Opinions on the Optimal Role of Ipilimumab/Nivolumab in RCC

Alan Tan, MD (Moderator)

Director of GU Medical Oncology

Assistant Professor, Department of Internal Medicine

Division of Hematology, Oncology and Cell Therapy

Rush Medical College

Chicago, IL

DISCUSSION QUESTIONS

• What are your perspectives on the frontline immunotherapy plus tyrosine kinase inhibitor (IO/TKI) and IO/IO (dual immunotherapy) regimens for clear cell renal cell carcinoma?​
• Please discuss your real-world experience with each IO/TKI regimen.

YAN JI, MD: About the nivolumab [Opdivo] plus ipilimumab [Yervoy] regimen, I think everybody is looking at the tail [of the Kaplan-Meier overall survival curve] because…everybody is thinking that some patients probably get [complete remissions] by using dual immunotherapy. Although we realize that the response rate is low, 39%, and the duration of response is not as good as IO/TKI.¹ I think it’s definitely [favored due to] the tail. In what kind of patient would you use ipilimumab/nivolumab? In my mind, the [optimal] patient does not have a large disease burden, and they have time to respond, so you still have time, if needed, to change the treatment, right?

ALAN TAN, MD: Exactly.

JI: So your [goal is] to give the patient a long-term benefit. That’s probably where my thoughts are in terms of using ipilimumab/nivolumab. Do you agree or do you have other patients you will also consider ipilimumab/nivolumab?

TAN: I, like many academic genitourinary oncologists, love ipilimumab/nivolumab because of that tail of the curve. We have a trial with the Alliance for Clinical Trials in Oncology called the PDIGREE study [NCT03793166] that’s investigating that. So, if a patient has intermediate or poor risk, they would get ipilimumab/nivolumab up to 4 cycles and then based on an adaptive approach, if they have partial response or stable disease, they’ll get randomized to just nivolumab or nivolumab plus cabozantinib [Cabometyx]. We’re going to find out hopefully sometime in the next couple years the results of that study. I think that one might be a more valid sequence of events than triplet therapy. I’m not so sure I’m optimistic about triplet therapy based on COSMIC-313 [NCT03937219]. I think trying to get that ipilimumab in there because of that durable response and that possible “cure” is what we’re trying to look for.

I think I’ve [successfully treated] several patients with ipilimumab/nivolumab, but I can’t safely say that I’ve [had durable complete remission with] as many, or any, patients with IO/TKI. These patients [who needed IO/TKI] right off the bat are so symptomatic. Based on my experience, hypercalcemia is the one thing that sticks out. If you have uncontrolled hypercalcemia and a bad performance status or maybe pleural effusions, those are the scenarios where I need to get them on IO/TKI. Otherwise, they may die and none of these data mean anything because they don’t get to another line of therapy after 3 months. So that would be a real shame when we have such good progression-free survival [Kaplan-Meier] curves for all these regimens.

JI: Have you ever done [a trial] where a patients have a high disease burden, you gave them cabozantinib/nivolumab, and once the disease got under good control, changed to nivolumab/ipilimumab?

TAN: That is one of my ideas for a trial design I’m going to possibly pitch to Exelixis. Because, in my opinion, a reverse PDIGREE approach would be more fruitful. Get them on nivolumab/cabozantinib for a couple months, get their disease burden down, then before they progress, add in ipilimumab/nivolumab without the cabozantinib. No triplet, just nivolumab/ipilimumab up to 4 cycles, and then maybe do nivolumab maintenance or even nivolumab/cabozantinib maintenance. That kind of ‘sandwich’ approach makes more sense to me. I like your thinking there, Dr Ji.

GRACE SUH, MD: I echo the sentiments on the tolerability of the IO/TKI combination. That has been my go-to for first-line [therapy] for most patients who present with a large volume of disease. But the limitation has certainly been the adverse events [AEs] and the dosing.

TAN: Do you have any preference as far as an IO/TKI regimen and dose reduction? Is there something that is easier to dose reduce or dose adjust?

JOMEL LABAYOG, MD: I’ve been a user of axitinib [Inlyta] and pembrolizumab [Keytruda] because the data came out earlier on, and I’ve had [patients] continue on. Sometimes I’ve had to reduce their axitinib dose, but, unlike some of the other correspondents, I’ve had very limited toxicities with, and it’s per patient. It’s not as if I have a large cohort.

I have a question with ipilimumab and nivolumab. Everyone talks about 4 cycles, but is there any benefit to continue the ipilimumab beyond if the patient is tolerating it, to keep on going?

TAN: That is a good question. I always have wondered why only 4 cycles. In general, we think that the risk of grade 3/4 AEs is going to be much higher if the patient got more than 4 cycles. We think that an induction of 4 cycles of ipilimumab/nivolumab may help differentiate responders versus nonresponders. But there are trials in other tumor types where there is a more spread-out version of ipilimumab/nivolumab and you go for more cycles. I think that that should be considered as a study in the future.

JASON SUH, MD: If you look at the [NCCN guidelines], ipilimumab/nivolumab is not recommended for the favorable-risk group, right?²

TAN: It’s not approved, but I do consider it for select patients with favorable risk. There are some patients who can get complete responses, about 10% of patients.¹ We don’t have a biomarker to pick out the ones whose disease is driven by inflammatory disease or angiogenesis. Most favorable-risk patients are probably driven by angiogenic [reasons]. There’s probably a subset that has immune-inflamed phenotype, and they can also respond to ipilimumab/nivolumab but I think we require more data for that.

_References:

_{1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126}

_{2. NCCN. Clinical practice guidelines in oncology. Kidney cancer, version 4.2023. Accessed January 25, 2023. https://bit.ly/2TAx1m3}