Peers Discuss Impressions of Tivozanib’s Role as Third-Line RCC Therapy

Sumanta K. Pal, MD

Codirector, Kidney Cancer Program

Professor, Department of Medical Oncology & Therapeutics Research

City of Hope

Duarte, CA

CASE SUMMARY

A 71-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 (20 × 15 mm). A decision was made to initiate systemic therapy with pembrolizumab (Keytruda) plus axitinib (Inlyta).

On follow-up, the patient’s disease had a confirmed partial response. 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 treated with 60 mg of cabozantinib (Cabometyx) once a day. Nine months later, disease progression was documented. The patient wanted to continue active therapy.

DISCUSSION QUESTIONS

• What are the goals of therapy going into the third line?
• What factors most influence your choice of therapy?

SUMANTA PAL, MD: When you get into the third-line setting of RCC, how do your priorities change? Are you still focused on progression-free survival [PFS] and overall survival, or are you thinking more about palliation?

BASSAM MATTAR, MD: Typically palliation, but I have seen good results with tivozanib [Fotivda] and patients are living a while with it. I usually go with pembrolizumab plus axitinib first, then cabozantinib second. This way, I know I have a second option. If I use cabozantinib plus nivolumab [Opdivo], then I don’t know what to use as a second line. I have some problems with using tivozanib as second line from insurance. I have not seen that any one of the 3 [tyrosine kinase inhibitor (TKI) plus immunotherapy (IO) regimens] are better than the others with a big difference. With bone [metastatic] disease, I may use cabozantinib as a first line. That has been my approach for those patients. I’m one of the physicians who sees a lot of [patients with recurrent disease]; I have more than 5 [treated in the] second line, and probably 4 patients in the third line.

JIGAR SHAH, MD: In the community oncology setting, the patient population is little bit different than in the academic [setting]. Palliation is the No. 1 goal and close attention is given to the adverse event profile and tolerability. Depending on the patient population, the insurance also plays a role in terms of what they are going to be approved for, and what their out-of-pocket cost is going to be.

PAL: That makes perfect sense. I didn’t incorporate that financial element, but I definitely think that’s an important one.

PAL: [Approximately] 80% of participants chose tivozanib in this setting, with 13% choosing lenvatinib [Lenvima]/everolimus [Afinitor]. Dr Rapisuwon, what would you choose in this setting?

SUTHEE RAPISUWON, MD: [I would choose] lenvatinib plus everolimus; we know, at least from our experience… often when we start people with IO/IO, and if IO doesn’t work, then we move on to cabozantinib. Cabozantinib would give a [progression-free interval] of maybe 9 to 12 months, then when a patient might progress on cabozantinib, they can still respond to lenvatinib/everolimus—although you just have to dose-reduce lenvatinib a lot.

PAL: I tend to have the same experience with lenvatinib and we’ll talk about some of the toxicity considerations around the drug.

DISCUSSION QUESTIONS:

• Have you used tivozanib? If so, what are your impressions of it?

PAL: Dr Mattar, you had mentioned that you treated patients with tivozanib. Are [the data from TIVO-3 (NCT02627963)] fairly consistent with your experience with it?

MATTAR: Yes, I have a patient who is still responding. I’ve had a patient who started it and then had issues with infection, and went on dialysis, so I was anxious to keep it. I don’t know what your experience is using it in dialysis. I know the package insert does not define how to use it. But this patient is still doing well. It’s been 6 to 8 weeks now. I’m watching it, making sure that I’m seeing him more often. But my experience has been very good.

PAL: The challenge in dialysis is if we need to use [tivozanib], you use it. In clinical practice what I’ve done is started on a low dose in my patients on dialysis. I’ve started at 0.89 mg, see if they tolerate that, then I’ll escalate to 1.34 mg. It’s similar principle for [other] TKIs. I’ve occasionally started low and worked my way up very quickly, not waiting months to do this. I might increase the dose after a week or 2.

BRIAN RINI, MD: Because they’re mostly hepatically metabolized, I’ve tended to treat [those patients] like I treat anybody else. It’s been a handful of patients, probably not even a dozen over the years, but I haven’t run into trouble. I haven’t found [dialysis] as limiting or dose modifying.

SASSAN FARJANI, MD: I’ve used [tivozanib] in the third-line setting. I have to say I’m very impressed. I have patients with relatively good PFS on the drug and tolerating very well. Going back to the conversation that we had before, in the third-line setting many of these patients have some decline in their performance status. I am very impressed at how they’re tolerating this TKI. It’s tempting to see more studies to see that drug in a frontline setting.

BENJAMIN GARTRELL, MD: I’ve been hearing about tivozanib for a long time. I’ve been in practice for 12 years and I remember hearing about it when I was a fellow. The thing that impresses me about it is that it is quite VEGF-receptor specific. We know from some other VEGF receptor–specific TKIs like axitinib that response rates are pretty low after a previous TKI exposure. But with tivozanib, we do see some meaningful responses after previous TKIs. I find it to be well tolerated. Generally, in the third line I will go with lenvatinib/everolimus, but I would have a conversation with the patient. I generally think lenvatinib/everolimus is more active and tivozanib is better tolerated.^1,2 I try to figure out what that patient’s particular goals are. But tivozanib has been well tolerated. Obviously, we run into hypertension, and we make dose adjustments and we’re very comfortable with it.

_References

_{1. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21(1):95-104. doi:10.1016/S1470-2045(19)30735-1}

_{2. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-1482. doi:10.1016/S1470-2045(15)00290-9}