Berg Discusses Tolerability Challenges of IO/TKI in Advanced RCC

Stephanie A. Berg, DO (MODERATOR)

Medical Oncologist, Lank Center of Genitourinary Oncology

Dana-Farber Cancer Institute

Boston, MA

EVENT REGION New England

PARTICIPANT LIST Santosh Kumar, MD | Philip Brooks, MD | Barbara Bjornson, MD | Naheed Alam, MD | Madhavi Gorusu, MD

BERG: Does anyone start with 400 mg, or do you do the 200 mg every 3 weeks and then broaden to every 6 weeks after toxicity checks? How do we dose pembrolizumab [Keytruda] nowadays? This is a question for all immunotherapy, [but pembrolizumab is] the only one that offers [dosing every 6 weeks].¹

KUMAR: I usually do every 3 weeks. I like to see the patients every 3 to 4 weeks, just to make sure they are doing OK. With the 6 weeks, I feel uncomfortable with not seeing them for that long.

BERG: Do you ever extend it to 6 weeks, Dr Kumar?

KUMAR: I have done it in a couple of cases. Unfortunately, in 2 cases, it was coincidental that both developed some colitis. Fortunately, it was not that severe, so I just went back to the every 3 weeks [dosing] and they did fine.

BROOKS: I start patients at every 3 weeks, but if they’re tolerating it well and they’re doing well and I don’t feel I need to see them every 3 weeks, I will try to shift them over to 6 weeks. But I have had patients who did not feel as well. There haven’t been any major adverse events [AEs], but I’ve had patients tell me they haven’t felt as well, [and] had increased fatigue. There are patients for whom I go back to 3 weeks, but most patients tolerate it well, and when they’re doing well, I try to keep them out of the clinic more.

BERG: With COVID-19 and with staffing sometimes, [infusion] chair time can be tough if you don’t have it. Does anyone do every 6 weeks [ from the start]?

BJORNSON: There’s a very low advantage to that, and there’s a high price for doing it. You have 5% of patients who have significant toxicity.

ALAM: It depends on the patient, but for patients whom you can trust, I do switch to every 6 weeks and they do fine.

BERG: Nivolumab [Opdivo] used to be every 2 weeks, and then they moved it to every 4 weeks and…I don’t know if I would ever do nivolumab every 2 weeks by choice.² But… with pembrolizumab…I always find that we think the same way, where we do every 3 weeks and then we go to 6 weeks eventually. But I would never give nivolumab every 2 weeks.

[What is] the lowest dose of lenvatinib [(Lenvima) with which] you saw an effect? Has anyone done 4 mg, or does anyone start at 18 mg, which wasn’t studied in RCC because it’s [reduced from] 20 mg to 14 mg? Does anyone do 18 mg? I can’t imagine there’s a huge difference between 18 mg and 20 mg…. I’ve never used less than 10 mg or 8 mg of lenvatinib. I’m sure there is some effect at lower [doses].

ALAM: Once you get a maximum response, I’ve had a few patients in some other diseases who can go to a lower dose. Once you have what you think is a maximum reached response, it potentially sustains the mechanism of action.

BERG: I agree, because we stop immunotherapy [IO] at 24 months, but we don’t stop the TKI [tyrosine kinase inhibitor]. Has anyone stopped TKI after the 2 years if they have stable disease, or do you keep them on it?

KUMAR: If they have no evidence of disease, then I stop it. I have stopped it on 2 patients and they are doing fine.

BERG: That’s great. You must be happy.

KUMAR: Oh, yes. They just come for their pembrolizumab. These are patients I started 3 or 4 years ago, so they’re doing fine.

BERG: That’s great. These are not drugs to be on for that long a time. I don’t know if we know the right answer to the indefinite TKI right now, but, I agree, if you have a patient who has stable disease and a solid deep partial response with very little cancer left, I think it would behoove us to go lower or just hold and scan. The disease is probably indolent at some point, but it is nerve-racking because…RCC isn’t [using] circulating tumor DNA right now as other cancers are. I want it to be because it would help me a lot.

What do you normally counsel patients to look out for when they come back for their first toxicity visit after starting a regimen like this?

GORUSU: I have to yet see a patient who has tolerated anything more than 16 mg; maybe 12 mg is [typical]. We [tend to] forget about…the proteinuria [with] lenvatinib. In patients with diabetes, that may be the reason for the proteinuria…but I feel like we check so many things [such as] electrolytes and endocrine [levels] with the immune checkpoint inhibitors [ICIs], [yet] we need to remind ourselves [of the] proteinuria.

BERG: That’s a great point because in all these trials, you were excluded if you had [1 g or higher/24 hours] proteinuria. So we don’t know what the real damage is for men and women with baseline proteinuria, and as oncologists, we’re not getting standard urinalysis [UA] unless they have symptoms. Even if they’re diabetic, they might get a UA once a year as a screening, but [we should] follow that, especially on cycle 1/day 1 where checking it, if they just happen to have it and doing a protein/creatinine ratio through it. Because nephrotic syndrome is [rare] with these drugs, but it has been reported.

DISCUSSION QUESTION

• Do potential AEs drive your decision-making, and which ones are they?

BROOKS: [The challenge is] balancing all the AEs from the targeted agents and the immunotherapy agents. Fatigue is a life-changer for patients and there aren’t any treatments for it. It diminishes their quality of life, so that’s been a problem, especially with lenvatinib. Hypertension and diarrhea, we can deal with. I go through a bunch of the toxicities but…I give them a list and we tell them that there are a lot of potential toxicities, and anything out of the ordinary we want to hear from them because it’s hard to just pick out 1 or 2.

BERG: It is tough when you give them a 3-page handout with all the lists…sadly, we don’t have time [to do more].

We give a handout, tell them to come back, [and say] we will keep an eye on them and call us if anything [happens].

BROOKS: It would be helpful if we knew, with all these different TKIs… which are the ones that stand out the most for each TKI. There are some unique AEs not just with the TKIs but with so many of the other drugs we use. A lot of them have unique AEs, whether it be headache that gets better with caffeine, or rash. When I haven’t used the medicine a lot…and there are 100 AEs, it’s hard to prioritize to the patient which is the most likely. I end up going over some of the key ones that I’ve seen with TKIs and stress to get back to us if there are any problems.

BERG: For cabozantinib [Cabometyx], at least, they get a paronychia issue that can be detrimental to quality of life, especially with the palmar-plantar erythrodysesthesia on their hands and feet.³ Nausea [is significant with] cabozantinib compared with lenvatinib; I always have my patients do ondansetron or prochlorperazine before cabozantinib because they have to take it on an empty stomach. Premedicating with ondansetron has been helpful for them to get over the way that they take the drug. Hepatitis is always tricky because we see it early a lot, but you can also see [ICI-related] hepatitis early. A lot of us recognize it’s usually the TKI when it happens first, but you have to decide which one to hold and what grade it is…. Axitinib [Inlyta] use is sometimes preferred because its [half-life] is so short, and… you can go down to 1 mg twice a day for axitinib.⁴ It’s a learning curve for that drug, but it has a lot more modifications…whereas cabozantinib is 40 mg, 20 mg, [then] 20 mg every other day.³ Lenvatinib is pretty easy with the dose packs, but you have to get new prescriptions for [4-mg capsules] if you change your patients’ doses.

DISCUSSION QUESTION

• For a patient in complete or partial response to a frontline ICI-containing regimen, how do you decide whether to switch therapy, hold all therapy, or only hold ICI therapy with an immune-related AE requiring discontinuation?

BERG: Does anyone go beyond the 24 months of IO treatments…? Do you set that goal in the beginning where you say you’re going to be on this for 2 years or is it something where you more talk about it toward the end of the 2 years if you have a patient approaching that?

BJORNSON: The first discussion is, “Can you tolerate it and is it going to be effective?” so the duration tends to be a later discussion.

BERG: Do you stop at 2 years, though, if you’re at 18 months?

BJORNSON: Typically, that is the natural end for somebody who is not progressing and is stable or has complete response. That’s about what they can tolerate, with some exceptions.

BERG: I agree. Has anyone run into insurance problems [if] you wanted to extend it beyond the 2 years?

BJORNSON: It doesn’t seem like insurance has an end point or stop measure.

BROOKS: I’ve never had a problem in continuing it. You mentioned earlier that you haven’t gotten into circulating tumor DNA. I see Signatera being used so often in so many different diseases now. I’m using a lot of Signatera in a lot of different diseases.… I’ve had patients who had negative Signatera [test results] and a few weeks later had recurrent disease.

But if it’s negative, it is something that’s nice to be able to speak to your patients [about]. In melanoma, it does seem to corelate with long-term response if it’s negative.⁵

BERG: Yes, I agree. In colon cancer, it’s doing well too.… There’s definitely more to come, and there [are] a lot of data out there for physicians publishing what they’ve seen with Signatera, and if it’s going to be used in a prospective trial to make decisions, it’s going to be interesting.

If you do stop at 2 years and they have a relapse…within 6 months or 1 year, [would you] rechallenge? That’s still not universal, what we define as IO failure. Most say 6 months after the last dose of immunotherapy…would anyone rechallenge less than 6 months?

BJORNSON: My experience is when patients relapse quickly, it’s widespread disease and declares itself, and sometimes it ends up being more of a palliative approach.

BERG: Sure, and IO in that setting getting a good response is not typical of what we know for immunotherapy…but we know it’s not unheard of, especially if their performance status doesn’t allow them to get…a TKI, [whereas] IO would be helpful and palliate a lot of their symptoms.

REFERENCES:

1. Keytruda. Prescribing information. Merck Sharp & Dohme Corp; 2021. Accessed April 9, 2024. https://tinyurl.com/4uxzxzaz

2. Opdivo. Prescribing information. Bristol Myers Squibb; 2018. Accessed April 9, 2024. https://tinyurl.com/2kxcpcsv

3. Cabometyx. Prescribing information. Exelixis, Inc; 2021. Accessed April 9, 2024. https://tinyurl.com/39pdhrd9

4. Inlyta. Prescribing information. Pfizer Inc; 2022. Accessed April 9, 2024. https:// tinyurl.com/5y2fzyvs

5. Eroglu Z, Krinshpun S, Kalashnikova E, et al. Circulating tumor DNA-based molecular residual disease detection for treatment monitoring in advanced melanoma patients. Cancer. 2023;129(11):1723-1734. doi:10.1002/cncr.34716