Treatment Selection and Dosing Strategies Based on Trial Data in RCC

Benjamin Garmezy, MD

Assistant Director of Genitourinary Research

Sarah Cannon Research Institute at Tennessee Oncology

Nashville, TN

DISCUSSION QUESTIONS

• What are your key takeaways from the CheckMate 9ER (NCT03141177), KEYNOTE-426 (NCT02853331), and CLEAR (NCT02811861) study data?​
• Does your choice of IO/TKI [immunotherapy/tyrosine kinase inhibitor] regimen vary based on patient profile? ​
• What patient factors influence the choice?​

BENJAMIN GARMEZY, MD: I’d love to hear opinions of this data, making your own kind of comparisons of what you saw on and maybe what surprised you.

UDAY DANDAMUDI, MD: When you look at the comparison of all these trials like CLEAR or CheckMate 9ER or KEYNOTE-426, there are similar data. It [comes down to] the comfort of what you're used to, that's the most important. I used to use lenvatinib [Lenvima] with pembrolizumab [Keytruda] but I moved to nivolumab [Opdivo] with cabozantinib [Cabometyx] because cabozantinib at 40 mg seems to be well tolerated compared with lenvatinib at 20 mg. When I use lenvatinib 20 mg, I need to scale down the dose significantly faster because of the adverse events [AEs].

GARMEZY: How often do you feel like you have to dose reduce the cabozantinib/nivolumab?

DANDAMUDI: If I started cabozantinib 40 mg, so far, I have not significant change anybody's dose at this point of time. Rather, on and off I give breaks in the cabozantinib treatment depending upon the patient's AEs, but in general, I don't compromise on the dose.

GARMEZY: OK, thanks. What about your thoughts, Dr Sharma?

NEERAJ SHARMA, MD: You had made a comment that you get used to 1 combination and get good at it, and that's my thought [as well].

GARMEZY: Which [combination] do you use?

SHARMA: I [previously] selected cabozantinib/nivolumab [for a favorable-risk patient].

KETAN DOSHI, MD: I have used cabozantinib/nivolumab more frequently because of previous use in thyroid cancer and familiarity with the drug. But looking at the CLEAR data, it looks like the HRs are pretty good [HR for progression or death in intent-to-treat population, 0.47; 95% CI, 0.38-0.57; P < .0001].¹ One could get comfortable adjusting the dose with it, then it would be easy [to adjust depending on] high, low, or intermediate risk, [so] you can just use…lenvatinib/pembrolizumab. But I haven't switched as of yet.

GARMEZY: Does anyone vary which IO/TKI combination they're going to give based on the patient, or are they all just sticking with the one they know and using that one?

AHSAN SHAH, MD: If the patient has bone or central nervous system [CNS] metastases, I typically go for cabozantinib/nivolumab. I've been little bit more comfortable with axitinib [Inlyta] and pembrolizumab, but on the flip-side cabozantinib/nivolumab was fairly well tolerated as well. With lenvatinib, I am not so lucky. At least from my experience, I've always had to do a dose reduction.

GARMEZY: So basically pembrolizumab/axitinib is your workhorse; cabozantinib/nivolumab is your bone and CNS [option]. What about anyone else? Is anyone else switching the IO/TKI based on the patient?

JORGE HURTADO, MD: I do something very similar. Depending on the patient, and...if I have good reason to think I can [get a good response], I probably will use pembrolizumab and lenvatinib. For those who have a higher metastatic burden, etc, I tend to use cabozantinib/nivolumab. I don't use pembrolizumab/axitinib that much.

GARMEZY: We've already talked about comparing the differences in the toxicity profiles. A lot of you have mentioned the tolerability issues with lenvatinib, probably because of the 20 mg dose that it goes with, but [generally] these multikinase drugs can be hard to tolerate. Are you more commonly interrupting and restarting at the same dose or interrupting and starting at a reduced dose upon re-initiation?

SIMON BLANC, MD: I interrupt and then I restart at a lower dose. It depends on what complications we are talking about and the grade of complications, etc. But in general, I [restart] at a lower dose. I always have a ramp-up period for all TKIs. I never start full dose on those patients.

GARMEZY: [Out of] axitinib/pembrolizumab, cabozantinib/nivolumab, or lenvatinib/pembrolizumab, which was your preferred [combination]?

BLANC: I use axitinib/pembrolizumab.

GARMEZY: So do you start at 3 mg?

BLANC: I start at 3 mg and I go up every couple of weeks or every 4 weeks, depending on how they tolerate it.

GARMEZY: When you reduce the dose back down, does that tend to be enough? Where would you go if they were at 5 mg? Would you reduce to 4 mg?

BLANC: [Yes], 4 mg; I just drop [the dose] by 25%.

GARMEZY: Does someone else have thoughts on interruptions and how we're restarting the TKI?

DOSHI: Besides what [Dr Blanc] said, it also depends on how the patient is. There are some patients who are so much on the edge that they get AEs and then if they get the AEs again [after resuming treatment], they will [panic] and stop everything. For those kinds of patient, I will definitely reduce the dose even if the AE was mild and if I have to interrupt. If they are a ‘fighting spirit’ kind of patient and the AE was mild, then I may rechallenge them with the same dose after a break.

GARMEZY: What drives your decision on IO/TKI combinations? It's very clear that you all have your most preferred one, some of you are using multiple [combinations], but is it to do with the IO partner or the TKI partner when you make that choice? Is anyone making decisions based on nivolumab versus pembrolizumab? Or is it all based on the TKI?

DOSHI: It will be the TKI because we are all familiar with nivolumab and pembrolizumab. That wouldn't make us choose something different. I don't [prefer] to give nivolumab or…pembrolizumab, but if we are used to the TKI, we are going to go with whatever partner it comes with.

References:

1. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716