Treating Renal Cell Carcinoma With Tyrosine Kinase Inhibition

Comparing Physician Experience With Trial Data for Frontline RCC Regimens

During a live virtual event, Sumanta K. Pal, MD, discussed with participants how their experience with immunotherapy and tyrosine kinase inhibitor therapies aligned with the data from pivotal clinical trials. This is the second of 2 articles based on this event.

CASE SUMMARY:

A 61-year-old man with an active lifestyle had a history of low-volume, indolent metastatic clear cell renal cell carcinoma (RCC) and was post‒left nephrectomy and adrenalectomy​. He was observed based on low-volume and indolency of disease and patient preference​.

Five years after his nephrectomy, there was continued indolent growth on scans, increased total tumor burden, new paratracheal lymph node metastasis (2.0 x 1.5 cm) and greater than 10 pulmonary nodules on a CT scan. A lung biopsy confirmed metastatic clear cell RCC​. His laboratory results were within normal limits and his ECOG performance status was 0.

Cabozantinib (Cabometyx) 40 mg once daily plus nivolumab (Opdivo) 240 mg once every 2 weeks was initiated as frontline therapy​.

DISCUSSION QUESTIONS

  • What are your perspectives on the CheckMate-9ER (NCT03141177), KEYNOTE-426 (NCT02853331), and CLEAR (NCT02811861) study data?​
  • When you think about the immune checkpoint inhibitor (ICI)/tyrosine kinase inhibitor (TKI) combination regimens for favorable-risk metastatic RCC, what differentiators come to mind? Thinking about each combination, what patient profile comes to mind? ​
  • Please discuss your real-world experience with each ICI/TKI regimen. ​
  • How does the safety profiles of each regimen compare?​
  • Thinking about each regimen, how often do you have to modify/interrupt/discontinue for toxicity?​
  • To what extent does/should the TKI guide treatment selection? How much consideration do you give to the TKI included in each regimen? ​

SUMANTA K. PAL, MD: When thinking about these data, what are your thoughts? Does it change your perspectives at all in frontline strategy? Does it support your treatment strategy today?

MOHAMED KHASAWNEH, MD: It matches well with my personal experience and the published data. Nivolumab and ipilimumab [Yervoy] is not for the faint of heart. It is a tough treatment with the rates of grade 3 and 4 adverse events [AEs] at about 55%, discontinuation rates at 31%.1 The colitis can be horrible, pneumonitis can be severe. This is only for young, fit patients with the understanding that grade 3 and 4 AEs are high.

The cabozantinib/nivolumab data are very intriguing, especially for patients who put more emphasis on quality of life.2 I’ve been using that. Lenvatinib [Lenvima] is difficult to administer, especially at higher doses. Diarrhea can be disabling. Fatigue can be difficult. A lot of patients require dose interruption or dose reduction/discontinuation.

In practice when I use axitinib [Inlyta], I use it at 5 mg [once daily] for 4 weeks. If it’s tolerable, I increase it to 7 mg, and then I increase it to 10 mg for patients who are tolerating it. You can either start low and go high or start at the standard dose with the FDA-approved dosing.3 But the data match well with my personal experience, and the major points that I discuss for patients when I want to initiate a new regimen.

PAL: That’s a very good, sophisticated perspective on the approach.

KATY BECKERMANN, MD:I sometimes [choose treatment] based on what clinical trial opportunities we have in the first or second line. If I’m already trying to think ahead, that might factor in a little bit which of the TKI and ICI combinations [I choose]. I have the most familiarity using axitinib plus pembrolizumab [Keytruda] just based on the timing of its FDA approval but have since been tending to use either cabozantinib/nivolumab or lenvatinib/pembrolizumab subsequently. I think starting at that sweet spot of 40 mg of cabozantinib is so much easier for patients to tolerate. If I start lenvatinib/pembrolizumab, I don’t start the lenvatinib at 20 mg. I can’t get patients to stay on it, so I tend to either start at 18 mg or 14 mg and then try to dose escalate if I need to.

PAL: That’s good, practical real-world guidance. I’ve talked to a lot of my colleagues in the community who have used lenvatinib in other settings that I’m less familiar with:—thyroid, uterine cancer, etc—and many have taken to starting with an attenuated dose. The thing that always sits in the back of my mind is if you start a patient on lower-dose lenvatinib, how do you know they’re getting that same impact based on the phase 3 data? It’s tough to know. But I agree that there are few patients who can tolerate lenvatinib at 20 mg.

BECKERMANN: I am not asking specifically [about] combinations, but in your practice with single-agent TKI, do you tend to start the maximum dose and then dose reduce based on AE profile or take more of the axitinib approach where you start at 5 mg and then increase based on hypertension or [similar]?

PAL: I try to stay dogmatic about dosing in the frontline setting because I want to see if we can extract that benefit that we’re seeing across the phase 3 studies. In fact, even in the second-line setting, I try [to] tether myself to the dose as long as the patient is not too frail. But by the time it gets to third line, then I start getting a little bit experimental. The goal there is purely palliative. I had a patient who was on sixth-line treatment and was begging to get a therapy, and I put them on 4 mg of lenvatinib as their sixth line of treatment. She responded beautifully for a period of 3 months to 4 mg of lenvatinib if you can believe it. [This was] not at all per the label…but I was just blown away that she came to clinic a month later, had just been taking 4 mg, but had gone from flat on her back from very bad retroperitoneal metastases to upright and walking around.

KHALEEL ASHRAF, MD: I probably use mostly axitinib/pembrolizumab. That’s something I have been more comfortable with.

I have a patient who is a fairly healthy man in his 60s with RCC lung metastasis. He had nephrectomy and his recurrence came back after 2 years or so. He was placed on lenvatinib/pembrolizumab and had beautiful response. The maximum lenvatinib dose he could take was 12 mg; after some time he had significant tolerance issues, and the dose was reduced to 4 mg. The PET scan around that time showed complete remission. Eventually he wanted to stop the lenvatinib. He also had other issues [including] high blood pressure, so he didn’t want to take it. He didn’t want an alternative drug, and, at that time, his PET scan was negative, so I discontinued the pembrolizumab. Then he had developed brain metastasis, and received radiation therapy. His systemic disease is under excellent control. Which of these TKIs, if I wanted to start [again], would have the best blood-brain barrier penetration?

PAL: There are very limited data to guide here, but there was a nice paper in JAMA Oncology in 2021 from the Dana-Farber group.4 They did a very detailed analysis of cabozantinib as it pertained to intracranial metastases and showed that you can get some nice reductions in intracranial metastases with cabozantinib therapy. There’s also some translational data from a French group suggesting that, and this might be why cabozantinib works quite well in bone and in the brain. Bone metastases and brain metastases may have more MET expression. That’s one of the cabozantinib targets. So that might be good rationale for using cabozantinib in a patient with brain metastases.

References:

1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

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. Inlyta. Prescribing information. Pfizer; 2020. Accessed September 9, 2022. https://bit.ly/3L3ZJbx

4. Hirsch L, Martinez Chanza N, Farah S, et al. Clinical activity and safety of cabozantinib for brain metastases in patients with renal cell carcinoma. JAMA Oncol. 2021;7(12):1815–1823. doi:10.1001/jamaoncol.2021.4544