Sequencing for Metastatic Clear Cell Renal Cell Carcinoma After Prior Therapy

Discussing Tolerability of Tivozanib as Third-Line Therapy for mRCC

During a Targeted Oncology case-based roundtable event, Randy F. Sweis, MD, discussed with participants their experience with the tolerability of tivozanib for recurrent advanced renal cell carcinoma. This is the first of 2 articles based on this event.


A 54-year-old man with a history of metastatic renal cell carcinoma (mRCC) had undergone a left nephrectomy and adrenalectomy. He had clear cell RCC (ccRCC) and metastases in his adrenal gland. Four years later, the patient had a recurrence of his cancer. A biopsy showed lung nodules consistent with ccRCC. In retrospect, it had been present on scans for at least 2 years prior.

The patient was observed based on the low volume and indolence of the disease and on his preference. Eighteen months later, a reexamination showed continued indolent growth on scans, with an increased total tumor burden, and a new paratracheal lymph node (2.0×1.5 cm). A decision was made to initiate systemic therapy with pembrolizumab (Keytruda) plus axitinib (Inlyta).

On follow-up, the patient’s disease was stable. The patient reported moderate diarrhea (well controlled with antidiarrheal medication) and mild fatigue. After cycle 6, he developed fatigue, mild shortness of breath, and mild cough without chest pain. At approximately week 18, a chest CT scan confirmed grade 3 pneumonitis. Pembrolizumab treatment was held, and intravenous steroids were administered. Pembrolizumab then was discontinued, and the patient continued on axitinib.

Fourteen months after the initiation of systemic therapy, the patient reported increasing back pain, mild nausea, weight loss, and new onset of persistent rib pain. Imaging confirmed disease progression: the paratracheal lymph node had been 20×15 mm and was now 25×28 mm; there were new mediastinal and hilar nodal involvement, new retroperitoneal nodes, and new lytic lesions. He had an ECOG performance status of 1.

The patient was given 60 mg of cabozantinib (Cabometyx) once a day. Four months later, disease progression was documented. The patient wanted to continue active therapy.


  • What are the goals of therapy going into the third line? ​
  • What factors influence your third-line regimen selection for a patient like this?​

RANDY F. SWEIS, MD: [For this patient] we are talking about third-line therapy, post-pembrolizumab/axitinib and cabozantinib.

RAYMOND LOBINS, DO: At this point I’d be asking about the patient’s performance status, frailty, and how he tolerated the last line of chemotherapy.

SWEIS: Those are definitely important factors there. A lot of the time, at this point the patients have lost a lot of weight, their performance status has declined, and the worst-case scenario is some patients may not be eligible for further therapy with bad disease biology where you have rapid growth.

What are you most likely to recommend for this patient upon disease progression outside of a clinical trial?

CHRISTOS KYRIAKOPOULOS, MD: I think the answer is, “it depends.” It depends on previous adverse events, when we’re talking about a tyrosine kinase inhibitor [TKI] or a combination of TKI plus an mTOR inhibitor, and the patient is a bit young. For somebody with slow base of disease progression and of toxicities from previous treatment who would most like to focus more on quality of life, I think tivozanib [Fotivda] is the right answer.

For somebody who’s more symptomatic, tolerated previous treatment well, and wants to be aggressive, there’s nothing wrong with lenvatinib [Lenvima] plus everolimus [Afinitor]. Usually I present both options. I explain the pros and cons, what to expect from the treatment, and usually the patient decides.

I’ve seen patients go either way. Some patients decide to try lenvatinib/everolimus, some patients decide to pick tivozanib. I think it’s a different goal of treatment, and those who have different expectations.

SWEIS: I agree. Is your clinical experience with tivozanib consistent with the notion that it’s generally easier for patients?

KYRIAKOPOULOS: I just saw a patient who had a similar scenario: he started with axitinib/pembrolizumab, then had cabozantinib, and then tivozanib. He had a lot of toxicity to axitinib but even more toxicity with cabozantinib. So far he’s tolerating tivozanib better than the previous 2 [regimens] without any change in the dose, whereas we did 1 dose reduction with axitinib plus treatment breaks and 1 dose reduction of cabozantinib plus treatment breaks.

SWEIS: That’s good to hear. Does anybody else have tivozanib experience?

LOBINS: Yes, it’s pretty well tolerated. [Patients had] high blood pressure and I had 1 patient who had some gastrointestinal issues.1 They just didn’t get hungry and always felt a little bit nauseated, but other than that, I’ve used it a number of times and it’s well tolerated.


  • What factors influence your use of tivozanib?

NANDINI KALAKOTA, MD: For me it sounds like the tolerability is probably a big factor. I think when you’re going down to the third line, you’re looking at performance status and weighing the risks and the benefits for quality of life. I think the week off [after 3 weeks of daily treatment] is also nice for patients.1 They tend to like that time away from treatment.

GOWRI RAMADAS, MD: I agree. At that point, if they can tolerate it, I think lenvatinib has great efficacy but using it in other disease states as well as RCC could be a little bit more difficult sometimes. That, with having some efficacy as well, I think is what makes it more favorable to use.

XIN YAO, MD: I used it for at least 3 patients. One patient might have needed a dose reduction, but overall, I think they tolerate it much better than cabozantinib.

SHAKER DAKHIL, MD: I think the NCCN [National Comprehensive Cancer Network] guidelines are huge because that’s what’s going to control the [insurance] coverage. [However], I always have skepticism when we have these [treatment] breaks in patients. Sunitinib [Sutent] was a problem when they gave you 6 weeks and then 4 weeks and 2 weeks off. [It was a problem to] wait until the patient is [seriously ill] then give them 2 weeks off.

Tolerability is very important, and before I go to dose reduction, I probably would go to a 2 weeks on, 1 week off schedule. That would be equivalent of reducing the dose by 30% in these patients, and sometimes that’s all it takes. Sunitinib now is using 2 weeks on, 1 week off instead of the 4 weeks and 2 weeks off.2

SWEIS: That’s a good point. The sunitinib seems to be much better with that schedule than the 4 weeks on and 2 weeks off, although this is starting somewhere in between there, but that’s an interesting strategy to switch, if it comes out that you are getting a little more dosing that way, compared with the 0.89 mg capsule, because that’s closer to a 40% reduction [from the 1.34 mg capsule].


1. Fotivda. Prescribing information. AVEO Pharmaceuticals Inc; 2021. Accessed October 20, 2022.

2. Deng H, Li M, Wu Q, et al. A 2/1 Sunitinib dosing schedule provides superior antitumor effectiveness and less toxicity than a 4/2 schedule for metastatic renal cell carcinoma: a systematic review and meta-analysis. Front Oncol. 2020;10:313. Published 2020 Mar 6. doi:10.3389/fonc.2020.00313