Nick Mulcahy

June 11, 2012

June 11, 2012 (Chicago, Illinois) — The investigational oral agent tivozanib (AVEO and Astellas) showed superior progression-free survival, compared with sorafenib, in patients with advanced renal cell carcinoma who were both pretreated and treatment-naive, according to the results of an open-label phase 3 trial.

These results for tivozanib, which is a tyrosine kinase inhibitor, were presented here at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).

However, the use of sorafenib as the trial comparator was a "major topic" because it is perceived as the "least effective" tyrosine kinase inhibitor — "the sort of dog of the field," said Tim Eisen, PhD, discussant of the session in which the data were presented.

"I very much want to see comparative data with pazopanib or sunitinib," said Dr. Eisen, who is from the University of Cambridge in the United Kingdom, about 2 of the other tyrosine kinase inhibitors used in this setting.

Still, the multinational trial, known as TIVO-1, took place at 86 centers and "establishes tivozanib as a first-line treatment option in clear cell renal cell carcinoma," noted Dr. Eisen, who was also one of the TIVO-1 investigators.

In the study, progression-free survival in patients treated with tivozanib was 11.9 months, compared with 9.1 months in those treated with sorafenib (hazard ratio [HR], 0.797; P = .042). The objective response rate was 33% for tivozanib and 23% for sorafenib (P = .014). The results are based on independent radiologic reviews.

Interestingly, the results for sorafenib are better than has been seen in previous studies, Dr. Eisen noted. "Not all dogs behave as expected," he said, extending the metaphor and explaining that the current results for sorafenib are "at the top end of what we would expect."

Tivozanib was especially useful in treatment-naive patients, who comprised 70% of study population. In those patients, progression-free survival was 12.7 months with tivozanib and 9.1 months with sorafenib (HR, 0.756; P = .037). "This is the first phase 3 trial to show greater than 12 months progression-free survival in treatment-naïve patients [with advanced renal cell carcinoma]," said Dr. Eisen.

TIVO-1 is noteworthy in terms of its comparator, noted one of the investigators. "This phase 3 clinical study used an approved targeted comparator drug to evaluate first-line renal cell carcinoma treatment," said lead study author Robert J. Motzer, MD, in a press statement. He is from the Memorial Sloan-Kettering Cancer Center and Weill Medical College, Cornell University, in New York City.

Patient Preferences to the Fore

Advanced renal cell carcinoma is the ninth most commonly diagnosed cancer in men and women in the United States. However, the number of systemic treatment options suggest a much higher ranking.

With the final phase 3 data on the way, tivozanib joins the many other potential treatments for renal cell carcinoma; 7 new drugs have been approved for this indication in recent years. The market leader is sunitinib (Sutent, Pfizer), which has about 50% to 70% of the market share for first-line use and has been used to treat more than 100,000 patients so far, according to a Pfizer spokesperson.

However, another trial presented at the meeting reported a patient preference for pazopanib (Votrient, GlaxoSmithKline) over sunitinib, as reported by Medscape Medical News. That trial involved 168 patients who took one of the drugs for 10 weeks and then the other for 10 weeks.

Of the 126 respondents who completed the questionnaire on preference, 70% said they preferred pazopanib, 22% said they preferred sunitinib, and 8% expressed no preference.

Not be outdone, AVEO and its partner, Astellas, just announced plans to initiate its own patient preference clinical study to evaluate tivozanib and sunitinib for patients with advanced kidney cancer.

Dr. Eisen said that the adverse-effect profile of tivozanib is "very good," but he does not know if it will "translate into patient preferences." He said that he needs to see quality-of-life data, which Dr. Motzer did not present.

Another issue related to the use of tyrosine kinase inhibitors — which block vascular endothelial growth-factor (VEGF) receptors — looms large, said Dr. Eisen. With all 3 VEGF receptors now blocked to some extent, the potency of these agents appears to have been "maximized," he explained. "Novel strategies" are now needed to improve results, and might include dose escalation at progression or starting and stopping therapies based on response, Dr. Eisen added.

More Study Details

The TIVO-1 study involved 517 patients randomized in a 1:1 ratio to either tivozanib 1.5 mg once daily for 3 weeks followed by 1 week of rest or to sorafenib 400 mg twice daily continuously in a 4-week cycle.

The patients had all undergone nephrectomy, and all had RECIST-defined measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

The patients were either treatment-naïve or had received no more than 1 previous systemic therapy for metastatic disease. Patients who had received previous VEGF- or mTOR-targeted therapy were excluded.

All demographics were well balanced in the 2 groups, except fewer patients in the tivozanib group than in the sorafenib group had an ECOG 0 status of 0 (45% vs 54%; P = .035).

In the subpopulation of patients who were pretreated with systemic therapy, including cytokines (30% of total study population), median progression-free survival was the same as it was for the overall population — 11.9 months for tivozanib and 9.1 months for sorafenib.

The most common adverse event (all grades and grade 3 or higher) for tivozanib was hypertension and for sorafenib was hand–foot syndrome.

Common Adverse Events in the 2 Groups

Adverse Event All Tivozanib Events
(Grade 3/4 Events)
All Sorafenib Events
(Grade 3/4 Events)
Hypertension 44% (25%) 34% (17%)
Hand–foot syndrome 13% (2%) 54% (17%)
Diarrhea 22% (2%) 32% (6%)
Fatigue 18% (5%) 16% (4%)
Neutropenia 10% (2%) 9% (2%)


The rate of dose interruptions due to adverse events was 18% for tivozanib and 35% for sorafenib (P < .001). The rate of dose reductions was 14% for tivozanib and 44% for sorafenib (P < .001).

Overall survival data are not yet mature. However, the trial allowed patients in the sorafenib group to cross over to tivozanib and for those in the tivozanib group to receive another therapy.

In total, 53% of patients randomized to sorafenib went on to receive subsequent therapy; nearly all received tivozanib after sorafenib. Only 17% of patients randomized to tivozanib went on to receive a subsequent therapy.

The study was funded by AVEO. Dr. Motzer reports relationships with Pfizer, AVEO, GlaxoSmithKline, and Novartis. Some coauthors report relationships with AVEO, and some are company employees. Dr. Eisen reports relationships with AVEO, Bayer, GlaxoSmithKline, Pfizer, Roche, and AstraZeneca.

2012 Annual Meeting of the American Society of Clinical Oncology: Abstract 4501. Presented June 2, 2012.

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