Peers Discuss Management of IO/TKI Toxicities and Dosing Strategies in Frontline RCC

Elizabeth M. Wulff-Burchfield, MD

MODERATOR

Assistant Professor of Medicine

University of Kansas Medical Center

Kansas City, KS

EVENT REGION Great Plains

PARTICIPANT LIST Kevin Palka, MD | Chang-Qing Xun, MD | Somasekhara R. Bandi, MD | Blaine Knox, MD | Sakeer Hussain, MD | Bassam I. Mattar, MD

DISCUSSION QUESTION

• Based on your own experience, how does the efficacy and safety profile of nivolumab (Opdivo) plus ipilimumab (Yervoy) compare with immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) regimens for metastatic ccRCC?

WULFF-BURCHFIELD: When you think about nivolumab and ipilimumab compared with one of these TKI/IO regimens… what do you think about in terms of safety?

PALKA: I’ve used a lot of lenvatinib [Lenvima] for thyroid cancer, and those patients had a lot of adverse events [AEs] with that, [including] hypertension. It was not an easy drug. I’ve had a lot of success with the dual immunotherapy. I haven’t had a lot of horrible AEs with them…. I don’t know if the toxicity with the oral TKIs is that much better. Where we are is rural, and it takes a long time to get oral drugs and chemotherapy. I agree that if you have a symptomatic patient, giving them the TKI and immunotherapy is going to have a better response rate, but if it takes you a month to get the pills, that doesn’t really help the patient, and sometimes it’s easier to get the intravenous treatment started through the hospital infusion rather than wait for the drugs.

XUN: My experience is that you may not see a quick response but you do see the dual IO get disease stabilized. If we can just stabilize, I’m OK with that, and the toxicity profile, in my opinion, is a lot better.

WULFF-BURCHFIELD: It’s hard when talking to patients about it. Sometimes they have a false sense of security with the idea that [the TKI] is just a pill and they take a handful of pills every morning. We all know TKIs are very different.

XUN: In the patients with favorable-risk disease, I’m not fond of TKI because of the toxicity profile.

WULFF-BURCHFIELD: So it’s sparing patients that longitudinal toxicity with the TKI.

BANDI: In favorable-risk disease, I’m weighing the risks and benefits. Do we really need an IO combination up front? I’m not sure. I do use nivolumab plus cabozantinib [Cabometyx]. I’ve got good luck with it. Of all the TKIs, I think that is probably more manageable for patients, at least in my experience.… Maybe the lower response rates [in CheckMate 214 (NCT02231749)] initially were because of the higher [number of] patients with poor-risk disease in that group, but ultimately, the median overall survival [OS] is longest for that.¹ We don’t know what it is going to be for the CLEAR study [NCT02811861], so it might be about the same or better, but maybe because it [has more] patients with favorable-risk disease, overall response rates are higher initially compared with the IO/IO study.²

WULFF-BURCHFIELD: Are there any other factors that you might weigh more heavily with favorable risk? For example, quality of life seems extra important for patients who have a longer median OS.

XUN: You have to consider, if patients have no symptoms or very minimal symptoms, whether you are giving them a treatment that causes more problems than the disease itself.

WULFF-BURCHFIELD: It’s tough to sit across from the patient who’s experiencing that and say, “This is for your own good,” especially given that some of these OS curves are crossing 1.0. It all occurs to us: Is it for their own good? It’s a lot of responsibility.

CASE UPDATE

Cabozantinib plus nivolumab was initiated. A partial response was noted on CT imaging at 4 months after cabozantinib plus nivolumab initiation. During cycle 9, the patient reported fatigue, weakness, and a 10-lb weight gain.

Workup showed low free thyroxine (T4), high thyrotropin (TSH), and morning cortisol and corticotropin within normal limits. MRI of brain showed a normal pituitary gland, and cardiac evaluation (echocardiography) results were negative. The patient was treated with levothyroxine. Cabozantinib plus nivolumab was restarted when free T4 returned to normal range.

WULFF-BURCHFIELD: This patient ends up developing fatigue, weakness, and weight gain, so we would all do an endocrine workup. We do this all the time. We see that this patient has a low free T4 and a high TSH; that suggests he has some central hypothyroidism. I don’t see that very often. I think it’s a less commonly reported AE. When you are talking to your patients about what to expect in terms of immune-related AEs, what do you tell them you see the most, and are there any that you know or that seem to be…more common in RCC compared with some of the other populations to whom you give IO?

KNOX: The most common issues for me have been rash and the immune-related AE of hypophysitis. I’ve had a few recently where they’ve got a multitude of issues and I need to closely work with the endocrinologist. The scariest one for me is always adrenal insufficiency, in which patients [go to] the emergency department and are thought to have sepsis and you find out they have adrenal insufficiency.

BANDI: Myasthenia is another; I’ve had a patient with ocular myasthenia.

WULFF-BURCHFIELD: I’ve seen that as well, and it’s frightening.

DISCUSSION QUESTIONS

• Please discuss your real-world experience with each IO/TKI regimen. How do the safety profiles of each regimen compare?
• How often do you have to modify/ interrupt/discontinue for toxicity?
• What influences your decision to initiate therapy at a dose lower than the protocol dose?

WULFF-BURCHFIELD: One thing I think is important is the asymmetry, with more of a liver signal for cabozantinib and nivolumab [vs sunitinib (Sutent)], which is something that is difficult [Table 1⁴]. Given the half-life of cabozantinib, if patients are having elevated levels of AST [aspartate aminotransferase] and ALT [alanine aminotransferase], it’s hard not to want to immediately put those patients on steroids. It is difficult to consider holding their cabozantinib and just follow results from their liver function tests [LFTs] every couple of days. If you’ve ever seen bad hepatitis cases, then it’s very disturbing to see those elevated levels in results from LFTs, but seeing that this combination has a greater proportion of AST and ALT elevations, it’s something we should probably all get a little bit of tolerance to when prescribing this regimen.

PALKA: I think it’s tougher to figure out which way to go with diarrhea, because on their fourth cycle, what’s causing the diarrhea?

WULFF-BURCHFIELD: It’s incredibly difficult. I use stool lactoferrin to help me with that sometimes. But my personal bias is that people could have a drug-induced colitis, even if it’s not immune checkpoint inhibitor induced. [It could be] from any drug that causes diarrhea. I should look into the proportion of patients who have elevated stool lactoferrin levels, if they have non–checkpoint inhibitor induced diarrhea syndrome. That would be interesting to know. But that’s the only tool I lean on to help me differentiate. When the half-life is that long, it’s hard to wait it out, especially with an intravenous fluid shortage. I have that same struggle as well.

Any grade of AE is a guarantee with almost every one of these regimens. However, we do see that the proportion of AEs does vary. CheckMate 214 has the lowest proportion of grade 3 or higher adverse events, although admittedly, things like myasthenia gravis [occur in] a lower proportion in patients who are only receiving single-agent immunotherapy with the TKI.1 Discontinuation rates look different across the spectrum [Table 2^1,3-5]. Interestingly, discontinuation rate and high-dose steroid use look similar among CheckMate 214, but numerically, there’s a higher number of patients who are discontinuing at least some of the regimen with CLEAR compared with that, and we’re seeing relatively few discontinuations with CheckMate 9ER [NCT03141177]. Does this align with how patients are tolerating treatments in your practices?

HUSSAIN: With lenvatinib, I usually use dose escalation. I start with 10 mg. That was my best experience. At 20 mg, most of the patients don’t tolerate it up front, so I just go up slowly.

WULFF-BURCHFIELD: That’s an intense dose to start on. When you are thinking about dose modifications that are almost a guarantee with some of these regimens, how much worry do you have about compromising efficacy?

HUSSAIN: I do, but in my experience, if you start at 20 mg, most of them do not complete it. The first patient I started on len-vatinib at 20 mg quit treatment completely. I thought they probably would be [able to complete it if I escalated] the dose to 20 mg in 2 months’ time, and most of the time, it is possible.

KNOX: When a young patient with very good functional status is sitting in front of you and they just want to know which one works the best, it’s hard to answer that question when you look at the OS curve. But the basic answer that I’ve given is that I think lenvatinib has the best data in terms of response rates, if that’s the basic question. I think it’s a little harder to tolerate and has more AEs, but the data incorporated in those outcomes are accounting for that and accounting for those dose reductions. I agree that the higher doses theoretically are better. I like for patients to be on a higher dose if they can tolerate it, but those outcomes are still with dose reductions and holding treatment and potentially discontinuing it.

WULFF-BURCHFIELD: I counsel patients in that way as well. If I’m going to offer patients lenvatinib and pembrolizumab, then I offer them 20 mg, and that’s based on…findings from a noninferiority trial comparing starting dose of lenvatinib of 18 mg with 14 mg, and 14 mg was not noninferior to 18 mg.⁶ It’s suspected that this occurs based on the fact that there’s more FGFR inhibition at these higher doses of lenvatinib. Some of these patients need weekly visits and are getting their dose reduced 2 and 3 weeks into treatment, but I tell them that the data are true, in spite of the fact that everybody is going to go down on their dose. I had a 22-year-old patient who was on lenvatinib/pembrolizumab and had to reduce the dose to something like 12 mg. I agree that dose reduction is expected.

If we have patients who are going to go to hospice unless they get a response, objective response is crucial. But outside of that, if the median OS is the same, how much does objective response rate matter for individual patients? We don’t know.

DISCUSSION QUESTION

• When IO/TKI is preferred, what drives your choice of IO/TKI combinations?

WULFF-BURCHFIELD: When you think about the IO/TKI regimens, do you all see trends in these regimens in terms of toxicity or tolerability, and when you’re choosing them, what is driving you?

BANDI: I choose based on TKI AEs.

WULFF-BURCHFIELD: In your population, what specifically drives that? Is it that one is more toxic than the other? I think you said earlier that cabozantinib/nivolumab tends to be more tolerable.

BANDI: It tends to be much [better tolerated]. The lenvatinib combination is the hardest for me.

MATTAR: I agree with that. I try to avoid lenvatinib in any disease: uterine, thyroid, or RCC. I have tried to adjust the dose. Every time I tried lenvatinib, even if I went to a lower dose and did not start at 20 mg, I’ve had problems. I’m used to cabozantinib. I’m very comfortable with that. Sometimes insurance is dictating pembrolizumab vs nivolumab. Then I end up doing axitinib [Inlyta] vs cabozantinib, but in general, cabozantinib/nivolumab is my first line.

WULFF-BURCHFIELD: It sounds like the specific TKI is important to your patient’s experience and how you might prioritize different treatments.

PALKA: Dr Wulff-Burchfield, do you use much axitinib? I don’t like lenvatinib, and I would use cabozantinib, but I haven’t used much axitinib.

WULFF-BURCHFIELD: I prioritize axitinib for patients whom I think might get to a delayed nephrectomy, because I think its [unique] quality is its short half-life. Or if I have someone who has inflammatory bowel disease and I’m worried about differentiating between their inflammatory bowel disease flaring vs a drug-induced diarrhea from their TKI, then axitinib having such a short half-life means that 2 to 3 days after holding it, that drug is gone. I find that it’s easier for those specific scenarios, but based on these data, I don’t prescribe a lot of axitinib right now. Early on, there was a perception that it was easier, but that’s not necessarily what the data have borne out.

DISCLOSURE: Wulff-Burchfield previously reported roles as consultant/advisor for Astellas, Aveo Oncology, BMS, Exelixis, Janssen, and Pfizer.

_REFERENCES

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