Tailoring TKI Dosing Strategies to Real-World Patients With RCC

When treating with immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations, dose reduction and discontinuation is sometimes needed due to treatment-related adverse events (TRAEs). In a virtual Case-Based Roundtable event, participants and moderator Che-Kai Tsao, MD, MS, discussed the trial discontinuation rates and how they compared to real-world practice. Tsao, medical director of the Ruttenberg Treatment Center at the Tisch Cancer Institute at Mount Sinai Hospital and associate professor of Medicine, Hematology and Medical Oncology, at Icahn School of Medicine at Mount Sinai in New York, asked participants how they treat patients using TKIs including dose escalation vs dose reduction strategies.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

DISCUSSION QUESTIONS

• Do the discontinuation rates reported in the first-line IO combination trials align with your own clinical experience? ​
• If you modify the starting dose for tolerability, do you believe it is affecting efficacy? ​

Che-Kai Tsao, MD, MS: If we look at all TRAEs, we’re talking about an AE profile in the 90-plus percent range.^1-4 But some of the things we care [about include] grade 3 and above TRAEs, because for grade 3 AEs, this would then involve potentially stopping the medication—at least holding it for a long time. With immune-mediated AEs, there is the possibility of using high-dose corticosteroids. From ipilimumab [Yervoy] plus nivolumab [Opdivo], the [rate of] grade 3 or above TRAEs was 48%.¹ In the IO/TKI studies, this ranged from 61% to 74%.^2-4

If you look at discontinuation due to AEs, ipilimumab/nivolumab stood out at 24% whereas if you look at other combinations, they were significantly higher, particularly when you take account of all type of discontinuations.^1-4 But out of all the IO/TKIs, in CheckMate 9ER [NCT03141177], only about 21% of the patients had discontinued one or both treatments due to the AEs, which was quite impressive as well.² Those things stood out at me.

Gabriel Jung, MD: I think the data support what I have experienced. I don’t have too much experience with the other combinations, but for the cabozantinib [Cabometyx] plus nivolumab, especially with the symptomatic bone metastases, I feel like patients did get more response and clinical benefit in terms of decreasing symptoms from the disease. So, I agree that the data support my experience.

Tsao: Dr Belenkov, could I ask you about your axitinib [Inlyta] plus pembrolizumab [Keytruda] experience? The [trial] discontinuation rate was [31% or higher] for axitinib/pembrolizumab,⁵ which hasn’t been my experience using it. What has been your experience in using axitinib/pembrolizumab?

Elliot Belenkov, MD: I don’t use much of that combination, and you have much more experience than I do, but [my experience] falls into the same category.

Tsao: Dr Kumar, if you modify the starting dose for tolerability, do you believe that it’s affecting efficacy? I think one of the reasons why cabozantinib/nivolumab was much more tolerable is the fact that we’re starting cabozantinib at a 40-mg dose. Do you think maintaining a very high TKI dose in the beginning matters?

Santosh Kumar, MD: It does. We don’t have the data from cabozantinib/nivolumab, but we know from lenvatinib [Lenvima] plus pembrolizumab that the higher the dose of lenvatinib you start, rather than escalating the dose, helps the progression-free survival [PFS]. The cabozantinib dose of 40 mg is pretty tolerable. I have used it in patients in their 70s. The only people who I cut down the starting dose to 20 mg for are the people who are in their 80s, or if they have a borderline [ECOG] performance status, like 2. But if they have an ECOG [performance status] of 1 and they are in their 70s, even they tolerate 40 mg [cabozantinib] with nivolumab pretty well.

Tsao: Thank you for sharing that. There is a body of data for TKIs alone that dose intensity does matter in terms of disease control durability. There are some preclinical studies that suggest that maintaining early, higher dosage upfront may impact the synergistic effect of IO/TKI therapy at the same time. If you look at the CLEAR study [NCT02811861] where 73% of patients had dose reductions—and we see patients who are much more frail than clinical trial candidates—I think that patients can tolerate what they can tolerate.⁴ A lot of the time, going up to 20 mg of lenvatinib is challenging, so you have to balance the clinical reality with these hypothetical advantages.

Looking at these data, would they change your practice patterns across the different combination choices? [What are] any of the things that resonated with you, and how would that change your practice?

Stuart Feldman, MD: I don’t think I would change my dosing. The issue is that the patients whom I’ve treated with lenvatinib have mostly ended up on a 10-mg dose and had a very good response. I’m not sure there’s that much of a difference between 10 mg, 18 mg, and 20 mg, and 10 mg is clearly well tolerated. The issue I had was the hypertension, which had to be better managed, and I’ve seen proteinuria with it. But once we got down to 10 mg, it was clear sailing, and the response was maintained.

When they come up with these doses, they’re based on maximal tolerated dose in phase 1 trials, and then they take that dose and go through phase 2 trials, find a tumor type that works, and that becomes the dose. But as we’re finding out in a lot of other tumor types where there are multiple drugs in the same class—for instance, in breast cancer, they’ve already lowered the dose of ribociclib [Kisqali] and given it in the adjuvant setting over 3 years instead of 2 years with another drug.⁶ They play with the dosing, and they play with the toxicity. When you have multiple drugs within the same class, and you don’t compare them head-to-head in trials, we end up discussing this, and it becomes a matter of opinion.

Tsao: Thank you for sharing your insights. Certainly, when you look at real-world data of outcomes and dosage, they’re very different than what we see in clinical trials because of the type of patients who we see in real-world practice. Dr Dai, what are your thoughts?

Tong Dai, MD: Considering all the options, it looks like if the patient needs faster response, pembrolizumab plus lenvatinib might be a better choice. But for the majority of patients, cabozantinib/nivolumab is better tolerated and has good efficacy.

Belenkov: [Are there] any data on…starting with this lower dose of TKI and ramping it up? We do this with the VEGF inhibitors in colon cancer like regorafenib [Stivarga], and it turned out to be much better tolerated. I wonder if you have this experience or data in RCC?

Tsao: There was a second-line study looking at lenvatinib at 14 mg vs 18 mg with everolimus [Afinitor].⁷ This [showed] moderately better PFS, not a lot better, and a little better in terms of response rates. We have a body of evidence that with TKI alone, dose intensity is important. But at the same time, in my practice, particularly with patients with poor functional status, I generally like to start a little bit lower. But I’m very aggressive in terms of dose titration and in fact, at times when there is mixed response or there is oligoprogression, I may even consider titrating up the dose with some levels of success.

If you put patients on 20 mg of lenvatinib and they’re miserable within the first 2 weeks, they may be much less likely to be [adherent] going forward. So as long as there is an intention to titrate the dose based on tolerability later on, I’m a big believer that patients can tolerate what they can tolerate, and it is up to us as the medical oncologist to try to balance the patient’s disease control with their quality of life. Taking a less aggressive approach upfront and titrating later is a very reasonable approach.

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DISCLOSURES: Tsao previously reported consultancy honoraria from Bayer, Exelixis, Lantheus, and Pfizer.

REFERENCES:

1. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079

2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

3. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

4. Motzer RJ, Porta C, Eto M, et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. J Clin Oncol. 2024;42(11):1222-1228. doi:10.1200/jco.23.01569

5. Keytruda. Prescribing information. Merck & Co, 2021. Accessed November 10, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf

6. Slamon DJ, Fasching PA, Hurvitz S, et al. Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer. Ther Adv Med Oncol. 2023;15:17588359231178125. Published 2023 May 29. doi:10.1177/17588359231178125

7. Pal SK, Puente J, Heng DYC, et al. Assessing the safety and efficacy of two starting doses of lenvatinib plus everolimus in patients with renal cell carcinoma: a randomized phase 2 trial. Eur Urol. 2022;82(3):283-292. doi:10.1016/j.eururo.2021.12.024