Choosing Among Frontline IO/TKI Regimens in Advanced RCC

Treatment selection for advanced renal cell carcinoma (RCC) has become increasingly individualized as multiple immune checkpoint inhibitor/tyrosine kinase inhibitor (IO/TKI) combinations have demonstrated strong efficacy in the frontline setting. During a virtual Case-Based Roundtable event, Daniel Landau, MD, hematologist/oncologist at the Medical University of South Carolina, and oncologists in Georgia reviewed pivotal clinical trial data and discussed how factors such as toxicity profiles, sites of metastases, and patient comorbidities influence their choice of first-line regimen in clinical practice.

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This is part 2 of a 2-part series. Read part 1.

EVENT RECAP

Before opening the floor for discussion, participants reviewed efficacy and safety data from 3 pivotal phase 3 trials that established IO/TKI combinations as frontline standards of care for advanced RCC: CheckMate 9ER (NCT03141177), KEYNOTE-426 (NCT02853331), and CLEAR (NCT02811861).

The phase 3 CheckMate 9ER trial (NCT03141177) compared the combination of nivolumab (Opdivo) plus cabozantinib (Cabometyx) with sunitinib (Sutent) in previously untreated advanced RCC.¹ The study demonstrated significant improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) with the combination regimen, establishing nivolumab plus cabozantinib as a standard first-line treatment option.

Participants also reviewed findings from the phase 3 KEYNOTE-426 trial (NCT02853331), which evaluated pembrolizumab (Keytruda) plus axitinib (Inlyta) vs sunitinib in treatment-naive advanced RCC.² The combination significantly improved OS, PFS, and ORR compared with sunitinib across International Metastatic RCC Database Consortium (IMDC) risk groups, supporting its widespread adoption as another preferred frontline regimen.

Finally, the group examined results from the phase 3 CLEAR trial (NCT02811861), which compared lenvatinib (Lenvima) plus pembrolizumab, lenvatinib plus everolimus (Afinitor), and sunitinib in previously untreated advanced RCC.³ Lenvatinib plus pembrolizumab produced significant improvements in PFS, OS, and ORR vs sunitinib, while lenvatinib plus everolimus improved PFS but did not demonstrate an OS benefit. Together, these findings established lenvatinib plus pembrolizumab as another preferred first-line treatment option for advanced RCC.

DISCUSSION QUESTION

• After reviewing the CheckMate 9ER, KEYNOTE-426, and CLEAR trials, what is your preferred regimen?
  • Why? If your preference changed, what impacted your decision (patient characteristics, disease characteristics, efficacy data, safety data, etc)?

Daniel Landau, MD: Were these data that you were familiar with? Did you just see data presented in a different way? Any thoughts at all?

Carlos Osmon, MD: What I personally like about axitinib is the short [half-life], and also the fact that it comes in 1-mg tablets that you can have a pretty easy maneuvering—you can stop it, you can go into every other day, and you can make a lot of different adaptations with it. I think that’s an important advantage.

Landau: I agree with you.

Ioana Bonto, MD: The fact that there's no OS advantage [in the CLEAR trial for lenvatinib plus everolimus]—we all like the PFS, but we all like the OS even more, so [the efficacy data are] a little bit disconcerting, especially at the cost of the toxicities. But then when you look at the numbers, the numbers at the end of the tail are becoming really low, so it's hard to know. Maybe there is actually significant difference, but we just don't have the statistical power to see it.

Landau: Absolutely.

Sanggyu Bae, MD: The efficacy is hard to compare between trials, so I think it boils down to bone-heavy metastases [favoring] cabozantinib, and toxicity profile—what the patients' medical problems are, or if you want some rapid response, you might choose one you feel like has a higher response rate, like the lenvatinib combination. But at the same time, like others, I had a lot of trouble with hypertension [with lenvatinib]; I was so scared managing those patients. So I think we have all great options; we just have to choose based on patients' medical issues, their preference, and what the sites of their metastases are, and go from there.

Landau: I always say the best problem we can have as oncologists is having too many good options. We have too many diseases where we have no options, so it's wonderful that we have things that we can pick between. Unfortunately, we're not going to have any true head-to-head studies coming out anytime soon with these different combinations. …I would say the real-world data generally have been consistent with what the studies have shown, so I agree.

Bae: Dr Landau, can I ask you a question? What is your preference [for] first-line treatment [for] someone with [central nervous system; CNS] metastases?

Landau: Presumably we're going to irradiate the CNS metastases…before we go in with the systemic therapy. Personally, I've actually used a lot of the cabozantinib-nivolumab in that setting. Cabozantinib does have some CNS penetration. Patients with active CNS metastases were excluded from the study, but patients who had treated CNS metastases were not, so if they did have prior radiation, they were able to enroll, and the data did suggest that there was activity on even the treated metastatic disease.¹ So because most studies did not include that data, and cabozantinib-nivolumab did, that's what I go with.

Bae: Let's say you started on them initially, and the patient is getting radiation, would you hold cabozantinib during radiation?

Landau: Yes, most of the time I start the cabozantinib after the radiation. Exactly.

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DISCLOSURES: Landau previously reported serving on speakers bureaus for Pfizer and Sanofi.

REFERENCES

1. 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

2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

3. 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