Pal Discusses Long-Term Tolerability and Discontinuation of Frontline TKI and IO for mRCC

Peers & Perspectives in OncologyMay 2024
Volume 2
Issue 7
Pages: 72

During a Case-Based Roundtable® event, Sumanta K. Pal, MD, moderated a discussion on quality of life data and experiences with dose discontinuation of frontline combination therapy for patients with renal cell carcinoma.

Sumanta Pal

Sumanta K. Pal, MD


Codirector, Kidney Cancer Program

Chair, Kidney and Bladder Cancer Disease Team

Professor, Department of Medical Oncology & Therapeutics Research

City of Hope

Duarte, CA

EVENT REGION California, Oregon, Washington

PARTICIPANT LIST Arati Chand, MD | Sanjay Sharma, MD | Amanda Sun, MD | Herschel Wallen, MD | Thomas Marsland, MD | Nihal Abdulla, MD


The patient is a man aged 61 years with an active lifestyle and a history of low-volume, indolent, metastatic clear cell renal cell carcinoma (mRCC). After left nephrectomy and adrenalectomy, he was observed based on his preference as well as on low volume and indolence of disease.

Three years after surgery, continued indolent growth and increased total tumor burden (new paratracheal lymph nodes [2.0 × 1.5 cm] and more than 10 pulmonary nodules) were seen on CT. A lung biopsy confirmed mRCC. Laboratory results were within normal limits, and ECOG performance status was 0.


  • What drives your selection of first-line therapy for favorable-risk clear cell RCC?

CHAND: For the favorable-risk patients, I have used the IO [immunotherapy] plus TKI [tyrosine kinase inhibitor] combination; I haven’t used the IO/IO regimen for the longest time. Although, I’ve heard…that those patients are probably ones you could potentially cure, and in the 8-year survival data, 24% of patients tend to have very durable responses.1 If I have a very frail [older] patient with favorable-risk disease, single-agent TKI is not unreasonable in those patients, or single-agent IO in the second line. It just depends on the patient’s comorbidities and presentation; if they have severe cardiovascular disease, I may skip the TKI.

PAL: That’s a good, nuanced answer. It depends on whether that patient walks in with heart failure, or if they’ve got other real-world problems, severe asthma, etc. All these things might influence your treatment choice.

If you’re seeing a patient whom…you think has more indolent disease, how would you be approaching them with systemic therapy?

SHARMA: I try to be smart about it and figure out the differences between the TKIs and try to look at subcategories.

SUN: In the past I used a single-agent TKI. I had a patient on cabozantinib [Cabometyx] 5 years before progressing. Now we do the combination, TKI/ IO, so I use axitinib [Inlyta] plus pembrolizumab [Keytruda] more and…it has significantly more toxicity compared with TKI alone. [However], I don’t know for which patients [a single-agent] TKI is sufficient. The patient I treated years ago with a single agent…[when] she progressed, [because] her disease was indolent, I put on pembrolizumab. She was good for 2 years, and systemic disease was under control, and then [she developed] brain metastases. [In hindsight] I could have done a combination, but that was 2 to 3 years of pembrolizumab alone. It’s very individualized and it’s hard to choose, but now my tendency is to do the combination. I can imagine some patients do not need both up front.

PAL: That’s true. It’s hard to know whether these patients may best be served by the TKI component or the IO component.


  • What are your key takeaways from the phase 3 CheckMate 9ER (NCT03141177), KEYNOTE-426 (NCT02853331), and CLEAR (NCT02811861) study data?

PAL: I’m a big believer in the quality-of-life [QOL] data. I don’t believe that we’re assessing [them] consistently or appropriately across all studies, but there’s a trend toward significant benefit in quality of life with the cabozantinib plus nivolumab [Opdivo] study [Table2]. Whereas, despite the benefit in terms of overall survival and the marked benefit in progression-free survival [PFS], for instance that we saw on the CLEAR study, there’s no difference in QOL between lenvatinib [Lenvima] plus pembrolizumab and sunitinib [Sutent],3 and I feel that this is a dosing issue. If we started with a lower dose of lenvatinib on the CLEAR trial, we might not have seen the marked PFS benefit, but QOL might have been improved. If we had a better titration schedule for axitinib in KEYNOTE-426, maybe we’d have seen some QOL improvements.4 But I think the reason that CheckMate 9ER stands out is that we are using the lower dose of cabozantinib in the up-front setting. That explains the difference across these trials.

Quality-of-Life Improvement for Cabozantinib/Nivolumab vs Sunitinib in CheckMate 9ER (NCT03141177)

WALLEN: I’m wondering whether you would dose axitinib aggressively. Maybe you see a decline in QOL, but if you dose axitinib aggressively would it be [comparable in efficacy] to cabozantinib [plus nivolumab]? Or maybe cabozantinib is just a different animal altogether because it hits different targets.

PAL: My experience with axitinib…is when you go up from 5 mg twice daily to 7 mg twice daily to 10 mg twice daily, you run into toxicity constraints. I run into a lot of hypertension when I do that. Do you have the same experience with uptitrating axitinib?

SHARMA: Yes, for sure. It gets tough.

PAL: So, it becomes a QOL question at that point. A lot of people ask me the corollary of this, which is that with lenvatinib and pembrolizumab, can you start at a lower dose? Can you start at 10 mg…8 mg, or 12 mg? That lends itself to the dosing that we’re familiar with from hepatocellular carcinoma and other indications for lenvatinib.5 To which I say, I don’t know if you’re going get the PFS that you’re expecting with the regimen. I tend to be a purist in this setting. I would say that, for a patient who’s in the up-front setting, go with the dosing that was used in the clinical trials. To me, that lends itself to going with the cabozantinib/nivolumab dose that was looked at in CheckMate 9ER, but there is no right answer in this setting.

MARSLAND: Do you continue these treatments indefinitely? If [the patient has been treated for at least 5 years] and they’re looking good, do you continue the IO, or do you stop them?

PAL: In the context of the nivolumab plus ipilimumab [Yervoy] study, patients were allowed to continue the immunotherapy in perpetuity. I have a patient who was on CheckMate 214 [NCT02231749]. She’s been on nivolumab for 8 years, and I keep telling her [she can choose to discontinue it].

MARSLAND: Does [continuing nivolumab] make sense? Should we be doing that? I’m old enough to know that we [once] measured improvement in survival in weeks and months. Now, we’re at the point where you are asking, “When can we stop treatment?” At what point do we stop?

PAL: It’s well accepted that in a patient like that, you can start offering discontinuation at 2 years. With the TKI/IO regimens almost across the board, the IO was dropped after the 2-year mark. The challenge is that if a patient is on the TKI/IO regimen, it’s a real gamble to pull them off both of those at the 2-year mark. You must keep the TKI going, and in a lot of patients where I’ve dropped the IO-based therapy and then later dropped the TKI, I’m starting to see recurrences. That’s the 1 caveat of using the TKI-based therapies: You must sustain it long term.

This is a good opportunity for me to bring up a study that we published in The Lancet last year, which is CONTACT-03 [NCT04338269]. This was the only study to my knowledge that has so far looked at the concept of immunotherapy rechallenge. What I see a lot among second opinions…is a patient who starts on cabozantinib/nivolumab, then gets axitinib/pembrolizumab [or] gets lenvatinib/pembrolizumab. The CONTACT-3 study looked at the sequencing of IO-based therapies and showed that there’s no benefit to continuing immunotherapy [From the Data6]. If your patient has progressed on cabozantinib/nivolumab up front, there’s no point in giving pembrolizumab or nivolumab in the second- and third-line setting with the TKI; it should probably be a TKI monotherapy.

CONTACT-03 (NCT04338269) After Progression With Prior Immune Checkpoint Inhibitor

ABDULLA: If you have a patient who is lucky enough to have a complete response on a TKI/IO regimen, and you take them off the IO at 2 years, how long are you going to continue the TKI? Do you want to see if they can keep their response even after you discontinue the TKI?

PAL: I always give it a shot, especially [since] there are so many different patient phenotypes. I have patients who might be on cabozantinib/nivolumab who are down to 20 mg [cabozantinib] a day or 20 mg every other day. They’re not bothered at all by the adverse event profile. After 2 years, if they have a complete response, I’ll keep the cabozantinib going. But in most patients, if they’re having any sort of toxicity—and most are—I will at least experiment with dropping the drug and then do a 6-week interval scan instead of waiting until 3 months. I’ll…see if they’re losing their response to therapy. If they’re not, then I’ll go to another 3-month scan and another 3 months. I have successfully taken patients off TKI/IO, but I’m very delicate about removing the TKI in that scenario.

ABDULLA: For ipilimumab/nivolumab, do you [always] drop the ipilimumab after…4 doses?

PAL: The maximum for the ipilimumab would be 4 doses. We’d stop after 4 doses of ipilimumab, and unconditionally I’ve never gone past that. Then we continue nivolumab beyond that. The question is when to stop the nivolumab. In a complete response, you can stop as early as 1 year; I think that’s well accepted. Some patients might choose to hold until 2 years. I’ve been trying to persuade my patient to stop therapy with nivolumab for a very long time, but [she has continued] because it was permitted by the protocol. If you look deep at the CheckMate 214 data, you’ll see that a lot of patients who have sustained responses are still on nivolumab at those long-term end points.1 Because it was permitted in the protocol, she’s chosen to remain on [it], but most people would stop at 2 years.

ABDULLA: Are we still investigating the triplet therapy of nivolumab and ipilimumab with cabozantinib? Because [in COSMIC-313 (NCT03937219)] it met its PFS [end point], but the toxicity was too much.7 My question is, [we give] ipilimumab for 4 cycles, and that’s a very short period, and then the patient is on monotherapy with nivolumab. Why don’t we squeeze in the cabozantinib there, after they’re done with the ipilimumab, and continue with cabozantinib/nivolumab if they have a reasonable amount of disease?

PAL: There is a study running right now, which is called PDIGREE [NCT03793166], and…it is asking that very question. Patients start on nivolumab/ipilimumab, and if they have a complete response after 4 cycles of nivolumab/ ipilimumab, they stay on nivolumab as monotherapy. If they have progressive disease after 4 cycles, they get cabozantinib. If they have disease stabilization or a suboptimal partial response…they get randomly assigned to either nivolumab or cabozantinib plus nivolumab at that point.

The PDIGREE trial may get at that question of whether you need to get more aggressive therapy in the maintenance nivolumab setting, but I don’t think we have the answer to that yet. For the time being, I would not [add] on cabozantinib, and I’ve run into a lot of patients who have had great responses or stabilization. I’ve seen second opinions where cabozantinib is added on and has a ton of hepatic toxicity, and the patient ends up faring much worse. I wouldn’t [add] anything on in that setting.

But Dr Abdulla brings up an important study, which is COSMIC-313. This was a trial of nivolumab plus ipilimumab with or without cabozantinib. It was a positive study where there was a modest benefit in PFS, but we haven’t seen the overall survival data for that study yet.7 Also, the rate of grade 3/4 hepatic toxicity was 25%, so it was [very] high. There were lot of patients with severe liver toxicity, so I don’t think that’s a very appropriate regimen. You won’t see it reflected on the guidelines on that basis.

1. Tannir NM, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab (NIVO + IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): long-term follow-up data from the phase 3 CheckMate 214 trial. J Clin Oncol. 2024;42(suppl 4):363. doi:10.1200/JCO.2024.42.4_ suppl.363
2. Cella D, Motzer RJ, Suarez C, et al. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(2):292-303. doi:10.1016/S1470- 2045(21)00693-8
3. Motzer R, Porta C, Alekseev B, et al. Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022;23(6):768-780. doi:10.1016/S1470-2045(22)00212-1
4. Bedke J, Rini BI, Plimack ER, et al. Health-related quality of life analysis from KEYNOTE-426: pembrolizumab plus axitinib versus sunitinib for advanced renal cell carcinoma. Eur Urol. 2022;82(4):427-439. doi:10.1016/j.eururo.2022.06.009
5. Lenvima. Prescribing information. Eisai Inc; 2023. Accessed April 2, 2024.
6. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4
7. Choueiri TK, Powles T, Albiges L, et al; COSMIC-313 Investigators. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388(19):1767-1778. doi:10.1056/NEJMoa2212851
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