Kilari Discusses Frontline Treatment Selection Factors for mRCC

Deepak Kilari, MD (MODERATOR)

Associate Professor

Froedtert & the Medical College of Wisconsin Clinical Cancer Center

Milwaukee, WI

CASE SUMMARY

The patient is a 61-year-old man with an active lifestyle and a history of low-volume, indolent, clear cell metastatic 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 scan. A lung biopsy result confirmed mRCC. Laboratory results were within normal limits, and ECOG performance status was 0.

EVENT REGION Idaho, Minnesota, North Dakota, South Dakota, Wisconsin

PARTICIPANT LIST Nicole Jacobi, MD | Magdalena Flejsierowicz, MD | Pavan Bhamidipati, MBBS | Zhaohui Jin, MD

DISCUSSION QUESTIONS

• Is risk status alone the deciding factor in your first-line treatment decision-making?
  • What about patients with favorable- vs intermediate-risk disease?
  • In the cohort with intermediate- and high-risk disease, what factors lead you to think the patient may experience progression?
• What drives your selection of first-line therapy for favorable-risk clear cell mRCC?

JACOBI: With the National Comprehensive Cancer Network guidelines, the 3 combinations, axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab [Opdivo], and lenvatinib [Lenvima] plus pembrolizumab, are OK for patients with poor- or intermediate-risk disease.¹ It boils down to what you’ve been using the most. Maybe [it also depends on] issues with patients with hypertension or things like that. As long as you shy away from ipilimumab [Yervoy] plus nivolumab in favorable risk, I don’t think that, based on cross-trial comparison, we should prefer one over the other. One issue I once had was a patient who had polymyalgia rheumatica and didn’t want to go on an immunotherapy [IO], so then there was the question of which single-agent TKI [tyrosine kinase inhibitor] to use.

KILARI: In that scenario, I tend to use cabozantinib only because cabozantinib was compared with sunitinib [Sutent] in patients with intermediate- and poor-risk [disease] as single-agent therapy. It was more effective than sunitinib.² If a patient can tolerate cabozantinib, that’s what I would probably prescribe for patients who cannot tolerate IO. The other thing I use in my practice is if I see somebody with bone metastases, if I see somebody who has rapidly progressive disease and is very symptomatic, I tend to prefer IO/VEGF-TKI regimens compared with IO/IO. That’s just my bias, but I find that IO/ TKI tends to work a little faster, and for these patients who are already symptomatic, you want to [treat] them as fast as you can.

The response rates and the PFS [progression-free survival] seem to be better with IO/VEGF-TKI in these patients who have bone disease or visceral metastases, [so we] probably have 1 chance at [treating] them before they [experience progression]. In that scenario, I typically go for IO/TKI, whereas if they have disease but it’s mostly lymph node and lung disease, such as patients we used to [treat with] IL-2 in the past, then I would probably pick ipilimumab/ nivolumab, cabozantinib/nivolumab, or lenvatinib/pembrolizumab.

For those patients who have slowly growing disease [where] you have some time, I’d pick one of those options. For patients who have rapidly growing disease where I know I need to get this under control before I lose that window, I typically have given IO/TKI.

JACOBI: We have used pembrolizumab in the adjuvant setting, and then the patient had a relapse. Which time interval would you accept [for] reexposing somebody at least to IO/IO?

KILARI: I don’t think anyone knows the answer to that. We were all excited when we saw the lenvatinib/pembrolizumab data after ipilimumab/nivolumab. There was a phase 2 trial that came out of Memorial Sloan Kettering Cancer Center [in New York, New York,] where they gave lenvatinib/pembrolizumab as a second-line treatment to patients whose disease failed [to respond to] ipilimumab/nivolumab, and lenvatinib/pembrolizumab did significantly better than what we see with lenvatinib by itself.³ A lot of us started thinking maybe we should continue with immune therapy after immune therapy failure. But then the CONTACT-03 [NCT04338269] results came out, where they looked at cabozantinib plus atezolizumab [Tecentriq] vs cabozantinib, and they didn’t find any benefit with adding atezolizumab.⁴

In my practice, if a patient has relapse of disease after 6 months, I [go] back to IO. If they have it within 6 months, then I would just do single-agent VEGF-TKI. I have no data to back me up. The only reason why I do 6 months is I’m hoping that by 6 months, any immune effect from the IO should have washed away, and that’s the reason why they had their cancer come back. But we need [findings from] prospective trials to answer this question.

We always ask ourselves about the efficacy rate; lenvatinib/pembrolizumab had the highest PFS,⁵ but there is also quality of life. We need to give a drug that is not only effective but also has a good quality of life and a good safety balance where patients don’t have to decrease the doses constantly, patients don’t have to call us constantly. It’s mental health for providers, nurses, and for patients if there are fewer dose reductions, interruptions, and discontinuations.

DISCUSSION QUESTIONS

• What are your key takeaways from the CheckMate 9ER (NCT03141177), KEYNOTE-426 (NCT02853331), and CLEAR (NCT02811861) study data?
• When IO/TKI is preferred:
  • Does your choice of regimen vary based on patient profile?
  • What patient factors influence the choice?
  • Do the updated data change your choice?

KILARI: The complete response rate seemed to be similar except for lenvatinib/pembrolizumab; it seems to be the highest.⁶ Progressive disease is very low with lenvatinib/pembrolizumab and cabozantinib/nivolumab compared with the other arms.^6,7

If you look at [findings from] the studies by themselves, what we found was that if you get cabozantinib/nivolumab vs sunitinib, cabozantinib/nivolumab improved your quality of life [as opposed to] axitinib/pembrolizumab vs sunitinib and lenvatinib/pembrolizumab vs sunitinib, [although] lenvatinib/pembrolizumab and axitinib/pembrolizumab did not worsen quality of life.^8-10 Do you think you would change your regimen, or do you think it would be the same treatment options?

FLEJSIEROWICZ: I would not change it much, but I’m looking at the quality-of-life data, which are interesting. Maybe it’s not that noticeable if you…don’t have 10 patients per week to compare one regimen with the other in terms of quality of life. But it’s quite interesting to know that one is, in terms of efficacy, not much different from the other, but the quality of life may play a huge role in how I’m going to select it.

KILARI: I’m glad that they’re focusing on quality of life. It’s also interesting that there was a presentation at [the American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California,] this year where they were modifying the quality-of-life questionnaire.¹¹ If we look at these questionnaires, they’re lengthy, and they’re trying to modify them so that patients can answer them more easily without thinking.

I think the difference between cabozantinib/nivolumab and lenvatinib/pembrolizumab is that the starting dose of cabozantinib is a little lower, whereas we typically start at 20 mg lenvatinib, and depending on how they do, we might have to dose-reduce them most of the time.

JACOBI: Do you ever ramp up your dose slowly with lenvatinib, [even though] that wasn’t necessarily reflected in the study?

KILARI: If I see somebody who has frailty but has frailty because of their disease rather than their comorbidities, then I favor [giving] a full dose of lenvatinib, knowing that they need disease control. But if they have frailty from their comorbidities other than their disease…I start at 14 mg, wait for a month, then go to 18 mg, and then go up to 20 mg. In my practice, I typically have not been able to go beyond 18 mg for most patients, and I stay at 14 mg for most patients. But that’s a great point. Do we start higher, which then causes more problems…or do we start low and then go up? That’s something that we should be thinking about more often.

BHAMIDIPATI: With nivolumab/cabozantinib, when comparing poor-risk disease data across the trials, the data seem to have more patients with poor-risk disease on nivolumab/cabozantinib. Were there more responses in the poor-risk disease group in findings from the nivolumab/cabozantinib study compared with pembrolizumab/lenvatinib?

KILARI: If you divided based on subgroups, favorable- vs intermediate- vs poor-risk disease, I think both of them compared favorably in terms of objective response rates.^6,7 I don’t think we saw much difference with one or the other.

All of us in academics are spoiled. We have pharmacists, we have nurses. We don’t do toxicity management that much unless they can’t do it. If I have to do all the toxicity management myself, there are a lot of challenges. There are multiple phone calls, blood pressure checks, skin checks, [etc]. How have you been managing this? Do you have good nursing teams, or do you do it mostly by yourself?

JIN: Usually, our pharmacist or nurse gives education and we only see the patient occasionally. Most of the time, toxic check is done by our nursing team or pharmacist.

KILARI: When using each of these regimens, have you had to often reduce the dose, or do most of these patients tolerate the full dose?

JIN: I think we are more comfortable with the cabozantinib because the dosing seems to be easier for the patient to tolerate because it is 40 mg. Some patients needed to hold the treatment occasionally; blood pressure and diarrhea are difficult to control.

KILARI: It’s challenging when you have so many patients in clinic and you have to constantly dose-reduce or dose-modify. What I’ve done with cabozantinib sometimes and even with lenvatinib sometimes—lenvatinib has more ways of decreasing the dose—[is] 5 days on and 2 days off or 4 days on and 3 days off. It’s not FDA recommended, but we all have our small things that we do trying to make patients tolerate these regimens.…

We’ve been debating a lot in our field as to who should be getting single-agent TKI and whether there is a role for single-agent TKI. There’s…a trial that we did with single-agent treatments. It’s going to be interesting to see what we find in our trial data. I think single-agent TKI still has a role in some patients.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 3.2024. Accessed May 20, 2024. https://bit.ly/2TAx1m3

2. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115-125. doi:10.1016/j.ejca.2018.02.012

3. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946-958. doi:10.1016/S1470-2045(21)00241-2

4. 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

5. Choueiri TK, Eto M, Motzer R, et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023;24(3):228-238. doi:10.1016/S1470-2045(23)00049-9

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

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

8. 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

9. 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

10. 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

11. Bergerot CD, Castro DV, Bergerot PG, et al. Development of a patient-centered health-related quality of life (HRQOL) measure for metastatic renal cell carcinoma (mRCC): a three-phase study. J Clin Oncol. 2024;42(suppl 4):365. doi:10.1200/JCO.2024.42.4_suppl.365