Physicians Discuss Counseling on Immunotherapy Discontinuation in RCC

Manojkumar Bupathi, MD, MS (Moderator)

Associate Director

Genitourinary Cancer Research

Sarah Cannon Research Institute at HealthOne

Denver, CO

DISCUSSION QUESTIONS

• What are your impressions of the time to subsequent therapy after cabozantinib (Cabometyx) plus nivolumab (Opdivo) in CheckMate 9ER (NCT03141177)?
• What are your impressions of continuing cabozantinib after discontinuation of nivolumab? How do you counsel patients on the discontinuation of nivolumab after 2 years?

MANOJKUMAR BUPATHI, MD: Looking at the time to subsequent therapy in patients who’ve completed 2 years of nivolumab, [the median time was 20.6 months (95% CI, 7.9–not estimable)].¹ This is a post-hoc analysis, and among patients who’ve discontinued nivolumab after 2 years, 88% continued to receive cabozantinib. Do these data tell you anything in terms of efficacy or tolerability? Does it help you in any way or is it just more information?

BIPINKUMAR AMIN, MD: Why did they discontinue nivolumab?

BUPATHI: Usually, after 2 years of therapy, continuing on immunotherapy hasn’t been shown to be beneficial. I typically do the same thing. After 2 years of treatment, I generally discontinue immunotherapy at that point and just continue them on single agent.

ROMEO MANDANAS, MD: I think it reflects that the cabozantinib adverse events are generally well tolerated. Eighty-eight percent of the patients were able to continue with it.

BUPATHI: Is it helpful to you in any way?

BENJAMIN TEPLY, MD: There is a lot of anxiety whenever we talk to our patients about stopping after 2 years. I find I have to start telling them early on what the expectations are. Initially, you have to manage expectations. You’re not sure how things are going to go in the first year and if patients are doing well, you don’t tell them after 2 years, [suddenly] we’ll do an immunotherapy holiday. Patients are pretty nervous about it. I have a lot that refuse. They [say] to keep giving it to them because that’s what they’ve been doing. It could be reassuring that you don’t see some huge immediate drop off with everyone progressing after stopping.

BUPATHI: I agree. Part of the concern is toxicity, right? Continuing on immunotherapy even after 2 years, you certainly worry about longer-term toxicity or continued exposure to toxicity relating to that drug. I worry that may be of concern. Having said that, the patient response is certainly valid. I’ve had patients that refused and would say under any circumstance [they are] not going to stop [treatment]. Do most patients stop, or do they just continue onwards on both therapies?

AMIN: So with immunotherapy after 2 years, as far as we know, there’s no efficacy; is that right?

BUPATHI: There are no data to suggest that continuing longer than 2 years on immunotherapy has any more benefit.

AMIN: Are there data to support that cabozantinib beyond 2 years is beneficial?

BUPATHI: That is [for] immunotherapy in general, not specifically to kidney cancer, but immunotherapy duration of treatment. When you look at the…trial design, immunotherapy stopped after 2 years and cabozantinib continued on.

AMIN: But…is there benefit of cabozantinib that [supported why it is] continued?

BUPATHI: There is ongoing benefit of cabozantinib. You’re still treating metastatic disease. The thought is that you’re still treating the underlying disease, so you’d still be deriving benefit with cabozantinib.

You’d still be assessing for response…. You’d still see responses. [However,] I’ve had patients where we stopped immunotherapy after 2 years and they continued on…just cabozantinib, for 10 months, a year and then started having progressive disease.

AMIN: So that doesn’t show the benefit [if] they have progressed. How do you stop the cabozantinib at the same time? And if you’re not seeing any shrinkage then [how do you] know they're responding?

BUPATHI: When you look at the trial design, they continued on maintenance therapy with cabozantinib thereafter, and all these trials were done the same way.

Looking at the toxicity or the safety data from CheckMate 9ER for nivolumab/cabozantinib versus sunitinib, when you look at both in combination the discontinuation rates were 27.2%, nivolumab was 10.6%, cabozantinib was 9%, and the sunitinib was 10.3%.² [Approximately] half the patients in each arm had at least 1 dose reduction in general.

_References:

_{1. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl_6):603. doi: 10.1200/JCO.2023.41.6_suppl.603}

_{2. Powles T, Choueiri TC, Mauricio B, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl_6):350. doi:10.1200/JCO.2022.40.6_suppl.350}