Brielle Benyon

Treatment with tivozanib (Fotivda) was associated with a fivefold increased likelihood of experiencing long-term progression-free survival (PFS) compared to treatment with sorafenib (Nexavar) among patients with pretreated relapsed/refractory renal cell carcinoma (RCC), according to the latest findings from the TIVO-3 trial presented during the 2022 ASCO Genitourinary Cancers Symposium.

TIVO-3 included 350 patients with relapsed/refractory RCC who received 2 or more prior lines of systemic therapy. Half were randomized to receive tivozanib, while the other half received sorafenib. Superior PFS findings for the tivozanib arm led to the TKI’s approval last March, while longer-term follow-up with a data cutoff of May 24, 2021, continued to show that, on average, tivozanib was superior.

“In this analysis, we assessed the proportion of TIVO-3 patients with relapsed/refractory mRCC who achieved a [long-term] PFS at regular intervals up to 4 years after initiation of [tivozanib] or [sorafenib],” the researchers wrote on their poster presentation, noting that they tracked survival data from the TIVO-3 trial at 6-, 12- 18-, 24-, 30-, 36, 42, and 48-month marks.

However, since there was a low number of patients at the 42- and 48-month marks at the time of the data cutoff, the researchers could not conduct any inferential statistical analyses.

At the 3-year mark, landmark long-term PFS rates, as assessed by the investigators, were 12.3% (95% CI, 8-18) and 2.4% (95% CI, 1-6) in the tivozanib and sorafenib arms, respectively. Tivozanib continued to best sorafenib at the 4-year mark, too, with PFS rates at 7.6% (95% CI, 4-13) and 0%, respectively.

“[Investigator assessed] PFS analyzed with extended follow-up was consistent with the [independent review committee] PFS in the primary analyses,” the researchers wrote in a poster of the findings. “OS continued to mature with longer follow-up, now demonstrating a nonsignificant trend in favor of [tivozanib].”

The patient population was well-balanced between the tivozanib and sorafenib arms, with 34, 109, and 32 patients in the favorable, intermediate and poor risk groups, respectively in the tivozanib arm. Meanwhile, on the sorafenib arm, there were 36 patients with favorable risk, 105 with intermediate risk, and 34 with poor risk disease. The majority of patients in each group (128 for tivozanib and 131 for sorafenib) had no prior immunotherapy, and 79 patients in the tivozanib group had treatment with 2 TKI therapies, compared with 80 patients in the sorafenib group. All patients included in the analysis had an ECOG score of 0 or 1.

Of note, subgroups with 15% long-term PFS at 3 years include IMDC favorable risk, female gender, ECOG performance score of 0, and an average age of 65 years old.

“A clinically relevant proportion of patients were alive and progression-free at 3 and 4 years after initiating [tivozanib] therapy compared with sorafenib, and this difference was consistent across all clinical and demographic subgroups evaluated,” the researchers concluded.

1. 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. Presented at: 2022 ASCO Genitourinary Cancers Symposium. Feb. 17-19, 2022. Virtual.

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Treatment with tivozanib was associated with a fivefold increased likelihood of experiencing long-term progression-free survival compared to treatment with sorafenib.

Tivozanib sustains PFS benefit over sorafenib in mRCC with long-term follow-up

A retrospective study of real-world outcomes with first-line tivozanib (Fotivda) in patients with metastatic renal cell carcinoma (mRCC) found that the VEGF-inhibitor was safe, tolerable, and induced similar clinical activity as other tyrosine kinase inhibitors used in this setting.

“We set out to evaluate the real-world use of tivozanib because we had some signals that this might be the preferred drug because of the toxicity profile. So, we gathered data across our 3 separate regional cancer centers from March 2017 to 2019 and looked at these outcomes,” study author Jonathan Heseltine, MBChB, of the Clatterbridge Cancer Centre in the UK, said while presenting the findings during the 2022 ASCO Genitourinary Cancers Symposium.

The retrospective trial involved 113 patients with mRCC – 82% (n = 93) with a confirmed clear cell histology, and 18% (n = 20) undefined. About half of the patients (52%; n = 59) were determined to be an intermediate prognosis per International Metastatic RCC Database Consortium (IMDC) standards. Twenty-two percent (n = 25) had favorable prognosis, and 26% (n = 29) had poor prognosis. Sixty-six percent (n = 75) had undergone a previous nephrectomy.

At a median follow-up of 25.9 months (range, 18.3-44.7 months), the overall response rate (ORR) was 29%. There were no complete responses, and 29% of patients experienced partial response, 39% stable disease, 26% progressive disease, and 6% of patients were not evaluable.

Of note, 88.5% of patients started tivozanib at the full dose, with 67% maintaining dose intensity; 11.5% started treatment with a dose reduction because of prior TKI-related toxicities or comorbidities. Median number of cycles was 7 (range, 1-33).

Median progression-free survival (PFS) was 9.0 months (95% CI, 6.0-12.1 months; 

<.0001), but varied among IMDC risk groups:

The IMDC favorable group had a median PFS of 23.0 months (95% CI, 7.6-38.4)

The IMDC intermediate group had a median PFS of 10 months (95% CI, 6.3-13.7)

The IMDC poor group had a median PFS of 3.0 months (95% CI, 1.5-4.5)

All-grade adverse events (AEs) were experienced in 77% of patients, with 14% being grade 3. Common AEs were: fatigue (42%; no grade 3), diarrhea (19%; <1% grade 3), mucositis (24%; 2% grade 3), anorexia (12%; <1% grade 3), and hypertension (7%; 2% grade 3) – an interesting finding, considering that the TIVO-1 clinical trial of tivozanib had a significant proportion of patients with serious grade 3 or low-level hypertension or dysphonia, which was not seen in the non-trial setting, Heseltine said.

The researchers mentioned that notable grade 3 events included abnormal liver function (3%), vascular events (2%), and seizure (<1%).

“The safety data was interesting in that we found that there were fewer patients reporting a grade 3 toxicity. There were no grade 4 or 5 toxicities,” Heseltine said.

There were no treatment-related deaths, but 18% of patients discontinued treatment due to toxicity.

“So, in summary, the key outcomes from our work is that the real-world data demonstrates a similar progression-free survival and overall survivor to the pivotal clinical trial, and that’s even with our population having a high proportion of poor-risk patients,” Heseltine said.

1. Heseltine J, Allison J, Wong S, et al. Tivozanib (T) as first-line (1L) treatment of metastatic renal cell carcinoma (mRCC): A real-world outcome review in North-West of England (NWE), UK. Presented at: 2022 ASCO Genitourinary Cancers Symposium. Feb. 17-19, 2022. Abstract 335. Virtual.

First-line tivozanib in patients with metastatic renal cell carcinoma was reported to be safe, tolerable, and capable of producing similar clinical activity as other tyrosine kinase inhibitors used in this setting.

Study highlights positive real-world outcomes with tivozanib in frontline mRCC

Real-world data presented during the 2021 ESMO Congress showed longer survival outcomes among patients with renal cell carcinoma (RCC) and prior VEGF-targeted therapy who received single-agent cabozantinib (Cabometyx) versus single-agent axitinib (Inlyta) in the second-line setting or later.

The retrospective cohort study analyzed outcomes from Public Health England’s Cancer Analysis System of adults who were diagnosed with stage III or IV RCC between January 1, 2011, and December 31, 2018, with follow-up lasting until January 31, 2020. A total of 440 patients received cabozantinib treatment, while 1045 received axitinib.

Median duration of treatment was longer for those who received cabozantinib (5.52 months; IQR, 2.73-11.74) than those on axitinib (4.60 months; IQR, 1.45-12.36).

Patients on the TKI inhibitor cabozantinib also had numerically longer median overall survival (OS) than patients given axitinib. In the unweighted analysis, median OS for cabozantinib was 11.41 months (IQR, 5.65-27.32) compared with 9.60 months (4.54-20.32). Similar results were found in the IPW analysis, with average OS lengths of 11.24 months (IQR, 5.65-27.98) and 10.39 months (IQR, 4.70-20.03) for the cabozantinib and axitinib arms, respectively.

“Both agents have been approved in the U.K. as second or later line treatment options for patients with advanced RCC—axitinib since 2012, and cabozantinib since 2016,” said study author Janet Brown, MB BS, MSc, MD, FRCP, Professor of Translational Medical Oncology at University of Sheffield, in her presentation of the data.

Notably, patients in the cabozantinib arm tended to have a more recent diagnosis, with 65% receiving a diagnosis between 2016 and 2018. Conversely, 80% of those on axitinib were diagnosed before 2016. In the United States, cabozantinib was approved by the FDA in December 2017 for first-line treatment, based on findings from the CABOSUN (NCT01835158) trial, which showed improved progression-free survival over sunitinib (Sutent), at 8.6 months and 5.3 months, respectively.

Characteristics between the cabozantinib and axitinib patient groups were otherwise balanced, with the average age being 62.5 years and 63.0 years, respectively. At diagnosis, 58.6% of patients in the cabozantinib cohort and 53.2% of those on the axitinib cohort had metastases, while 91.4% and 90.3%, respectively, had clear-cell histology. Regarding tumor size at diagnosis, 69.3% and 68.8% were 4.00 mm or smaller, in the cabozantinib and axitinib arms, respectively; 5.9% and 7.1% had tumors larger than 4.00 mm, and the remainder (24.8% and 24.1%) of patients had missing tumor sizes.

At diagnosis, 28.2% of patients given cabozantinib had an ECOG score of 0-1, compared with 20.4% of those on axitinib.

“Real-world evidence complements the results of randomized controlled trials,” Brown said. “This study demonstrates the potential for cabozantinib for conducting clinically relevant real-world research in England.”

1. Brown J, Harrow B, Marciniak A, McCarthy C, Cirneanu L, Protheroe A. Cabozantinib and axitinib after vascular endothelial growth factor therapy in patients with advanced renal cell carcinoma: a retrospective cohort study. Presented at: ESMO Congress 2021. September 16-21, 2021. Virtual. E-Poster 680P.

The retrospective cohort study assessed outcomes in patients with advanced renal cell carcinoma who received cabozantinib or axitinib in the second-line setting or beyond. 

Real-world results suggest survival advantage with cabozantinib versus axitinib in pretreated kidney cancer

The novel PI3K-y inhibitor eganelisib (IPI 549) boosted response rates in patients with metastatic urothelial carcinoma (mUC) treated with nivolumab (Opdivo), according to recent research presented at the 2021 Genitourinary Cancers Symposium.

“PD-1 inhibitors have demonstrated clinical benefit in metastatic urothelial carcinoma. However, clinical benefit remains low, particularly in PD-L1–low patients, who have [an average] overall response rate of only 16%,” said study author Piotr Tomczak, MD, PhD, of the Poznan University of Medical Sciences in Poznan, Poland.

The phase II MARIO-275 study (NCT03980041) included 49 patients with mUC who progressed on 1 or more platinum-based chemotherapy regimens and had no prior treatment with a checkpoint inhibitor. Study participants were stratified by baseline circulating monocytic myeloid suppressor cell (mMDSC) levels and randomized 2:1 to receive eganelisib plus nivolumab or placebo plus nivolumab.

Objective response rate (ORR) per RECIST v1.1 in patients with high baseline mMDSC levels (≥22.3) was the primary end point, and researchers also examined overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Duration of exposure was a median of 15 weeks for patients treated with – and 11 weeks for the placebo arm.

While no mMDSC-high patients responded to treatment with eganelisib, there was a higher response rate in the overall population treated with the combination regimen, compared to placebo ([30.3%; 95% CI, 16-9] vs [25%; 95% CI, 7-52], respectively). Additionally, there was a 38.5% ORR in mMDSC-low patients who received eganelisib (95% CI, 20-59), compared to 23.1% in the mMDSC-low patients who received placebo (95% CI, 5-54).

There were 5 PD-L1–positive patients (TPS >1%) in the combination treatment group, of which 4 (80%) responded to the addition of eganelisib to nivolumab (95% CI, 28-100), compared to 2 of 4 (50%) in the placebo group (95% CI, 7-93). In PD-L1–negative patients (TPS <1%) 6 out of 23 patients (26.1%) responded to the combination regimen (95% CI, 10-48), versus 1 of 7 (14.3%) in the placebo group (95% CI, 0-58). 

“The combination demonstrated improved ORR, disease control rates, and PFS when compared to the control, especially in the PD-L1–negative patients, who represent approximately 70% of the patient population,” Tomczak said.

When it came to PFS, 9.1% of patients responded on the combination therapy, compared to 8% on the placebo arm.

Common all-grade adverse events (AEs) in the eganelisib and placebo arms were pyrexia (33% vs 0%, respectively), decreased appetite (30% vs 19%), pruitis (24% vs 6%), asthenia (21% vs 31%), and transaminase elevation (21% vs 6%). The most common grade 3 or higher AEs were hepatotoxicity (15% vs 0%, respectively), transaminase elevation (12% vs 6%), and rash (9% vs 0%). After a safety review, the eganelisib dose was reduced from 40 mg to 30 mg, which lowered the rate of hepatic AEs.

“Importantly, nivolumab monotherapy in the control arm of MARIO-275 demonstrated clinical activity consistent with monotherapy with nivolumab in CheckMate-275, further adding to our confidence in interpreting the contribution of eganelisib [with] nivolumab in the controlled study,” Tomczak said.

Based on these findings, a larger study is being planned in the future to further evaluate eganelisib in PD-L1–low patients.

“Given the magnitude of unmet need in the PD-L1–low patient [population], Infinity is planning a registration and labeling study exploring the potential benefit of eganelisib for PD-L1–low patients, more broadly in other indications,” Tomczak said.

1. Tomczak T, Popovic L, Barthelemy P, et al. Preliminary analysis of a phase II, multicenter, randomized, active-control study to evaluate the efficacy and safety of eganelisib (IPI 549) in combination with nivolumab compared to nivolumab monotherapy in patients with advanced urothelial carcinoma. Presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021; Virtual. Abstract 436.

The novel agent eganelisib led to higher response rates with nivolumab in PD-L1–low patients with metastatic urothelial carcinoma.

Brielle Benyon

Articles

Tivozanib sustains PFS benefit over sorafenib in mRCC with long-term follow-up

Study highlights positive real-world outcomes with tivozanib in frontline mRCC

Real-world results suggest survival advantage with cabozantinib versus axitinib in pretreated kidney cancer

Eganelisib may boost response to nivolumab in mUC