Kidney Cancer Coverage from Every Angle

Tivozanib

Posted: Monday, November 15, 2021

Median survival for patients with metastatic renal cell carcinoma (RCC) has more than doubled in recent decades, in part because of the advent of targeted therapies such as the antiangiogenic tyrosine kinase inhibitors (TKIs).1,2 Tivozanib (Fotivda) is an oral TKI that inhibits the vascular endothelial growth factor receptor (VEGFR) kinase and other kinases.3 It is approved by the U.S. Food and Drug Administration for the treatment of relapsed or refractory RCC in adults who have received two or more prior systemic therapies,4,5 and it is listed among the recommended options for this population in the NCCN Clinical Practice Guidelines in Oncology, Kidney Cancer.6

The phase III randomized controlled TIVO-3 trial (ClinicalTrials.gov identifier NCT02627963) compared tivozanib with sorafenib among 350 patients with relapsed or refractory RCC who had a clear cell pathology or component and who had received at least two previous systemic treatments (including at least one VEGFR inhibitor). Patients who received tivozanib achieved significantly longer median progression-free survival (5.6 vs. 3.9 months; hazard ratio = 0.73) and similar overall survival versus sorafenib.7,8 Adverse events were as expected for drugs in this class and were considered manageable. To quantify the net health benefits given similar survival, an analysis of quality-adjusted time without symptoms of disease and toxicity favored tivozanib.9

“Tivozanib is a pretty easy drug to give. You just need to know that it’s available and approved and to use it in that third- and fourth-line relapsed or refractory setting. Then, patients will be pleasantly surprised by its activity and tolerability,” predicted Brian I. Rini, MD, Professor of Medicine with the urological cancers team and Chief of Clinical Trials, Vanderbilt-Ingram Cancer Center, Nashville. “As with any drug, once you start to use it and get some experience with it, and figure out where it fits best in your treatment algorithm, it becomes easier to use.”

“It’s really nice to have something specifically approved for third-line therapy,” commented Virginia Seery, RN, MSN, ANP-BC, AOCNP, an oncology-certified nurse practitioner at Beth Israel Deaconess, Boston. “Patients with RCC are faring better and living longer, and to have this additional option is great.”

Patient Selection

Clinical factors such as tumor characteristics, comorbidities, and physician and patient preferences may help guide therapy choice in the third- and later-line RCC settings.10 TIVO-3 analyses of progression-free survival favored tivozanib over sorafenib in most clinical subgroups, except for patients falling into the International Metastatic RCC Database Consortium (IMDC) poor-risk category.7

Molecular markers predicting benefit would go a long way toward personalizing drug choice, and numerous potential biomarkers for VEGFR TKI efficacy have garnered interest. However, RCC remains noteworthy as a cancer generally lacking predictive biomarkers for treatments.1,10-12 A study assessing potential associations between blood and tissue markers with outcomes in patients given tivozanib as first-line therapy for RCC was discontinued (NCT01297244), and the TIVO-3 trial did not have a biomarker component.13

“I wish we had a way to predict tivozanib benefit beyond the indication, but the reality is that we don’t, so at present, we give the drug empirically. A lot of it for me is toxicity driven,” Dr. Rini told JNCCN 360. “Unfortunately, we are not curing patients in the refractory kidney cancer setting. So, I pick [a drug therapy] based on its side-effect profile; although I’m trying to control disease, I also want the least amount of toxicity. Patients who have received three or four lines of standard therapy may be a little beat up from their cancer and its treatment. These patients can be started on tivozanib, which is active and generally well tolerated.”

Treatment should be personalized. Although VEGFR TKIs as a class are associated with similar adverse effects, they tend to occur with different frequencies and severities and may therefore influence the choice of therapy, Dr. Rini added. “Individual patients have individual needs and priorities, so there is not one magical equation,” he observed.

Sequencing Considerations

Prior therapies may also come into play when selecting third- and later-line RCC therapy. However, sequencing has become complicated as the options for earlier therapy are expanding and treatment algorithms change rapidly.10,11,14-17 At present, tivozanib stands apart as the only drug with evidence supporting its use in the third- and later-line settings after failure of a TKI and immune therapy.18

When selecting treatment for this patient population, concern about subsequent lines of therapy is not an issue, Dr. Rini noted. “I generally pick what I think is the best agent on that day,” he said. “I don’t select drugs based on what patients might receive afterward, because I don’t know if or when that is going to happen. I don’t know if or when they will have disease progression and how they are going to tolerate the drug.”

“In terms of what [treatments] patients have had before, the tivozanib label stipulates at least two prior systemic therapies. What those two therapies were doesn’t really matter,” Dr. Rini elaborated. Prior systemic therapies varied in the TIVO-3 trial—about 45% of patients had received two VEGFR TKIs; 27%, an immune checkpoint inhibitor plus a VEGFR TKI; and 28%, a VEGFR TKI plus another systemic agent such as an mTOR inhibitor.7

In Ms. Seery’s experience, selecting treatment for patients with advanced RCC who have already received multiple therapies is an imperfect science. “Often, when we are choosing, we review what prior therapies patients have had and how they tolerated them. Then, you can go back to the same drug class and get an additional benefit,” she told JNCCN 360.

Patient Education

Patient education about tivozanib occurs in two phases, according to Dr. Rini. “Our pharmacist meets with all patients starting on a new drug to talk about side effects and provides written material. I talk with patients as well about big-picture issues and what to expect,” he explained. “Then, their first few days and weeks of treatment provide practical education: they start to take the drug and start to experience side effects, and we manage them. There is an initial adjustment period for everyone.”

Ms. Seery pointed out that virtually all patients in this setting will have previously received a VEGFR TKI and therefore have some experience with this drug class. However, that experience may not necessarily carry over to tivozanib. “Every patient is an individual. Some patients do really well with certain drugs and not so great with others,” she said.

“The number-one tip for using tivozanib successfully is for patients to understand the side effects so they know what to watch for and how to prevent some of them,” Ms. Seery maintained. In her patient education, she stresses preventive care and the importance of contacting the team early about any issues. “We’d much rather be proactive in preventing and managing issues and thereby keep patients on therapy longer, which is obviously better for the efficacy of the drug,” she told JNCCN 360.

We’d much rather be proactive in preventing and managing issues and thereby keep patients on therapy longer, which is obviously better for the efficacy of the drug.

Preventing and Managing Common Adverse Effects

In the TIVO-3 trial, grade 1 or 2 adverse events occurring in at least 20% of patients in the tivozanib group were hypertension, diarrhea, fatigue, decreased appetite, dysphonia, and asthenia. Overall, grade 3 adverse events were minimal,7 and 11% experienced a severe adverse event.

“I’ve been using tivozanib extensively, and our experience in the clinic mirrors the phase III trial data,” Dr. Rini told JNCCN 360. “It’s a really well-tolerated drug.”

I’ve been using tivozanib extensively, and our experience in the clinic mirrors the phase III trial data. It’s a really well-tolerated drug.

Hypertension

Hypertension was the leading treatment-related adverse event in the TIVO-3 tivozanib group: 27% of patients developed grade 1 or 2 hypertension, and 20% developed grade 3 hypertension.7

“It’s a little challenging to start patients on this drug if they have uncontrolled high blood pressure, so we try to make sure their blood pressure is reasonably normal before starting,” Ms. Seery noted. “It’s okay if they require antihypertensive medication, but when tivozanib is started, we might need to increase the dose of those medications or add a new agent.”

Ms. Seery recommends that patients have a home blood pressure cuff, check their blood pressure twice a day (morning and night), and bring the readings to their visits. She also advises patients when to call the team regarding specific blood pressure parameters.

Gastrointestinal Toxicity

A sizable proportion of patients given tivozanib in the TIVO-3 trial experienced diarrhea (33% developed grade 1 or 2 and 2% developed grade 3), decreased appetite (24% and 4%), and nausea (19% and 0%).7

“Nutrition is a huge issue for these patients because their appetite is decreased, and they often have diarrhea. We have been encouraging early nutrition consults,” Ms. Seery said. “The dietician can assess the diet and suggest foods to help reduce diarrhea. Patients are encouraged to ‘graze’ rather than trying to eat three meals a day if their appetite has decreased.” Medications are considered for patients with persistent diarrhea or loss of appetite.

Tivozanib is taken once a day, and the timing of administration can be adjusted to address any gastrointestinal and other adverse effects. “Patients can start taking tivozanib at any time of day because it can be given with or without food. However, if they are having trouble with side effects, we can change the time of administration. This may improve tolerability,” Ms. Seery explained.

Fatigue

In the TIVO-3 trial, 29% of patients in the tivozanib group developed grade 1 or 2 fatigue, and 4% developed grade 3 fatigue.7 This side effect can be challenging in the third-line setting, according to Ms. Seery. Therefore, she encourages patients to stay active as much as physically possible.

“Some studies suggest that physical activity will help combat fatigue and improve feelings of general well-being. It may also help patients sleep better and therefore feel more rested,” Ms. Seery told JNCCN 360. Stimulants can be considered for persistent or bothersome fatigue.

Hand-Foot Skin Reaction

Approximately 16% of patients in the TIVO-3 tivozanib group developed hand-foot skin reaction or palmar-plantar erythrodysesthesia syndrome of grade 1 or 2, and another 1% developed grade 3 hand-foot skin reaction.7 

“We do some teaching upfront and tell patients to be proactive about the potential for hand-foot skin reaction. For example, we recommend that patients start applying a urea-based lotion on their hands and feet daily and put gel insoles into their shoes,” Ms. Seery reported. “We also recommend they avoid extreme temperatures for their hands and feet.”

Ms. Seery also cautions patients to avoid activities that might cause too much pressure on the skin. For example, patients should either avoid doing yardwork or wear padded gloves when engaging in such activity. However, patients should stop immediately if their hands or feet become red or feel tender. Once hand-foot skin reaction occurs, it can be treated with a steroid cream. 

Dose Reductions and Interruptions

Tivozanib is given on 28-days cycles. The recommended dose is 1.34 mg once daily, with or without food, for 21 days followed by 7 days off treatment.3

“Maintaining the dose of tivozanib is important. We start all patients at the identical dose, but for some, that will be too much,” Dr. Rini explained. In his experience, roughly 10% of patients need a dose reduction or interruption because of an adverse event—a much lower incidence than that seen on the TIVO-3 trial (24% required a dose reduction, 48% required a dose interruption).7

“The drug is well tolerated, but as for any TKI, giving patients a break from the drug once in a while can be helpful,” Dr. Rini stated. “If a patient has toxicity necessitating an interruption, you may want to use your clinical judgment on dosage. Then, when the toxicity is better, you may want to restart the drug at the same dose or a lower dose.”

Ms. Seery stresses a proactive strategy to minimize time off treatment. “The earlier we know about a side effect, the better. For example, once a patient has severe blisters and is experiencing a lot of pain in the hands and feet, it is clear we should have stopped the drug a week before,” she said. “It’s better to be proactive and hold a drug earlier than it is to wait until side effects become severe. Improvement takes longer and time off the drug is prolonged.”

It’s better to be proactive and hold a drug earlier than it is to wait until side effects become severe. Improvement takes longer and time off the drug is prolonged.

Tolerability after restarting tivozanib is unpredictable, in Ms. Seery’s experience. “Some patients will tolerate it, and others will not. Or, they may tolerate it for months and then begin to have trouble again. It varies and can be patient-specific.”

Looking Ahead

At present, tivozanib is approved only as a monotherapy.3 However, combining VEGFR TKIs with immune therapy in metastatic RCC is a potential approach to improve efficacy and overcome resistance.2,19,20

The ongoing TiNivo trial is testing the combination of tivozanib and nivolumab in 25 patients with treatment-naive or previously treated metastatic RCC.21 Findings thus far suggest promising antitumor activity. There is increased toxicity with the combination, but patients in the study achieved a median progression-free survival of 18.9 months. 

“Going forward, a lot of new combinations for this cancer are under investigation, and that may be a key future strategy for improving outcomes,” Ms. Seery concluded.

Disclosures

Brian I. Rini, MD, has served as a consultant to Arrowhead; has received research funding from Peloton Therapeutics; and has received research funding and honoraria from Aveo Pharmaceuticals, AstraZeneca, Pfizer, Bristol Myers Squibb, Roche, and Merck.

Virginia Seery, RN, MSN, ANP-BC, AOCNP, has served on the advisory board of Aveo Pharmaceuticals.

References

1. Adashek JJ, Salgia MM, Posadas EM, et al. Role of biomarkers in prediction of response to therapeutics in metastatic renal-cell carcinoma. Clin Genitourinary Cancer 2019;17:e454–e460.

2. Hsieh JJ, Purdue MP, Signoretti S, et al. Renal cell carcinoma. Nature Reviews Disease Primers 2017;3:17009.

3. Aveo Pharmaceuticals, Inc. Fotivda® (tivozanib). Full Prescribing Information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212904s000lbl.pdf. Accessed October 29, 2021.

4. U.S. Food and Drug Administration. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. March 10, 2021. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tivozanib-relapsed-or-refractory-advanced-renal-cell-carcinoma. Accessed October 29, 2021.  

5. Chang E, Weinstock C, Zhang L, et al. FDA approval summary: tivozanib for relapsed or refractory renal cell carcinoma. Clin Cancer Res. September 22, 2021 [online ahead of print].

6. Motzer RJ, Jonasch E, Agarwal N, et al. NCCN Clinical Practice Guidelines in Oncology, Kidney Cancer. Version 1.2022. To view the most recent version of these guidelines, visit NCCN.org.

7. 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. The Lancet Oncology 2020;21:95–104.

8. Pal SK, Escudier BJ, Atkins MB, et al. Final overall survival results from a phase 3 study to compare tivozanib to sorafenib as third- or fourth-line therapy in subjects with metastatic renal cell carcinoma. Eur Urol 2020;78:783–785.

9. Szarek M, Needle MN, Rini BI, et al. Q-TWiST analysis of tivozanib versus sorafenib in patients with advanced renal cell carcinoma in the TIVO-3 study. Clin Genitourin Cancer 2021;19:468.e1–468.e5.

10. Khan Y, Slattery TD, Pickering LM. Individualizing systemic therapies in first line treatment and beyond for advanced renal cell carcinoma. Cancers 2020;12:3750.

11. Gkolfinopoulos S, Psyrri A, Bamias A. Clear-cell renal cell carcinoma: a comprehensive review of agents used in the contemporary management of advanced/metastatic disease. Oncol Rev 2021;15:530.

12. Miron B, Xu D, Zibelman M. Biomarker development for metastatic renal cell carcinoma: omics, antigens, T-cells, and beyond. J Pers Med 2020;10:225.

13. Aveo Oncology. A phase 3, randomized, controlled, multi-center, open-label study to compare tivozanib hydrochloride to sorafenib in subjects with refractory advanced renal cell carcinoma. PROTOCOL: AV-951-15-303. Available at https://www.clinicaltrials.gov/ProvidedDocs/63/NCT02627963/Prot_000.pdf. Accessed October 29, 2021.

14. Hofmann F, Hwang EC, Lam TB, et al. Targeted therapy for metastatic renal cell carcinoma. Cochrane Database Syst Rev 2020;10:CD012796.

15. Schmidt AL, Tabakin AL, Singer EA, et al. Next steps: sequencing therapies in metastatic kidney cancer in the contemporary era. ASCO Educational Book 2021;41:1–11.

16. Westerman ME, Wood CG. Editorial commentary: Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Ann Transl Med 2020;8:1037.

17. Bex A. Sequencing therapy for advanced renal cancer. Lancet Oncol 2020;21:9–11.

18. Mori K, Schmidinger M, Quhal F, et al. What is next in second- and later-line treatment of metastatic renal cell carcinoma? review of the recent literature. Curr Opin Urol 2021;31:276–284.

19. Meza L, Bergerot PG, Agarwal N, et al. Is there a role for novel TKI/ICI combinations in metastatic renal cell carcinoma? definitely maybe. Ann Oncol 2021;32:12–14.

20. Sharma R, Kadife E, Myers M, et al. Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma. J Exp Clin Cancer Res 2021;40:186.

21. Albiges L, Barthélémy P, Gross-Goupil M, et al. TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma. Ann Oncol 2021;32:97–102.



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