At the FDA Oncologic Drugs Advisory Committee’s May 2 meeting, Aveo Pharmaceuticals Inc. will have to make its case for approval of the renal cell carcinoma drug tivozanib despite failing to heed the agency’s advice to conduct a second pivotal study due to a negative survival trend in the sole Phase III trial.

ODAC is being asked to vote on whether another trial is needed to better characterize tivozanib’s risk/benefit profile before approval can be considered “given the uncertainty in overall survival and availability of multiple therapies” for advanced renal cell carcinoma, according to briefing documents released April 30.

Aveo’s sole pivotal study met its primary endpoint of progression-free survival. However, the results for overall survival, a secondary endpoint, showed an unfavorable survival trend for tivozanib versus the comparator agent, Onyx Pharmaceuticals Inc./Bayer HealthCare LLC’s Nexavar (sorafenib). The company has attributed this result to the study’s one-way crossover design, geographic distribution of patients and extensive use of subsequent targeted therapy by patients in the sorafenib arm.

During a pre-NDA meeting in May 2012, FDA recommended Aveo “conduct a second adequately powered randomized trial in a population comparable to that in the U.S.”

Aveo noted in an August 2012 Securities and Exchange Commission filing that FDA had “expressed concern” about the survival data and would review the findings at the time of NDA filing and review Also see "Aveo’s Tivozanib Will Face Challenging Survival Data At ODAC Review" - Pink Sheet, 26 February, 2013..

However, FDA was so uncomfortable with the negative survival trend that during a May 2012 pre-NDA meeting it “recommended that the sponsor conduct a second adequately powered randomized trial in a population comparable to that in the U.S.,” the agency's briefing document states.

“In considering the results from a single randomized trial submitted in support of marketing approval of a new molecular entity, FDA expects that the trial will be adequately designed and well conducted and that the results will be internally consistent,” the agency said. “We are asking the ODAC’s advice on whether this single trial is sufficient to support approval of tivozanib for the indication of treatment of patients with advanced renal cell cancer or whether an additional trial is necessary before considering marketing approval.”

Seven Drugs Already Approved

Tivozanib is a tyrosine kinase inhibitor with activity against all three vascular endothelial growth factor receptors. The compound is designed to optimize VEGF blockade while minimizing off-target toxicities.

If approved, tivozanib would be the eighth drug indicated for the treatment of advanced renal cell carcinoma. Of the seven currently available drugs, six were approved on the basis of a PFS improvement and a favorable, though non-statistically significant, survival benefit. Pfizer Inc.’s Torisel (temsirolimus) demonstrated a statistically significant overall survival benefit in patients with a poor prognosis.

According to FDA, pivotal trials for five of the seven drugs employed a crossover design, and information on use of subsequent targeted therapies was known for three of the drugs. “Despite crossover/subsequent therapy, the point estimates for the HR for OS for the 7 approved drugs are all less than 1 and do not suggest a detrimental effect on survival with the approved product,” the briefing document states.

In the pivotal TIVO-1 trial (AV-951-301), 517 patients who were either newly diagnosed or had received prior cytokine treatment were randomized to tivozanib or sorafenib. Patients in the sorafenib arm who experienced disease progression were offered tivozanib under a separate extension study protocol (AV-951-09-902); however, there was no similar crossover for patients who experienced disease progression in the tivozanib arm.

Among 257 patients randomized to sorafenib, 163 (63%) received any subsequent targeted therapy, with 156 receiving tivozanib. In the tivozanib arm, only 41 of 260 patients (16%) received subsequent targeted therapy after disease progression.

Approximately 88% of the trial population was enrolled in Central and Eastern Europe, with approximately 8% (40 patients) coming from North America and Western Europe; the number of U.S. patients is not broken out in either FDA’s or Aveo’s briefing material for the meeting.

FDA said second-line targeted therapy generally is not available in Central/Eastern Europe, where the bulk of patients were enrolled. “This is not consistent with the practice patterns in the U.S. and it is, therefore, unclear whether the patients in this study were representative of those in the U.S.,” the briefing document states.

In a recent interview with “The Pink Sheet” DAILY, Aveo Chief Medical Officer William Slichenmyer downplayed any potential for concerns about generalizability of the pivotal study data to the U.S. patient population. During the study and up to measurement of the PFS endpoint, patients were managed identically independent of geography, he said.

In the primary analysis, tivozanib was associated with a statistically significant 20% PFS improvement as determined by an independent review committee, with a median PFS of 11.9 months compared to 9.1 months in the sorafenib arm.

Crossover Design Created “Major Imbalance”

The final analysis for overall survival, which was conducted after all patients had been followed for at least two years, showed a 25% increased risk of death in the tivozanib arm, although this finding did not reach the level of statistical significance. Median overall survival in the tivozanib arm was 28.8 months, compared to 29.3 months in the sorafenib arm.

Aveo attributed the trend for longer survival in the sorafenib arm to the greater proportion of patients who had access to and were treated with second-line targeted therapy in the extension protocol. The company’s explanation is heavily premised on the trial’s one-way crossover format and the large enrollment of patients from Central/Eastern Europe – issues that resulted from, and perhaps should have been anticipated in, the clinical program’s design. As such, they may hold little sway in convincing ODAC members that a new trial is not warranted prior to approval for U.S. patients.

The imbalance in use of next-line targeted therapy “is the most plausible explanation for the trend toward longer overall survival” in the sorafenib group, Aveo said.

“Although the overall survival hazard ratio indicates a trend that favors the control arm, this result can be explained due to a confluence of factors including: 1) adoption of an active comparator, 2) a high rate of utilization of next-line tivozanib by patients in the control arm and 3) limited access to next-line therapy for patients in the tivozanib arm,” Aveo's briefing document states.

The one-way crossover design “resulted in a major imbalance in utilization of next-line targeted cancer therapies for patients enrolled in study 301,” the company said. “Only 13% of tivozanib patients who discontinued therapy in study 301 were treated with next-line targeted cancer therapy, owing to the fact that access to next-line therapies was severely limited in the countries where the great majority of patients in study 301 were enrolled.”

“This imbalance in the utilization of next-line cancer therapies is the most plausible explanation for the trend toward longer overall survival in patients originally randomized to sorafenib in study 301, most of whom were subsequently treated with tivozanib upon progression,” the company said. “The comparison of overall survival for patients enrolled in study 301 is essentially a comparison of outcomes for two groups of patients: those who received a single-line of therapy (tivozanib) vs. those who received two lines of therapy (sorafenib followed by tivozanib). Given published observations that patients who receive multiple lines of therapy have longer overall survival when compared to patients who receive only a single line of therapy, the results of the overall survival analysis are unsurprising.”

In making the case for tivozanib’s efficacy, the company points out that in the extension study, “tivozanib showed evidence of anti-tumor activity as next-line crossover therapy for patients who experienced disease progression on sorafenib in study 301.” Median PFS in this group was 8.4 months, and the objective response rate for confirmed responses was 13.5%, the company said.

The company also highlighted the statistically significantly higher overall response rate for tivozanib in the pivotal trial, 33% versus 23%.

However, FDA’s briefing document calls into question the response rate findings, saying the rate in the comparator arm was not consistent with that seen in previous studies involving sorafenib.

Safety Findings

Tivozanib was associated with a higher rate of hypertension (45% versus 35%) in the pivotal trial. Nevertheless, Aveo has stressed the compound’s tolerability as among its strongest points, with safety advantages over sorafenib that include lower rates of some events, such as hand-foot syndrome and diarrhea, which are very bothersome to patients and likely to lead to dose reductions or discontinuation.

In the pivotal trial, 13% of tivozanib patients experienced hand-foot syndrome, compared with 54% in the sorafenib arm. The rates of diarrhea were 22% for tivozanib arm and 33% for sorafenib.

Among tivozanib patients in the pivotal trial, 27% experienced a dose interruption and 16% had a dose reduction, compared to 70% and 44%, respectively, in the sorafenib arm. However, FDA said the degree of dose reductions/interruptions in the study is not consistent with other studies of sorafenib.

“It is important to note that the number of patients requiring permanent discontinuation of study drug in the adverse event dataset (33 tivozanib vs. 32 sorafenib) was similar between arms,” the agency said.

Approval Or New Study? That’s The Question For Tivozanib Panel Review

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