NCCN Updates Clear Cell RCC Guidelines


The National Comprehensive Cancer Network has updated its Clinical Practice Guidelines to include tivozanib as a recommended regimen for subsequent therapy in patients with clear cell renal cell carcinoma.

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines to include tivozanib (Fotivda) as a recommended regimen for subsequent therapy in patients with clear cell renal cell carcinoma (RCC), according to an announcement from AVEO Oncology.1

The current NCCN guidelines for RCC categorically make treatment recommendations for frontline or subsequent options of patients with the disease. Specifically, the network now recommends tivozanib as a subsequent treatment for patients with clear cell RCC who have previously received 2 or more systemic therapies (category 2a).

The addition of the agent to the guidelines follows the March 2021 FDA approval of tivozanib for the treatment of adult patients with relapsed/refractory advanced RCC, after 2 or more previous systemic therapies. The regulatory decision was based primarily on data from the phase 3 TIVO-3 trial (NCT02627963), which examined tivozanib vs sorafenib (Nexavar), showed that the final hazard ratio (HR) for overall survival (OS) was 0.97 (95% CI, 0.75-1.24; P = .78).2 At a median follow-up of 38 months for tivozanib and 40 months for sorafenib, the median OS was 16.4 months (95% CI, 13.4-22.2) and 19.2 months (95% CI, 15.0-24.2), respectively.

Prior data showed that the next-generation VEGF TKI significantly improved progression-free survival (PFS) over sorafenib in patients who had received 2 or 3 prior regimens.3 The median PFS with tivozanib was 5.6 months (95% CI, 5.3-7.3) vs 3.9 months (95% CI, 3.9-5.6) with sorafenib (HR, 0.73; 95% CI, 0.56-0.94; P = .0165).

“[Tivozanib’s] addition to the NCCN Guidelines provides further validation for its potential to serve as an important evidence-based, well-tolerated treatment option for patients with relapsed or refractory advanced RCC,” Michael Bailey, president and chief executive officer of AVEO, stated in a press release. “As previously announced, launch efforts are now underway, and we are committed to bringing this promising therapy to as many appropriate patients as possible.”

Tivozanib is a potent and highly selective VEGF inhibitor that targets VEGFRs 1, 2, and 3 and was designed to have a long half-life to improve tolerability and efficacy. In the phase 3 TIVO-3 trial, investigators set out to compare the use of tivozanib with sorafenib in patients with relapsed/refractory RCC.3

To be eligible for enrollment, patients needed to have histologically or cytologically confirmed recurrent or metastatic disease; an ECOG performance status of 0 or 1; and have progressed on at least 2 previous regimens, including a VEGFR TKI. Patients were stratified by International Metastatic RCC Database risk and prior TKI regimen.

A total of 350 patients were randomized 1:1 to receive either tivozanib (n = 170) or sorafenib (n = 159). Patients received treatment until disease progression. The primary end point of the trial was PFS, while secondary end points included OS, objective response rate (ORR), and duration of response, as well as safety and tolerability.

Overall, 18% of those (n = 31) on the tivozanib arm experienced a partial response to treatment vs 8% in the sorafenib arm (n = 14). The ORR in the investigative arm was 34.0% vs 24.0% in the control arm.

Additional data presented during the 2021 Genitourinary Cancers Symposium showed that among a subset of patients who received 2 prior VEGFR TKIs, the median PFS in the investigative and control arms was 5.5 months (95% CI, 3.6-7.4) and 3.7 months (95% CI, 3.6-3.9), respectively (HR, 0.57; 95% CI, 0.39-0.83; P = .003).4 The ORRs in this subset were 15.2% and 7.5%, respectively.

Moreover, the HR for PFS in patients who were in the third line and received prior axitinib (Inlyta) was 0.73, while the ORRs were 18% vs 8% in the investigative and control arms. The HR for PFS in those who were in the fourth line and previously received axitinib was 0.64, and the ORR was 11% with tivozanib vs 10% with sorafenib. Lastly, in third- and fourth-line populations with any prior axitinib, the HR for PFS was 0.68; ORRs in the investigative and control arms were 13% and 8%, respectively.

Regarding safety, treatment-related toxicities were experienced by 84.0% of those in the tivozanib arm vs 94.0% of those in the sorafenib arm. Serious treatment-related adverse effects (AEs) were reported in 11.0% of those in the investigative arm and 10.0% of those on the control arm. The most frequently experienced AE that were grade 3 or 4 in severity in the tivozanib and sorafenib arms was hypertension, which was reported in 21.0% vs 14.0% of patients, respectively. The most common any-grade toxicities linked with tivozanib included hypertension (38.0%), diarrhea (33.0%), fatigue (29.0%), and reduced appetite (27.0%).

Significantly reduced dose reductions and interruptions because of toxicities were reported with tivozanib vs sorafenib, at 48.0% and 63.0%, respectively (P = .0164), despite almost double the average time of cycles initiated for the tivozanib arm, at 11.9 months vs 6.7 months, respectively. Eight percent of patients on the investigative arm experienced treatment-related toxicities that resulted in permanent discontinuation of treatment vs 15.0% in the control arm.


  1. AVEO Oncology announces addition of FOTIVDA (tivozanib) into National Comprehensive Cancer Network Clinical Practice Guidelines. News release. AVEO Oncology. March 29, 2021. Accessed March 30, 2021.
  2. AVEO Oncology Announces U.S. FDA Approval of FOTIVDA® (tivozanib) for the Treatment of Adult Patients with Relapsed or Refractory Advanced Renal Cell Carcinoma. AVEO Oncology. News release. March 10, 2021. Accessed March 30, 2021.
  3. Pal SK, Escudier B, Atkins MB, et al. TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC). J Clin Oncol. 2020;38(suppl 15):5062. doi:10.1200/JCO.2020.38.15_suppl.5062
  4. Rini BI, Pal SK, Escudier B, et al. TIVO-3: tivozanib in patients with advanced renal cell carcinoma (aRCC) who have progressed after treatment with axitinib. J Clin Oncol. 2021;39(suppl 6):278. doi:10.1200/JCO.2021.39.6_suppl.278

This article was originally published on OncLive as, "NCCN Updates Guidelines to Include Tivozanib as Recommended Regimen in Clear Cell RCC."

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