Vaishampayan on Long-Term Considerations With Tivozanib in RCC

Ulka Vaishampayan, MD

Professor, Internal Medicine

Director, Phase I Program

Coleader, Translational and Clinical Research Program

University of Michigan Rogel Cancer Center

Ann Arbor, MI

CASE SUMMARY

• A 71-year-old man with a history of metastatic renal cell carcinoma (RCC) 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.
  • It was subsequently recognized that nodules had been present on scans over 2 prior years.
  • The patient was observed based on low volume and indolent behavior of the disease and on patient preference.
• Eighteen months later, a reexamination showed continued indolent growth on scans, with an increased total tumor burden, a new paratracheal lymph node (2.0 × 1.5 cm), and multiple growing pulmonary nodules.
• A decision was made to initiate systemic therapy with pembrolizumab (Keytruda) plus axitinib (Inlyta).
• On follow-up, the patient’s disease was stable.
• Adverse events reported were moderate diarrhea (well controlled with antidiarrheal medication) and mild fatigue.
• After cycle 6, the patient developed fatigue, mild shortness of breath, and mild cough without chest pain.
  • The pulse oximeter reading was 93% at rest.
  • He had no fever, no recent sick contact, and his influenza vaccine was up-to-date.
• His infectious workup was negative.
• After approximately 18 weeks, a chest CT confirmed grade 3 pneumonitis.
  • Pembrolizumab was held and oral steroids were administered.
  • Pembrolizumab was discontinued and the patient continued 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: growth of paratracheal lymph node (was 20 × 15 mm; now 25 × 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes, and new lytic osseous lesions.
• ECOG performance status: 1
• Cabozantinib (Cabometyx) 60 mg once daily was initiated.
• Nine months later, disease progression was documented.
• The patient would like to continue active therapy.

TARGETED ONCOLOGY: What was the focus of the TIVO-3 study (NCT02627963)?

VAISHAMPAYAN: TIVO-3 was the registrational study of tivozanib [Fotivda] vs sorafenib [Nexavar]. This study involved patients with advanced [clear cell renal cell carcinoma] who had [undergone] 2 or 3 prior regimens [that had failed], so [this was] a heavily pretreated population. Their prior treatment had to include at least 1 VEGFR tyrosine kinase inhibitor [TKI], so patients could have had sunitinib [Sutent] followed by nivolumab [Opdivo].¹ The timing of the study was such that immunotherapy agents [IOs] were just beginning to get approved. For example, cabozantinib was prevalent and being used at the time.

This is also the one study that has post-cabozantinib efficacy data,¹ unlike any of the others. Recently, there was a press release of data from the CONTACT-03 study [NCT04338269], which was a study of second-line cabozantinib plus or minus atezolizumab [Tecentriq], a PD-L1 inhibitor, where the combination did not show benefit. Those are the most contemporary data that tell us that after you’ve used a frontline IO-based regimen, using a second- or third-line IO is not beneficial. The actual data have not been presented; this was a press release, but that is what that study showed.²

What was the setup of the TIVO-3 study?

The TIVO-3 study involved the 1:1 randomization of 350 patients. Tivozanib was given at a dose of [1.5 mg daily], and the tivozanib regimen was 3 weeks on, 1 week off, so there was a break built into the cycle. Treatment was given until progression. Sorafenib was given at the standard dose of 400 mg twice daily. The primary end point of the study was progression-free survival [PFS]. Secondary end points were overall survival [OS], objective response rate, duration of response [DOR], and safety.¹

What prior treatments had been received by the patients in the TIVO-3 study?

In the experimental arm, 27% of patients had received a TKI plus a PD-1 inhibitor. However, the majority—45%—had received 2 TKIs prior to coming onto the study, and [28%] had received a TKI plus some other therapy, [like an mTOR inhibitor, or were on another clinical trial]. A third of the patients were between 65 and 75 years of age and 10% were [older than] 75 years, so this was an [older], majorly pretreated patient population. The median time from initial diagnosis was [approximately 50] months—well balanced across both arms—and approximately 60% of patients in both arms] were of intermediate risk, which is typical. [Approximately] 20% of [patients in] each arm had favorable risk and approximately 20% had poor risk. Approximately 60% [of each arm] had received 2 prior regimens, and the remaining 40% had received 3 prior regimens.^3,4

How did PFS efficacy of tivozanib in this patient population compare with those on sorafenib?

With respect to PFS, tivozanib was superior to sorafenib. Not only were there increased chances of response, but the responses also tended to be durable. The 2-year PFS rate was [18% vs 5% in the experimental and control arms, respectively]. There was clearly a difference in the tail end and at 1 year in this pretreated patient population that favored tivozanib [28% vs 11%, respectively]. Further, the difference in PFS was statistically significant [between the tivozanib arm vs the sorafenib arm], at a median PFS of 5.6 months vs 3.9 months, respectively [HR, 0.73; 95% CI, 0.56-0.94, P = .0165].⁵

What effect did prior treatment with axitinib have on the tolerability of tivozanib?

Prior axitinib did not seem to influence the tolerance of tivozanib. Remember, [in this patient case, he] had received frontline axitinib plus pembrolizumab and second-line cabozantinib. Even though the VEGF TKI pathway is a common [mechanism of action of axitinib and tivozanib], it did not seem to make an impact, despite [the fact] that there were responses and sometimes durable responses [in this subgroup].⁵

How did tivozanib impact long-term PFS, DOR, disease control, and OS?

The landmark rate of long-term PFS showed how durable the responses were, and a [clinically] relevant proportion of the patients were alive at even 3 and 4 years [9.9% and 7.6%, respectively]— not as high as you’d like, but there are some [who] are alive 4 years out. The data continue to favor tivozanib over sorafenib, although the number of patients who have been followed that far is small [Figure⁶]. Even for patients who had received frontline IO-based therapy, the rate of PFS at 1 year was 35% with tivozanib and 4% with sorafenib.⁷

There was a large difference between the 2 [arms] in terms of DOR. For the patients who had a response—[23% of those treated with tivozanib and 11% with sorafenib]—the median DOR was 20.3 months with tivozanib [vs] a median of 9.0 months with sorafenib. The rate of disease control was also good, at [82% for tivozanib vs 69% for sorafenib].³ So far, no statistically significant difference has been noted between the tivozanib and sorafenib arms, with respect to OS. However, the OS data are continuing to mature as the small number of patients who had prolonged DOR continue to be followed on an ongoing basis.⁸

What are some practical considerations that apply to the use of tivozanib?

The toxicities associated with tivozanib are like those of other VEGF TKIs, but if dose modifications are required, there is a dose reduction available: 0.89 mg for 3 weeks on and 1 week off. You can reduce the dose in the case of toxicity, and dose reduction does work in helping manage the toxicity. Of course, diarrhea can be managed with antimotility agents, and nausea or vomiting also are things you can treat.⁹

How does your initial therapy choice influence sequencing?

Of course, we have to think about the patient as a continuum, thinking about whether you gave IO plus IO or IO plus a VEGF-targeted agent [in the first line]. Your second-line therapy is typically going to be a VEGF-targeted agent, for the most part. So far, in the second- or third-line setting, combinations are not approved except for lenvatinib [Lenvima] plus everolimus [Afinitor].¹⁰

If a patient received lenvatinib plus pembrolizumab as first-line therapy, can one still consider lenvatinib plus everolimus in the second or third line?

I don’t think I would, because the patient already progressed on lenvatinib. The real answer is that there is no evidence, but I can’t imagine you would want to keep treating with lenvatinib if a patient is progressing. You would have to use another TKI at that point. In the tivozanib [trial, approximately] 25% of the patients were on TKI plus another therapy, so maybe there were a few patients pretreated with lenvatinib and everolimus in that study.^3,4

_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. Exelixis provides update on phase 3 CONTACT-03 trial evaluating cabozantinib in combination with atezolizumab in patients with previously treated advanced kidney cancer. News release. Exelixis, Inc. March 2, 2023. Accessed June 17, 2023. https://tinyurl.com/yckcjcu7}

_{3. Verzoni E, Escudier B, Hutson TE, et al. TIVO-3: durability of response and updated overall survival of tivozanib versus sorafenib in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2021;39(suppl 15):4546. doi:10.1200/JCO.2021.39.15_suppl.4546}

_{4. Escudier B, Rini BI, Pal SK, 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):e16553. doi:10.1200/JCO.2021.39.15_suppl.e16553}

_{5. 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(6):783-785. doi:10.1016/j.eururo.2020.08.007}

_{6. Atkins MB, Verzoni E, Escudier B, et al. Long-term PFS from TIVO-3: tivozanib (TIVO) versus sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC. J Clin Oncol. 2022;40(suppl 6):362. doi:10.1200/JCO.2022.40.6_suppl.362}

_{7. Rini BI, Pal SK, Escudier B, et al. TIVO-3: a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). Poster presented at: 2019 Genitourinary Cancers Symposium; February 14-16, 2019; San Francisco, CA. Abstract 541. Accessed June 18, 2023. https://tinyurl.com/4pbk4jns}

_{8. Rini BI, Pal SK, Escudier B, et al. Maturation of overall survival (OS) in TIVO-3 with long-term follow-up. J Clin Oncol. 2022;40(suppl 16):4557. doi:10.1200/JCO.2022.40.16_suppl.4557}

_{9. Fotivda. Prescribing information. AVEO Pharmaceuticals Inc; 2021. Accessed June 18, 2023. https://tinyurl.com/yckfrmzr}

_{10. Lenvatinib in combination with everolimus. FDA. May 13, 2016. Updated May 16, 2016. Accessed June 18, 2023. https://tinyurl.com/59ve2mpx}