Key Efficacy and Tolerability Factors for Later-Line Therapies in RCC

Arnab Basu, MD, MPH

Assistant Professor

UAB Medicine

Birmingham, AB

DISCUSSION QUESTIONS

• From the TIVO-3 (NCT02627963) data set, what efficacy parameters appeal about tivozanib (Fotivda)?
• What role is there for sustained VEGF inhibition in the relapsed/refractory renal cell carcinoma (RCC) setting?

ARNAB BASU, MD, MPH: From all the data that you’ve seen of the TIVO-3 study, what struck you as being the most important pieces of that data that help you make the clinical decision on the patient?

AHMAD MAZIN SAFAR, MD: The duration of response is probably what I would pick, because although there was an impact, and there is no question that the study was positive.¹ In 50% of the population, the median progression-free survival [PFS] didn’t shift much. The benefit is probably only in 50%...and the tail difference is there [in the Kaplan-Meier curve], but at that time, the confidence is low, because we have [approximately] 6 patients on one arm and 13 on the other. That is not very high confidence, but…those who respond seems to have responded for quite a while, 20 months. To me, that is probably the most impressive, as opposed to the shift in the Kaplan-Meier curves [for PFS] or the fact that we have 4-year data, because the 4-year data is based on small numbers of patients.

BASU: That’s a great point. I don’t know if any of you have seen these patients in clinic where they were on tivozanib for a long time. It’s a smaller percentage of the refractory population. I have a couple of patients who have stayed on tivozanib and that is an interesting phenomenon when you’re looking at a TKI that tends to have a limited time of response.

CHRIS THEODOSSIOU, MD: In addition to the duration of response, I would choose the efficacy post axitinib.² It’s the first time we have a legitimate third-line agent.

BASU: That’s a good point, because axitinib is an important and usually well-tolerated TKI and tends to be a standard in the setting as well.

DISCUSSION QUESTIONS

• What is your experience with lenvatinib (Lenvima) plus everolimus (Afinitor)?
• How do you approach dosing?

BASU: What have you [experienced] using lenvatinib/everolimus? What kind of responses have you seen?

KEVIN GALLAGHER, MD: I have a patient on that regimen. I’m comanaging him with somebody at [The University of Texas MD Anderson Cancer Center]. This patient had the most indolent RCC [I’ve seen]. He started out when sorafenib [Nexavar] and sunitinib [Sutent] were used, he’s on the fourth line, and he’s now on this [regimen]. He’s had stable disease on this regimen for 14 to 16 months. Now we have dose reduced the everolimus significantly, but his quality of life is good and he has stable disease, so...he’s doing well.

BASU: [That is] a very favorable-risk patient. What lenvatinib dose is the patient on? You said everolimus was dose reduced.

GALLAGHER: Yes, 14 mg.

BASU: OK, 14 mg. [That is] a very decent dose of lenvatinib. It’s great that the patient is tolerating it.

DISCUSSION QUESTIONS

• What toxicities are most concerning to you in this setting?
• Which do you find most challenging to manage?

MICHELLE LOCH, MD: Fatigue is always the most difficult to manage.

GARY TIAN, MD: For me, I think [it is] the fatigue.

KAMALESH BALA, MD: I would agree, fatigue is the most difficult problem, especially when they stay on treatment for a long time.

BASU: I think that’s right on the button. [For] everything else, you can put something on. There’s no hand cream for fatigue. That’s such an important part of quality-of-life metrics: patients not being able to perform what they’re doing [normally]. Looking at fatigue, and the numbers for the different TKIs [reported in trials], does this seem congruent with what you’re seeing in clinic?

TIAN: Yes; I think it also depends on the dosage. For drugs like cabozantinib [Cabometyx] and lenvatinib, we try to not always use the maximum dose for the fatigue issue.

BASU: I’m curious, do you dose reduce cabozantinib upfront? Or if anybody’s ECOG performance status is 1 do you start them on 60 mg? Or do you start low and then assess the patient?

TIAN: I always try to...[start] based on the patient. In some patients, you cannot start a maximum dose. For a performance status of 1, a robust patient, we can probably start a full dosage. [For] lot of patients…I typically try to start a bit lower, but that’s my limited experience.

BASU: Yes, that’s a great strategy. Thanks for sharing that. So, it seems like some of you are assessing patients coming into the door, looking at the ECOG performance status already towards reducing in anticipation of fatigue.

DISCUSSION QUESTION

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• Please share your perspectives on the tolerability of tivozanib versus lenvatinib plus everolimus or other options you would strongly consider as third-line therapy for a patient like this. ​

BASU: Have any of you done tivozanib vs lenvatinib/everolimus and had the opportunity to compare these 2 regimens? I’m curious in your experience with the comparison, not just the clinical trial data, but in real life.

GALLAGHER: My experience is limited, but in the 1 patient I have on tivozanib, it seems to be well tolerated. The few patients who have had lenvatinib plus everolimus seemed to be struggling more. [They have had] hand/foot syndrome, diarrhea, and things like that. The tivozanib was pretty smooth, and this was even beyond third line. For this individual, it was the fifth line.

BASU: That’s great. These days patients are surviving to that line of therapy with reasonable ECOG performance status. Then, as you said, the quality of life now is a concern there.

_References:

_{1. Atkins MB, Verzoni E, Escudier B, et al. Long-term PFS from TIVO-3: Tivozanib (TIVO) versus sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC. J Clin Oncol. 2022;40(suppl_6):362. doi:10.1200/JCO.2022.40.6_suppl.362}

_{2. Rini BI, Pal SK, Escudier B, et al. TIVO-3: tivozanib in patients with advanced renal cell carcinoma (aRCC) who have progressed after treatment with axitinib. J Clin Oncol. 2021;39(suppl 6):278. doi:10.1200/JCO.2021.39.6_suppl.278}