Integrating Tivozanib into Treatment of Advanced RCC

Hans Hammers, MD, PhD​

Professor in the Department of Internal Medicine

UT Southwestern Medical Center​

Dallas, TX

CASE SUMMARY

A 71-year-old male with a history of metastatic renal cell carcinoma (mRCC), with a status of post‒left nephrectomy and adrenalectomy and then clear cell RCC (ccRCC)/metastases in adrenal​ recurred after 4 years. His lung nodules were consistent with ccRCC and these nodules had been on scans 2 years prior. He initiated systemic therapy with pembrolizumab (Keytruda) and axitinib (Inlyta) and was observed to have stable disease on follow up. However, after the pembrolizumab was discontinued the patient continued axitinib but 14 months after he reported subsequent pain. Imaging confirmed disease progression with growth of the paratracheal left nodule (was 20 x 15 mm; now 25 x 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes and new lytic osseous lesions​. His ECOG performance score is now 1.

Targeted Oncology^TM: What are some of the newer approaches to treating patients with RCC?

HANS HAMMERS, MD, PhD: We have many agents to choose from now, and they have differences to them. I would say the most used agents are cabozantinib [Jevtana], lenvatinib [Lenvima], axitinib, and tivozanib [Fotivda].¹ Sorafenib [Nexavar] I have not used for many years, and I don’t think many of us will go to that agent. Some of us may, at some point, go back to sunitinib [Sutent] or pazopanib [Votrient], but in my practice that is a rare event. Most of the time, when I think about using tyrosine kinase inhibitors [TKIs], it is going to be about implementing cabozantinib, lenvatinib, axitinib, and tivozanib, and they do have differences with regards to half-life, for example, to selectivity…. Some [of these agents] may be a bit more selective than others, such as axitinib and tivozanib as some of the less broad–acting agents, and then some of the classic salvage agents like cabozantinib and lenvatinib typically have broad activity.

Which of the available therapies do you consider the most active?

There are some differences in potencies. Typically, tivozanib and axitinib are very potent inhibitors when it comes to the VEGF pathway itself and are more selective than others.² We don’t fully understand why some VEGF TKIs can work quite well after [the patient has] progressed on a prior VEGF TKI. For example, it could be a difference in the potency with which we can subsequently inhibit the VEGF pathway itself. It might be an additional target that might be targeted such as the FGF receptor or c-MET.³ So, something that we don’t yet fully understand, and to a major degree it is still trial and error. But the sense, in general, is that if [the patient has a more] aggressive disease, you may initially [use] cabozantinib or lenvatinib, which are broad-acting agents. But it is well known that other agents such as axitinib or tivozanib can still work if they have progressed on prior agents.

What did the TIVO-3 study (NCT02627963) aim to achieve? What were the characteristics of the patients involved?

Tivozanib is a very selective agent and potent VEGF inhibitor. The dose is just 1.5 mg…and what some may not know is that it was also tested in the front-line setting, but there was an issue with the trial design, and probably for that reason alone it didn’t match what the FDA wanted initially.⁴ However, TIVO-3 led to the approval in the United States in patients with advanced cases of RCC and patients who have failed 2 or 3 prior regimens with at least 1 prior VEGF receptor TKI.⁵

Patients were stratified by the type of prior regimen, as well as per the International mRCC Database Consortium prognostic score, favorable, intermediate, and poor risk for these pretreated patients. They were then randomly assigned to either tivozanib standard dosing, 3 weeks on and 1 week off, vs sorafenib at 400 mg once daily.⁶ Dorafenib was probably chosen as an agent that is not the most attractive these days. I would say it’s a weaker comparator, but I would say a fair trial at the time when it was designed, especially for other parts of the world…. The primary end point was progression-free survival [PFS] by independent review, but secondary end points included overall survival [OS], duration of response [DOR], and safety.

The median age for these patients is roughly in the range of where we see kidney cancer patients in their early sixties. There was a male predominance and then most patients on this trial were at intermediate risk [n =62]. The prior treatment regimen breakdown was [about] 50% of patients had a prior TKI, and then went on this therapy, except during the time when the patients accrued there was roughly a third of patients who also had PD-1 exposure, and it is from that perspective [this trial had a higher percentage of patients with PD-1 exposure than others].

What were the results of the TIVO-3 study?

The median PFS was 5.6 months [95% CI, 5.3-7.3] vs 3.9 months [95% CI, 3.9-5.6] for sorafenib [HR 0.73; 95% CI, 0.56-0.94, P = .0165].⁷ But I think the more important part…is that at 2 years, roughly 18% of patients were still progression free, so almost a fifth of patients vs just 5% for sorafenib. Some patients can do quite well even after progression on 2 or 3 prior regimens with this agent. In general terms, you will get diminishing returns with these agents, but this seems to have significant activity, particularly for a subset of patients that may be reasonably durable.

[Looking at investigator assessed long-term PFS], there was still continued benefit, even at the 36-month mark [12.3%], and the 48-month mark [7.6%]. Roughly a quarter of patients had prior axitinib, so I think this is one of the more contemporary, if you will, patient populations. Looking at PFS by prior therapy…there was not too much of a difference, that it can essentially with prior any immunotherapy or TKI alone, with [about] a 12-month PFS of around 30% for any of [the prior therapy groups].

[The overall response rate (ORR)] was 23% for tivozanib and 11% for sorafenib, with a disease control rate of around 82% [in the tivozanib group]. The DOR was longer for tivozanib vs sorafenib with a median of 20 months vs 9 months, [respectively]. So speaking to a subset of patients, the responders can have quite a durable benefit on this particular therapy.

How should a physician handle toxicity with this therapy?

Like any TKI, diarrhea, nausea, and vomiting can be treated with additional agents to modify those AEs but can also be treated with dose interruptions or dose reductions. One of the things I would say when I think about tivozanib is that high blood pressure is one of the common AEs. It is also, interestingly, one of the agents with longer half-lives, so that is why it is given 3 weeks on and 7 days off.

For most patients, if you need to think about dose reduction, reduction by 1 dose level is sufficient to manage most patients. So, [if you start at] 1.34 mg, then go down to 0.89 mg, you can go down further to every other day of treatment if you need to, but I would say most patients will do well with this dose de-escalation [method]. The other thing to know, which can be more convenient for patients in some cases, is that they can take it with or without food. So, it is not as demanding as cabozantinib, which should be taken on an empty stomach.

_Reference:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer; version 4.2023. Accessed June 6, 2023. https://bit.ly/3tcwJXG}

_{2. Tucker MD, Rini BI. Predicting response to immunotherapy in metastatic renal cell carcinoma. Cancers (Basel). 2020;12(9):2662. doi:10.3390/cancers12092662.}

_{3. Fogli S, Porta C, Del Re M, et al. Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs. Cancer Treat Rev. 2020;84:101966. doi:10.1016/j.ctrv.2020.101966}

_{4. 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}

_{5. AVEO Oncology announces U.S. FDA approval of Fotivda® (tivozanib) for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma. News release. AVEO Oncology. March 10, 2021. Accessed June 21, 2023. https://bwnews.pr/3bw0FoW}

_{6. Escudier B, Rini B, Pal S, et al. TIVO-3: Age-related tolerability outcomes of tivozanib versus sorafenib in metastatic relapsed or refractory renal cell carcinoma, a subgroup analysis of the TIVO-3 clinical trial. J Clin Oncol. 2021;39(suppl_15). doi:10.1200/JCO.2021.39.15_suppl.e16553}

_{7. Atkins MB, Verzoni E, Escudier BJ, et al. Long-term PFS from Tivo-3: Tivozanib (TIVO) Vs sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC presented at: 2022 American Society of Clinical Oncology Genitourinary, February 17-19,2022; Abstract 362.}