Earlier this week, AVEO (AVEO) announced topline results from a phase III trial for tivozanib in renal cancer. Although technically the trial met its primary endpoint and could probably lead to approval, results were far from satisfactory.
AVEO intends to position tivozanib as the standard of care treatment for 1st line renal cancer, replacing Pfizer's (PFE) Sutent. As both drugs hit common targets, AVEO hoped that tivozanib's selectivity profile would enable it to be superior in terms of side effects and at least comparable to Sutent in terms of efficacy. The underlying issue with AVEO's clinical strategy was the idea of making tivozanib Sutent's successor without comparing it directly with the Pfizer drug.
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Sutent, which generated $1.06B in sales last year, is the most commonly used first line drug for renal cancer. It was approved based on impressive improvement in progression-free survival (PFS) from 5 months in the control arm to 11 months in the Sutent arm. Although Sutent is considered safer than chemotherapy agents, it is still associated with a great degree of side effects. These include liver toxicity, fatigue and diarrhea.
Shooting for indirect superiority
AVEO started with a large single-arm phase II in 1st line patients. The 272-patient study showed a PFS of 11.8 months in the general population. The activity in the patient population that was studied in Sutent's phase III trial (clear-cell histology and prior nephrectomy) was even more impressive - 14.8 months. (The Sutent study recruited only clear cell patients, 90% of them had had prior nephrectomy).
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The safety profile for tivozanib looked substantially better than that of Sutent, especially side effects that are not related to the drug's primary mechanism of action.
Based on the results, AVEO launched a phase III trial (TIVO-1) that evaluates tivozanib in 1st line renal cancer. Patients were allowed to have a history of prior systemic therapy but prior Sutent or Nexavar was excluded. Instead of using Sutent, Onyx's (ONXX) Nexavar was chosen as a comparator. Theoretically, Nexavar is approved for 1st line RCC but it is rarely used in that setting due to its limited efficacy (estimated PFS of just under 6 months).
Having such a weak opponent substantially increased AVEO's chances of showing superiority over the control arm, which the company believed was enough to gain FDA approval.