc, Bristol Myers Squibb, Pfizer, and the healthcare business of Merck KGaA, Darmstadt, Germany.