Toxicities in a Maintenance Setting
The FDA’s briefing document suggests strong consideration should be given to ridaforolimus’ toxicities. In the phase III trial, 70% of patients in the ridaforolimus arm had dose reductions; in total, there were 3,027 dose reductions in 239 patients. Dose delays were reported in 56% of patients on the drug.
"The number of patients who discontinued due to an adverse event (14% ridaforolimus, 2% placebo) is a particular concern in a drug intended for use as maintenance therapy," the FDA said. The most common adverse events reported were stomatitis, infections, fatigue, and rash.
Although the drug’s safety profile was similar to that of other mTOR inhibitors, adverse events of particular concern included pneumonitis, infection, and renal failure/impairment, the FDA said. Possible hypersensitivity reactions were reported in 10% of ridaforolimus-treated patients.
Pazopanib: Still No Survival Benefit
ODAC’s review of ridaforolimus will take place on the afternoon of March 20. During the panel’s morning session, the committee will consider a sarcoma indication for pazopanib.
GlaxoSmithKline is seeking to add a second use for its tyrosine kinase inhibitor, which was approved for renal cell carcinoma in 2009. In the pivotal 369-patient trial, pazopanib was associated with a statistically significant 65% improvement in PFS compared with placebo, according to the FDA’s analysis. Median PFS was 4.6 months in the pazopanib arm and 1.6 months in the placebo group.
There also was improvement in median PFS in the three prespecified histological subgroups of leiomyosarcoma, synovial sarcoma, and "other" STS, findings that suggest consistency of results in an otherwise heterogeneous population.
The phase III trial excluded patients with adipocytic STS or gastrointestinal stromal tumors, and this is reflected in the proposed indication as "Important Limitations of Use."
Although pazopanib was associated with a 13% reduced risk of death, this survival advantage did not reach statistical significance in the final analysis. Median overall survival with pazopanib was 12.6 months, versus 10.7 months with placebo.
The FDA’s briefing document raises several concerns about imbalances in the treatment arms.
"Based on the results of the central pathology review, a higher proportion of patients on the pazopanib arm had a diagnosis of leiomyosarcoma while the proportion of patients with a diagnosis of ‘other’ STS was higher in the placebo arm," the agency said. "Considering the variable chemosensitivity of different histological subtypes of STS, this imbalance can potentially confound the results of the efficacy analysis."
The agency also noted that a higher proportion of patients in the placebo group had high-grade disease. "The higher enrollment of patients with high-grade disease in the placebo arm may confound the results of this study as these patients have biologically more aggressive disease."
More patients in the placebo arm received follow-up anticancer therapy after withdrawal of study treatment than in the pazopanib arm. "It is unclear whether this imbalance in post-treatment anticancer therapies can affect the final OS results of this trial, as the magnitude of survival benefit achieved from these therapies, if any at all, is unknown."
Another possible explanation for the "inconsistency" between PFS and OS is that "a larger PFS effect would be necessary to achieve a parallel OS benefit," the FDA said.
In the pivotal study, 58% of pazopanib patients had a dose interruption and 39% had a dose reduction. An additional 14% of patients discontinued pazopanib therapy due to toxicity.
"The four adverse events most commonly contributing to a dose reduction and/or a dose interruption were fatigue, diarrhea, hypertension, and nausea," the FDA said. "Other important [adverse events] leading to dose modifications included skin disorder (hand and foot syndrome) and exfoliative rash, elevated liver transaminases, and left ventricular dysfunction."
The FDA found that pazopanib’s adverse event profile in STS patients was generally consistent with the current safety profile in renal cancer, albeit with some differences. As in the renal cell population, there were reported adverse events of fatal hepatotoxicity, fatal GI perforation, life-threatening hemorrhage, and severe hypertension. Additional adverse events with increased frequency in the STS population included myocardial dysfunction, thromboembolism, and pneumothorax.
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