FDA Panel to Assess Ridaforolimus, Pazopanib for Sarcoma

Merck and development partner Ariad Pharmaceuticals face a seemingly formidable task at the March 20 review of their investigational sarcoma therapy ridaforolimus by a Food and Drug Administration advisory panel.

The companies will have to persuade the Oncologic Drugs Advisory Committee (ODAC) that a statistically significant 26% improvement in progression-free survival (PFS), with a median benefit of just 2 weeks, is clinically meaningful in the maintenance setting for metastatic soft-tissue sarcoma (STS) or bone sarcoma.

They also will have to convince the panel that this benefit outweighs the risk of serious adverse events – including pneumonitis, renal failure, and hypersensitivity reactions – in the pivotal study of ridaforolimus (Taltorvic), a mammalian target of rapamycin (mTOR) inhibitor.

And they have to do all this after ODAC considers whether a soft-tissue sarcoma treatment indication should be added to the label of GlaxoSmithKline’s pazopanib (Votrient). Pazopanib demonstrated a statistically significant 65% improvement in progression-free survival, with a median benefit of 3 months, in a pivotal trial in patients who progressed following prior chemotherapy.

One efficacy parameter the two drugs share is that they both failed to demonstrate a statistically significant improvement in overall survival.

Ridaforolimus: Short PFS Benefit

Doxorubicin is the only FDA-approved drug for most adult sarcomas, Merck noted in its briefing document. The company is seeking to make ridaforolimus the first product approved as a maintenance therapy in sarcoma. The proposed indication is treatment of patients with metastatic STS or bone sarcoma whose disease has not progressed after at least four cycles of chemotherapy.

The New Drug Application rests on the results of a phase III trial presented at the American Society of Clinical Oncology (ASCO) meeting in June 2011. In the study, 711 patients were randomized to ridaforolimus or placebo; scans were performed every 8 weeks, and read by an independent review committee (IRC).

The data presented at ASCO showed ridaforolimus significantly reduced the risk of progression or death by 28%, according to IRC assessment. Median PFS was 17.7 weeks in the ridaforolimus arm and 14.6 weeks with placebo.

In discussing the study results, Ariad management asserted it was more important to look at the PFS hazard ratio than the 3-week median PFS benefit. Nevertheless, the small gain in median PFS was expected to raise the same types of questions about clinically meaningful improvement that led to FDA’s withdrawal of the metastatic breast cancer indication for Genentech’s bevacizumab (Avastin).

Such concerns about clinical significance are further heightened by the FDA’s analysis of the pivotal trial data – ridaforolimus fared even worse under the agency’s assessment.

While the drug was still associated with a statistically significant improvement in PFS, the hazard ratio increased to 0.74 (compared with 0.72 in the sponsor’s analysis), and the median PFS advantage shrank from 3 weeks to 2 weeks. Median PFS in the ridaforolimus arm was 16.1 weeks, compared with 14 weeks in the placebo arm, according to the agency’s analysis.

The FDA explained why its analysis differed from that of the sponsor, even though both relied on IRC-determined progression: "The difference between these involves the handling of scans read as new lesion/no progression by the IRC," the agency said. "The applicant analysis did not consider these new lesions as disease progression, while the FDA analysis, consistent with the RECIST [Response Evaluation Criteria in Solid Tumors] criteria, considered this to be progressive disease."

Investigator-assessed PFS suggested a more dramatic benefit with ridaforolimus, with a statistically significant 31% improvement and a 7-week advantage in median PFS over placebo. However, the FDA found considerable disagreement between investigator-assessed progression and the IRC’s evaluation. "Discordance occurred in 299 (42%) of patients. A difference in event (progression event vs. censoring) was seen in 107 patients and a difference in the time of progression in 228 patients," the agency wrote.

In its background briefing document, Merck, like Ariad, suggests that median PFS values underestimate ridaforolimus’ true treatment effect.

"Due to the shape of the Kaplan-Meier curves, the median when assessed by IRC is an underestimate of the effect of ridaforolimus on PFS compared to placebo, with an improvement of approximately 6 weeks in the median estimated by the hazard ratio or parametric modeling," the company said.

"These findings indicate that maintenance treatment of metastatic sarcoma patients with ridaforolimus significantly reduced the risk of disease progression or death."

In the final analysis, ridaforolimus was associated with a 7% improvement in overall survival (OS), but this did not reach the level of statistical significance. Median OS with ridaforolimus was 20.8 months, versus 19.6 months in the placebo group.

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.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Merck and development partner Ariad Pharmaceuticals face a seemingly formidable task at the March 20 review of their investigational sarcoma therapy ridaforolimus by a Food and Drug Administration advisory panel.

The companies will have to persuade the Oncologic Drugs Advisory Committee (ODAC) that a statistically significant 26% improvement in progression-free survival (PFS), with a median benefit of just 2 weeks, is clinically meaningful in the maintenance setting for metastatic soft-tissue sarcoma (STS) or bone sarcoma.

They also will have to convince the panel that this benefit outweighs the risk of serious adverse events – including pneumonitis, renal failure, and hypersensitivity reactions – in the pivotal study of ridaforolimus (Taltorvic), a mammalian target of rapamycin (mTOR) inhibitor.

And they have to do all this after ODAC considers whether a soft-tissue sarcoma treatment indication should be added to the label of GlaxoSmithKline’s pazopanib (Votrient). Pazopanib demonstrated a statistically significant 65% improvement in progression-free survival, with a median benefit of 3 months, in a pivotal trial in patients who progressed following prior chemotherapy.

One efficacy parameter the two drugs share is that they both failed to demonstrate a statistically significant improvement in overall survival.

Ridaforolimus: Short PFS Benefit

Doxorubicin is the only FDA-approved drug for most adult sarcomas, Merck noted in its briefing document. The company is seeking to make ridaforolimus the first product approved as a maintenance therapy in sarcoma. The proposed indication is treatment of patients with metastatic STS or bone sarcoma whose disease has not progressed after at least four cycles of chemotherapy.

The New Drug Application rests on the results of a phase III trial presented at the American Society of Clinical Oncology (ASCO) meeting in June 2011. In the study, 711 patients were randomized to ridaforolimus or placebo; scans were performed every 8 weeks, and read by an independent review committee (IRC).

The data presented at ASCO showed ridaforolimus significantly reduced the risk of progression or death by 28%, according to IRC assessment. Median PFS was 17.7 weeks in the ridaforolimus arm and 14.6 weeks with placebo.

In discussing the study results, Ariad management asserted it was more important to look at the PFS hazard ratio than the 3-week median PFS benefit. Nevertheless, the small gain in median PFS was expected to raise the same types of questions about clinically meaningful improvement that led to FDA’s withdrawal of the metastatic breast cancer indication for Genentech’s bevacizumab (Avastin).

Such concerns about clinical significance are further heightened by the FDA’s analysis of the pivotal trial data – ridaforolimus fared even worse under the agency’s assessment.

While the drug was still associated with a statistically significant improvement in PFS, the hazard ratio increased to 0.74 (compared with 0.72 in the sponsor’s analysis), and the median PFS advantage shrank from 3 weeks to 2 weeks. Median PFS in the ridaforolimus arm was 16.1 weeks, compared with 14 weeks in the placebo arm, according to the agency’s analysis.

The FDA explained why its analysis differed from that of the sponsor, even though both relied on IRC-determined progression: "The difference between these involves the handling of scans read as new lesion/no progression by the IRC," the agency said. "The applicant analysis did not consider these new lesions as disease progression, while the FDA analysis, consistent with the RECIST [Response Evaluation Criteria in Solid Tumors] criteria, considered this to be progressive disease."

Investigator-assessed PFS suggested a more dramatic benefit with ridaforolimus, with a statistically significant 31% improvement and a 7-week advantage in median PFS over placebo. However, the FDA found considerable disagreement between investigator-assessed progression and the IRC’s evaluation. "Discordance occurred in 299 (42%) of patients. A difference in event (progression event vs. censoring) was seen in 107 patients and a difference in the time of progression in 228 patients," the agency wrote.

In its background briefing document, Merck, like Ariad, suggests that median PFS values underestimate ridaforolimus’ true treatment effect.

"Due to the shape of the Kaplan-Meier curves, the median when assessed by IRC is an underestimate of the effect of ridaforolimus on PFS compared to placebo, with an improvement of approximately 6 weeks in the median estimated by the hazard ratio or parametric modeling," the company said.

"These findings indicate that maintenance treatment of metastatic sarcoma patients with ridaforolimus significantly reduced the risk of disease progression or death."

In the final analysis, ridaforolimus was associated with a 7% improvement in overall survival (OS), but this did not reach the level of statistical significance. Median OS with ridaforolimus was 20.8 months, versus 19.6 months in the placebo group.

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.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Merck and development partner Ariad Pharmaceuticals face a seemingly formidable task at the March 20 review of their investigational sarcoma therapy ridaforolimus by a Food and Drug Administration advisory panel.

The companies will have to persuade the Oncologic Drugs Advisory Committee (ODAC) that a statistically significant 26% improvement in progression-free survival (PFS), with a median benefit of just 2 weeks, is clinically meaningful in the maintenance setting for metastatic soft-tissue sarcoma (STS) or bone sarcoma.

They also will have to convince the panel that this benefit outweighs the risk of serious adverse events – including pneumonitis, renal failure, and hypersensitivity reactions – in the pivotal study of ridaforolimus (Taltorvic), a mammalian target of rapamycin (mTOR) inhibitor.

And they have to do all this after ODAC considers whether a soft-tissue sarcoma treatment indication should be added to the label of GlaxoSmithKline’s pazopanib (Votrient). Pazopanib demonstrated a statistically significant 65% improvement in progression-free survival, with a median benefit of 3 months, in a pivotal trial in patients who progressed following prior chemotherapy.

One efficacy parameter the two drugs share is that they both failed to demonstrate a statistically significant improvement in overall survival.

Ridaforolimus: Short PFS Benefit

Doxorubicin is the only FDA-approved drug for most adult sarcomas, Merck noted in its briefing document. The company is seeking to make ridaforolimus the first product approved as a maintenance therapy in sarcoma. The proposed indication is treatment of patients with metastatic STS or bone sarcoma whose disease has not progressed after at least four cycles of chemotherapy.

The New Drug Application rests on the results of a phase III trial presented at the American Society of Clinical Oncology (ASCO) meeting in June 2011. In the study, 711 patients were randomized to ridaforolimus or placebo; scans were performed every 8 weeks, and read by an independent review committee (IRC).

The data presented at ASCO showed ridaforolimus significantly reduced the risk of progression or death by 28%, according to IRC assessment. Median PFS was 17.7 weeks in the ridaforolimus arm and 14.6 weeks with placebo.

In discussing the study results, Ariad management asserted it was more important to look at the PFS hazard ratio than the 3-week median PFS benefit. Nevertheless, the small gain in median PFS was expected to raise the same types of questions about clinically meaningful improvement that led to FDA’s withdrawal of the metastatic breast cancer indication for Genentech’s bevacizumab (Avastin).

Such concerns about clinical significance are further heightened by the FDA’s analysis of the pivotal trial data – ridaforolimus fared even worse under the agency’s assessment.

While the drug was still associated with a statistically significant improvement in PFS, the hazard ratio increased to 0.74 (compared with 0.72 in the sponsor’s analysis), and the median PFS advantage shrank from 3 weeks to 2 weeks. Median PFS in the ridaforolimus arm was 16.1 weeks, compared with 14 weeks in the placebo arm, according to the agency’s analysis.

The FDA explained why its analysis differed from that of the sponsor, even though both relied on IRC-determined progression: "The difference between these involves the handling of scans read as new lesion/no progression by the IRC," the agency said. "The applicant analysis did not consider these new lesions as disease progression, while the FDA analysis, consistent with the RECIST [Response Evaluation Criteria in Solid Tumors] criteria, considered this to be progressive disease."

Investigator-assessed PFS suggested a more dramatic benefit with ridaforolimus, with a statistically significant 31% improvement and a 7-week advantage in median PFS over placebo. However, the FDA found considerable disagreement between investigator-assessed progression and the IRC’s evaluation. "Discordance occurred in 299 (42%) of patients. A difference in event (progression event vs. censoring) was seen in 107 patients and a difference in the time of progression in 228 patients," the agency wrote.

In its background briefing document, Merck, like Ariad, suggests that median PFS values underestimate ridaforolimus’ true treatment effect.

"Due to the shape of the Kaplan-Meier curves, the median when assessed by IRC is an underestimate of the effect of ridaforolimus on PFS compared to placebo, with an improvement of approximately 6 weeks in the median estimated by the hazard ratio or parametric modeling," the company said.

"These findings indicate that maintenance treatment of metastatic sarcoma patients with ridaforolimus significantly reduced the risk of disease progression or death."

In the final analysis, ridaforolimus was associated with a 7% improvement in overall survival (OS), but this did not reach the level of statistical significance. Median OS with ridaforolimus was 20.8 months, versus 19.6 months in the placebo group.

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.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.