Sarcoma & GIST

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 13-1 that the investigational agent ridaforolimus did not have a favorable risk-benefit profile when used as maintenance therapy in patients with metastatic soft-tissue or bone sarcomas that had stabilized with chemotherapy.

Members of the FDA’s Oncologic Drugs Advisory Committee cited the marginal effect on progression-free survival and the toxicity profile associated with the drug in a phase III clinical trial reviewed at a meeting on March 20.

While several panelists noted the need for such a treatment, ODAC’s chair, Dr. Wyndham H. Wilson, pointed out that patients are exposed for a longer period of time when a drug is approved as maintenance therapy. Therefore, the data showing benefit have to be more robust than do the data supporting use in a treatment setting, and the drug should be "reasonably well tolerated," said Dr. Wilson, chief of the lymphoma therapeutics section at the National Cancer Institute, Bethesda, Md.

Manufacturer Merck Sharp & Dohme Corp. has proposed that ridaforolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), be approved as a maintenance treatment at a dose of 40 mg daily for 5 days of the week.

The study involved 711 patients with metastatic soft-tissue sarcoma (STS) or bone sarcoma that had not progressed after at least four cycles of chemotherapy. Their median age was 53 years; 12 patients were aged 12-17 years. Most (90%) had soft-tissue sarcomas; the rest had bone sarcomas. About two-thirds of the tumors were high grade. About half the patients were in the United States.

Median progression-free survival, the primary end point, reached 17.7 weeks among those on ridaforolimus, compared with 14.6 weeks among those on placebo – a statistically significant difference that represented a reduced risk of 28% of disease progression or death, according to Merck’s analysis.

Overall survival was 91 weeks with ridaforolimus vs. 85 weeks with placebo. This was not significantly different, but the study was not powered to evaluate overall survival.

The safety profile was similar to the safety profile with other mTOR inhibitors, and there were more grade 3/4 adverse events among patients on ridaforolimus (64% vs. 25% on placebo). In all, 14% of those on ridaforolimus discontinued treatment, compared with 2% of those on placebo.

Grade 3/4 stomatitis (12% vs. 1%) and hyperglycemia (13% vs. 2%) were more common with ridaforolimus. There were also more cases of interstitial pneumonitis and renal failure.

Among the main issues raised by the FDA reviewers were that the clinical importance of the statistically significant improvement in progression-free survival was unclear, maintenance treatment did not lead to longer overall survival, and adverse events were a concern for a maintenance treatment in patients with stable disease. The panel agreed with the FDA reviewers.

To date, the FDA has approved three agents as maintenance therapy in patients with cancer: pemetrexed (Alimta) in nonsquamous non–small cell lung cancer (NSCLC), erlotinib (Tarceva) for NSCLC, and rituximab (Rituxan), for non-Hodgkin’s lymphoma. No drug has been approved for maintenance therapy in patients with sarcoma.

If approved, Merck plans to market ridaforolimus as Taltorvic; it is also being studied for various types of solid-tissue cancers, including lung, breast, endometrial, and ovarian cancer, according to the company.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in this meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 13-1 that the investigational agent ridaforolimus did not have a favorable risk-benefit profile when used as maintenance therapy in patients with metastatic soft-tissue or bone sarcomas that had stabilized with chemotherapy.

Members of the FDA’s Oncologic Drugs Advisory Committee cited the marginal effect on progression-free survival and the toxicity profile associated with the drug in a phase III clinical trial reviewed at a meeting on March 20.

While several panelists noted the need for such a treatment, ODAC’s chair, Dr. Wyndham H. Wilson, pointed out that patients are exposed for a longer period of time when a drug is approved as maintenance therapy. Therefore, the data showing benefit have to be more robust than do the data supporting use in a treatment setting, and the drug should be "reasonably well tolerated," said Dr. Wilson, chief of the lymphoma therapeutics section at the National Cancer Institute, Bethesda, Md.

Manufacturer Merck Sharp & Dohme Corp. has proposed that ridaforolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), be approved as a maintenance treatment at a dose of 40 mg daily for 5 days of the week.

The study involved 711 patients with metastatic soft-tissue sarcoma (STS) or bone sarcoma that had not progressed after at least four cycles of chemotherapy. Their median age was 53 years; 12 patients were aged 12-17 years. Most (90%) had soft-tissue sarcomas; the rest had bone sarcomas. About two-thirds of the tumors were high grade. About half the patients were in the United States.

Median progression-free survival, the primary end point, reached 17.7 weeks among those on ridaforolimus, compared with 14.6 weeks among those on placebo – a statistically significant difference that represented a reduced risk of 28% of disease progression or death, according to Merck’s analysis.

Overall survival was 91 weeks with ridaforolimus vs. 85 weeks with placebo. This was not significantly different, but the study was not powered to evaluate overall survival.

The safety profile was similar to the safety profile with other mTOR inhibitors, and there were more grade 3/4 adverse events among patients on ridaforolimus (64% vs. 25% on placebo). In all, 14% of those on ridaforolimus discontinued treatment, compared with 2% of those on placebo.

Grade 3/4 stomatitis (12% vs. 1%) and hyperglycemia (13% vs. 2%) were more common with ridaforolimus. There were also more cases of interstitial pneumonitis and renal failure.

Among the main issues raised by the FDA reviewers were that the clinical importance of the statistically significant improvement in progression-free survival was unclear, maintenance treatment did not lead to longer overall survival, and adverse events were a concern for a maintenance treatment in patients with stable disease. The panel agreed with the FDA reviewers.

To date, the FDA has approved three agents as maintenance therapy in patients with cancer: pemetrexed (Alimta) in nonsquamous non–small cell lung cancer (NSCLC), erlotinib (Tarceva) for NSCLC, and rituximab (Rituxan), for non-Hodgkin’s lymphoma. No drug has been approved for maintenance therapy in patients with sarcoma.

If approved, Merck plans to market ridaforolimus as Taltorvic; it is also being studied for various types of solid-tissue cancers, including lung, breast, endometrial, and ovarian cancer, according to the company.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in this meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 13-1 that the investigational agent ridaforolimus did not have a favorable risk-benefit profile when used as maintenance therapy in patients with metastatic soft-tissue or bone sarcomas that had stabilized with chemotherapy.

Members of the FDA’s Oncologic Drugs Advisory Committee cited the marginal effect on progression-free survival and the toxicity profile associated with the drug in a phase III clinical trial reviewed at a meeting on March 20.

While several panelists noted the need for such a treatment, ODAC’s chair, Dr. Wyndham H. Wilson, pointed out that patients are exposed for a longer period of time when a drug is approved as maintenance therapy. Therefore, the data showing benefit have to be more robust than do the data supporting use in a treatment setting, and the drug should be "reasonably well tolerated," said Dr. Wilson, chief of the lymphoma therapeutics section at the National Cancer Institute, Bethesda, Md.

Manufacturer Merck Sharp & Dohme Corp. has proposed that ridaforolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), be approved as a maintenance treatment at a dose of 40 mg daily for 5 days of the week.

The study involved 711 patients with metastatic soft-tissue sarcoma (STS) or bone sarcoma that had not progressed after at least four cycles of chemotherapy. Their median age was 53 years; 12 patients were aged 12-17 years. Most (90%) had soft-tissue sarcomas; the rest had bone sarcomas. About two-thirds of the tumors were high grade. About half the patients were in the United States.

Median progression-free survival, the primary end point, reached 17.7 weeks among those on ridaforolimus, compared with 14.6 weeks among those on placebo – a statistically significant difference that represented a reduced risk of 28% of disease progression or death, according to Merck’s analysis.

Overall survival was 91 weeks with ridaforolimus vs. 85 weeks with placebo. This was not significantly different, but the study was not powered to evaluate overall survival.

The safety profile was similar to the safety profile with other mTOR inhibitors, and there were more grade 3/4 adverse events among patients on ridaforolimus (64% vs. 25% on placebo). In all, 14% of those on ridaforolimus discontinued treatment, compared with 2% of those on placebo.

Grade 3/4 stomatitis (12% vs. 1%) and hyperglycemia (13% vs. 2%) were more common with ridaforolimus. There were also more cases of interstitial pneumonitis and renal failure.

Among the main issues raised by the FDA reviewers were that the clinical importance of the statistically significant improvement in progression-free survival was unclear, maintenance treatment did not lead to longer overall survival, and adverse events were a concern for a maintenance treatment in patients with stable disease. The panel agreed with the FDA reviewers.

To date, the FDA has approved three agents as maintenance therapy in patients with cancer: pemetrexed (Alimta) in nonsquamous non–small cell lung cancer (NSCLC), erlotinib (Tarceva) for NSCLC, and rituximab (Rituxan), for non-Hodgkin’s lymphoma. No drug has been approved for maintenance therapy in patients with sarcoma.

If approved, Merck plans to market ridaforolimus as Taltorvic; it is also being studied for various types of solid-tissue cancers, including lung, breast, endometrial, and ovarian cancer, according to the company.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in this meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel supports approval of the angiogenesis inhibitor pazopanib as a treatment for advanced soft-tissue sarcoma, despite some concerns about the degree of response in the main study considered for approval.

At its March 20 meeting, the Oncologic Drugs Advisory Committee (ODAC) voted 11-2 that pazopanib (Votrient) has a favorable risk-benefit profile as a treatment for advanced soft-tissue sarcoma (STS) in patients who have received prior chemotherapy, the new indication proposed by the manufacturer, GlaxoSmithKline.

In the pivotal placebo-controlled PALETTE study, the gain in median progression-free survival was 3 months, which was significant. The difference in median overall survival, a secondary end point, was 1.9 months, however, and this was not statistically significant.

Although panelists agreed that the effects of the drug were marginal, those voting in favor of approval said that they believed the effect was real. They reasoned that a 3-month benefit was meaningful to patients, as there are few options available for this rare tumor.

Several were encouraged by the fact that 14% of patients in the study remained still on treatment after 1 year (compared with 1% of those on placebo). Panelists also said that having a noncytotoxic treatment option for soft-tissue sarcomas would be beneficial.

Pazopanib, a tyrosine kinase inhibitor, targets the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and stem cell growth factor. It was approved in 2009 for the treatment of advanced renal cell carcinoma.

In the double-blind, phase III study, patients with soft-tissue sarcoma who had progressed during or following prior chemotherapy (including anthracyclines) were randomized to pazopanib, 800 mg daily, in tablet formulation (246 patients) or placebo (123 patients). They were examined every 4 weeks during a 12-week period and then every 8 weeks until evidence of progression, death, excessive toxicity, or patient withdrawal.

A little more than half the patients were female, their median age was 51-56 years; most were from the European Union, 12% were from the United States. The most common histologies were leiomyosarcoma (40% on placebo and 44% on pazopanib) and synovial sarcoma (11% and 10%, respectively).

Median progression-free survival, the primary end point, reached 4.6 months among those on pazopanib, compared with 1.6 months among those on placebo, a statistically significant difference that represented a 65% reduced risk.

Treatment was not associated with a statistically significant improvement in overall survival, however. It reached 12.6 months among those on pazopanib and 10.7 months among those on placebo, for a reduced risk of 13%.

With a few exceptions, the safety profile in sarcoma trials was similar to the safety profile of patients in renal cell carcinoma studies, with adverse effects that included hepatoxicity, hypothyroidism, and hemorrhagic events.

"From my own experience of treating many sarcoma patients, this is a drug I would like to have in my armamentarium," panelist Dr. Lee J. Helman, scientific director for clinical research, at the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

While he would have liked to see a greater impact on progression-free survival, he said, "It’s a little step ... but it’s a little step in a field that has had nothing."

The company has proposed that the indication include the statement "Important limitations of use: The phase [III] STS trial population excluded patients with adipocytic STS or gastrointestinal stromal tumors."

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in the meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel supports approval of the angiogenesis inhibitor pazopanib as a treatment for advanced soft-tissue sarcoma, despite some concerns about the degree of response in the main study considered for approval.

At its March 20 meeting, the Oncologic Drugs Advisory Committee (ODAC) voted 11-2 that pazopanib (Votrient) has a favorable risk-benefit profile as a treatment for advanced soft-tissue sarcoma (STS) in patients who have received prior chemotherapy, the new indication proposed by the manufacturer, GlaxoSmithKline.

In the pivotal placebo-controlled PALETTE study, the gain in median progression-free survival was 3 months, which was significant. The difference in median overall survival, a secondary end point, was 1.9 months, however, and this was not statistically significant.

Although panelists agreed that the effects of the drug were marginal, those voting in favor of approval said that they believed the effect was real. They reasoned that a 3-month benefit was meaningful to patients, as there are few options available for this rare tumor.

Several were encouraged by the fact that 14% of patients in the study remained still on treatment after 1 year (compared with 1% of those on placebo). Panelists also said that having a noncytotoxic treatment option for soft-tissue sarcomas would be beneficial.

Pazopanib, a tyrosine kinase inhibitor, targets the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and stem cell growth factor. It was approved in 2009 for the treatment of advanced renal cell carcinoma.

In the double-blind, phase III study, patients with soft-tissue sarcoma who had progressed during or following prior chemotherapy (including anthracyclines) were randomized to pazopanib, 800 mg daily, in tablet formulation (246 patients) or placebo (123 patients). They were examined every 4 weeks during a 12-week period and then every 8 weeks until evidence of progression, death, excessive toxicity, or patient withdrawal.

A little more than half the patients were female, their median age was 51-56 years; most were from the European Union, 12% were from the United States. The most common histologies were leiomyosarcoma (40% on placebo and 44% on pazopanib) and synovial sarcoma (11% and 10%, respectively).

Median progression-free survival, the primary end point, reached 4.6 months among those on pazopanib, compared with 1.6 months among those on placebo, a statistically significant difference that represented a 65% reduced risk.

Treatment was not associated with a statistically significant improvement in overall survival, however. It reached 12.6 months among those on pazopanib and 10.7 months among those on placebo, for a reduced risk of 13%.

With a few exceptions, the safety profile in sarcoma trials was similar to the safety profile of patients in renal cell carcinoma studies, with adverse effects that included hepatoxicity, hypothyroidism, and hemorrhagic events.

"From my own experience of treating many sarcoma patients, this is a drug I would like to have in my armamentarium," panelist Dr. Lee J. Helman, scientific director for clinical research, at the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

While he would have liked to see a greater impact on progression-free survival, he said, "It’s a little step ... but it’s a little step in a field that has had nothing."

The company has proposed that the indication include the statement "Important limitations of use: The phase [III] STS trial population excluded patients with adipocytic STS or gastrointestinal stromal tumors."

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in the meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel supports approval of the angiogenesis inhibitor pazopanib as a treatment for advanced soft-tissue sarcoma, despite some concerns about the degree of response in the main study considered for approval.

At its March 20 meeting, the Oncologic Drugs Advisory Committee (ODAC) voted 11-2 that pazopanib (Votrient) has a favorable risk-benefit profile as a treatment for advanced soft-tissue sarcoma (STS) in patients who have received prior chemotherapy, the new indication proposed by the manufacturer, GlaxoSmithKline.

In the pivotal placebo-controlled PALETTE study, the gain in median progression-free survival was 3 months, which was significant. The difference in median overall survival, a secondary end point, was 1.9 months, however, and this was not statistically significant.

Although panelists agreed that the effects of the drug were marginal, those voting in favor of approval said that they believed the effect was real. They reasoned that a 3-month benefit was meaningful to patients, as there are few options available for this rare tumor.

Several were encouraged by the fact that 14% of patients in the study remained still on treatment after 1 year (compared with 1% of those on placebo). Panelists also said that having a noncytotoxic treatment option for soft-tissue sarcomas would be beneficial.

Pazopanib, a tyrosine kinase inhibitor, targets the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and stem cell growth factor. It was approved in 2009 for the treatment of advanced renal cell carcinoma.

In the double-blind, phase III study, patients with soft-tissue sarcoma who had progressed during or following prior chemotherapy (including anthracyclines) were randomized to pazopanib, 800 mg daily, in tablet formulation (246 patients) or placebo (123 patients). They were examined every 4 weeks during a 12-week period and then every 8 weeks until evidence of progression, death, excessive toxicity, or patient withdrawal.

A little more than half the patients were female, their median age was 51-56 years; most were from the European Union, 12% were from the United States. The most common histologies were leiomyosarcoma (40% on placebo and 44% on pazopanib) and synovial sarcoma (11% and 10%, respectively).

Median progression-free survival, the primary end point, reached 4.6 months among those on pazopanib, compared with 1.6 months among those on placebo, a statistically significant difference that represented a 65% reduced risk.

Treatment was not associated with a statistically significant improvement in overall survival, however. It reached 12.6 months among those on pazopanib and 10.7 months among those on placebo, for a reduced risk of 13%.

With a few exceptions, the safety profile in sarcoma trials was similar to the safety profile of patients in renal cell carcinoma studies, with adverse effects that included hepatoxicity, hypothyroidism, and hemorrhagic events.

"From my own experience of treating many sarcoma patients, this is a drug I would like to have in my armamentarium," panelist Dr. Lee J. Helman, scientific director for clinical research, at the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

While he would have liked to see a greater impact on progression-free survival, he said, "It’s a little step ... but it’s a little step in a field that has had nothing."

The company has proposed that the indication include the statement "Important limitations of use: The phase [III] STS trial population excluded patients with adipocytic STS or gastrointestinal stromal tumors."

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in the meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.

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.

SAN FRANCISCO – Patients with gastrointestinal stromal tumors have a poorer prognosis if their primary tumor is located outside the gastrointestinal tract, researchers reported.

In an analysis of a U.S. population–based cohort of 2,591 patients who underwent surgery for gastrointestinal stromal tumors (GIST), 10% had primaries in the omentum, mesentery, retroperitoneum, or another location separate from the tubular gastrointestinal tract.

The 5-year overall survival rate for this group of patients with extragastrointestinal stromal tumors (EGIST) was 62%, which was significantly poorer than the 70% observed for those with primaries in the typical gastrointestinal tract location, mainly the stomach or small intestine.

Patients with primaries outside the gastrointestinal tract had larger tumors and more advanced stage, the study found. But even after adjustment for these potential confounders, extragastrointestinal location was still associated with a nearly 30% increase in the risk of death.

"The results of our study suggest that tumor location outside the gastrointestinal tract should be considered as an important variable, and risk stratification for prognosis should account for these rare GIST locations," said lead investigator Dr. Mary L. Guye, who presented the data at the gastrointestinal cancers symposium sponsored by the American Society of Clinical Oncology.

The reason for this poorer prognosis is unknown, said Dr. Guye, a surgical oncologist at the City of Hope National Medical Center in Duarte, Calif.

"It could be these are truly metastatic foci with an unidentified or unknown primary tumor, or they may simply be more aggressive tumors that arise de novo outside the gastrointestinal tract," she proposed, calling for further studies to investigate the tumor biology of these rare GIST tumors.

"Evaluation of histology, looking at tumor mitotic rate, and also mutational analyses may help to determine why extra-intestinal location confers a worse prognosis for GIST tumors," she said.

In an interview, Dr. Allan Pickens of Emory University in Atlanta, cochair of the scientific session in which the data were presented, said, "This was a great study [that further defined] the difference between the traditional GISTs that we treat more commonly and the ones that are outside of the gastrointestinal tract [and] have a worse prognosis."

Dr. Pickens agreed that molecular analyses will help better define how the two groups of tumors differ. "It would be interesting to see some of the microRNA information applied to those different tumors to see if it could predict those worse outcomes," he said.

Dr. Guye and her colleagues analyzed SEER (Surveillance, Epidemiology, and End Results) data for 1996-2008 to identify their study population with GIST, choosing the start year because that is when diagnosis of this tumor became more accurate, she explained.

Patients with primaries in and outside the gastrointestinal tract had similar age and racial distribution. But patients with EGIST were more likely to receive radiation therapy, to have tumors larger than 10 cm, and to have regional or distant disease.

Median overall survival was 120 months in the group with primaries in the gastrointestinal tract, and 105 months in the group with primaries in other locations (P = .002).

Additional analyses showed that location outside the gastrointestinal tract conferred a worse prognosis, even when tumors were matched for size and stage of disease, Dr. Guye reported. And the association stood up in multivariate analysis (P = .03).

However, "the SEER database does not include information on mitotic rate or information on systemic medical therapies," she noted. "Therefore, we were not able to include these factors in our analysis."

Dr. Guye and Dr. Pickens disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – Patients with gastrointestinal stromal tumors have a poorer prognosis if their primary tumor is located outside the gastrointestinal tract, researchers reported.

In an analysis of a U.S. population–based cohort of 2,591 patients who underwent surgery for gastrointestinal stromal tumors (GIST), 10% had primaries in the omentum, mesentery, retroperitoneum, or another location separate from the tubular gastrointestinal tract.

The 5-year overall survival rate for this group of patients with extragastrointestinal stromal tumors (EGIST) was 62%, which was significantly poorer than the 70% observed for those with primaries in the typical gastrointestinal tract location, mainly the stomach or small intestine.

Patients with primaries outside the gastrointestinal tract had larger tumors and more advanced stage, the study found. But even after adjustment for these potential confounders, extragastrointestinal location was still associated with a nearly 30% increase in the risk of death.

"The results of our study suggest that tumor location outside the gastrointestinal tract should be considered as an important variable, and risk stratification for prognosis should account for these rare GIST locations," said lead investigator Dr. Mary L. Guye, who presented the data at the gastrointestinal cancers symposium sponsored by the American Society of Clinical Oncology.

The reason for this poorer prognosis is unknown, said Dr. Guye, a surgical oncologist at the City of Hope National Medical Center in Duarte, Calif.

"It could be these are truly metastatic foci with an unidentified or unknown primary tumor, or they may simply be more aggressive tumors that arise de novo outside the gastrointestinal tract," she proposed, calling for further studies to investigate the tumor biology of these rare GIST tumors.

"Evaluation of histology, looking at tumor mitotic rate, and also mutational analyses may help to determine why extra-intestinal location confers a worse prognosis for GIST tumors," she said.

In an interview, Dr. Allan Pickens of Emory University in Atlanta, cochair of the scientific session in which the data were presented, said, "This was a great study [that further defined] the difference between the traditional GISTs that we treat more commonly and the ones that are outside of the gastrointestinal tract [and] have a worse prognosis."

Dr. Pickens agreed that molecular analyses will help better define how the two groups of tumors differ. "It would be interesting to see some of the microRNA information applied to those different tumors to see if it could predict those worse outcomes," he said.

Dr. Guye and her colleagues analyzed SEER (Surveillance, Epidemiology, and End Results) data for 1996-2008 to identify their study population with GIST, choosing the start year because that is when diagnosis of this tumor became more accurate, she explained.

Patients with primaries in and outside the gastrointestinal tract had similar age and racial distribution. But patients with EGIST were more likely to receive radiation therapy, to have tumors larger than 10 cm, and to have regional or distant disease.

Median overall survival was 120 months in the group with primaries in the gastrointestinal tract, and 105 months in the group with primaries in other locations (P = .002).

Additional analyses showed that location outside the gastrointestinal tract conferred a worse prognosis, even when tumors were matched for size and stage of disease, Dr. Guye reported. And the association stood up in multivariate analysis (P = .03).

However, "the SEER database does not include information on mitotic rate or information on systemic medical therapies," she noted. "Therefore, we were not able to include these factors in our analysis."

Dr. Guye and Dr. Pickens disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – Patients with gastrointestinal stromal tumors have a poorer prognosis if their primary tumor is located outside the gastrointestinal tract, researchers reported.

In an analysis of a U.S. population–based cohort of 2,591 patients who underwent surgery for gastrointestinal stromal tumors (GIST), 10% had primaries in the omentum, mesentery, retroperitoneum, or another location separate from the tubular gastrointestinal tract.

The 5-year overall survival rate for this group of patients with extragastrointestinal stromal tumors (EGIST) was 62%, which was significantly poorer than the 70% observed for those with primaries in the typical gastrointestinal tract location, mainly the stomach or small intestine.

Patients with primaries outside the gastrointestinal tract had larger tumors and more advanced stage, the study found. But even after adjustment for these potential confounders, extragastrointestinal location was still associated with a nearly 30% increase in the risk of death.

"The results of our study suggest that tumor location outside the gastrointestinal tract should be considered as an important variable, and risk stratification for prognosis should account for these rare GIST locations," said lead investigator Dr. Mary L. Guye, who presented the data at the gastrointestinal cancers symposium sponsored by the American Society of Clinical Oncology.

The reason for this poorer prognosis is unknown, said Dr. Guye, a surgical oncologist at the City of Hope National Medical Center in Duarte, Calif.

"It could be these are truly metastatic foci with an unidentified or unknown primary tumor, or they may simply be more aggressive tumors that arise de novo outside the gastrointestinal tract," she proposed, calling for further studies to investigate the tumor biology of these rare GIST tumors.

"Evaluation of histology, looking at tumor mitotic rate, and also mutational analyses may help to determine why extra-intestinal location confers a worse prognosis for GIST tumors," she said.

In an interview, Dr. Allan Pickens of Emory University in Atlanta, cochair of the scientific session in which the data were presented, said, "This was a great study [that further defined] the difference between the traditional GISTs that we treat more commonly and the ones that are outside of the gastrointestinal tract [and] have a worse prognosis."

Dr. Pickens agreed that molecular analyses will help better define how the two groups of tumors differ. "It would be interesting to see some of the microRNA information applied to those different tumors to see if it could predict those worse outcomes," he said.

Dr. Guye and her colleagues analyzed SEER (Surveillance, Epidemiology, and End Results) data for 1996-2008 to identify their study population with GIST, choosing the start year because that is when diagnosis of this tumor became more accurate, she explained.

Patients with primaries in and outside the gastrointestinal tract had similar age and racial distribution. But patients with EGIST were more likely to receive radiation therapy, to have tumors larger than 10 cm, and to have regional or distant disease.

Median overall survival was 120 months in the group with primaries in the gastrointestinal tract, and 105 months in the group with primaries in other locations (P = .002).

Additional analyses showed that location outside the gastrointestinal tract conferred a worse prognosis, even when tumors were matched for size and stage of disease, Dr. Guye reported. And the association stood up in multivariate analysis (P = .03).

However, "the SEER database does not include information on mitotic rate or information on systemic medical therapies," she noted. "Therefore, we were not able to include these factors in our analysis."

Dr. Guye and Dr. Pickens disclosed that they had no relevant conflicts of interest.

MIAMI BEACH – Preoperative chemotherapy or radiation – take your pick or both – improves overall survival of patients with large, soft-tissue sarcomas of the extremities, retrospective studies from two cancer centers suggest.

Looking at a cohort of 112 patients, investigators at the Mayo Clinic in Scottsdale, Ariz., saw no significant differences by treatment type in local control rates or overall survival.

But among patients with tumors measuring longer than 5 cm, the 3-year overall survival rate was 63% for those who had neoadjuvant radiation and surgery and 70% for those who had chemoradiotherapy and surgery, versus 40% with surgery alone (P = .03), radiation oncologist Jonathan B. Ashman and colleagues reported at the annual meeting of the American Society for Radiation Oncology.

"We found that patients who are treated with either neoadjuvant strategy – either radiation or chemotherapy/radiation – have bigger tumors, so they’re more aggressive tumors, but the local control is the same, so we think that the neoadjuvant therapy is helping more than we would expect from surgery alone," Dr. Ashman said in an interview.

In a separate study, Johns Hopkins Hospital investigators reported excellent local control and good overall survival rates for patients with large sarcomas of the extremities that were treated with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy.

The estimated 3-year overall survival rate was 66%, the estimated disease-free survival rate 58%, and estimated the local control rate 100% among 16 patients treated with interdigitated neoadjuvant chemotherapy and radiation using the MAID protocol (mesna, doxorubicin, ifosfamide and dacarbazine), reported radiation oncologist Dr. Raju Raval and colleagues from Johns Hopkins Hospital in Baltimore.

The Mayo Experience

The Mayo investigators retrospectively looked at whether adding chemotherapy to external beam radiation therapy and limb-sparing surgery added benefit for patients with stage II or III soft-tissue sarcomas of the extremities. The center’s sarcoma team recommends either neoadjuvant radiation or chemoradiotherapy for patients who have high-grade tumors and are likely to have narrow resection margins based on preoperative MRI imaging showing large tumor size or unfavorable location of the tumor relative to bone or to neurovascular structures.

"We found that patients who are treated with either neoadjuvant strategy – either radiation or chemotherapy/ radiation – have bigger tumors."

The investigators reviewed the charts of 91 patients treated for primary disease, and 21 treated for tumor recurrence from 1998 through 2009. Median follow-up was 22.1 months. Overall, 39 of the patients received neoadjuvant chemoradiotherapy, 37 neoadjuvant radiation, and 36 surgery alone. The majority of tumors in each treatment group were pathologic grade 3 or 4, and most were 5 cm or greater in their longest dimension.

Of the 39 patients who received some form of chemotherapy, 20 had concurrent weekly cisplatin 20-40 mg/m2, with the remainder receiving other protocols, including MAID and MAP (methotrexate, doxorubicin, and cisplatin).

Dr. Ashman said that although there is no clear evidence to support the use of weekly cisplatin in sarcoma, "our practice has been over the last 5-8 years to have patients who have large and high-risk tumors but otherwise have good performance status, with good renal function and no other contraindications to receive weekly cisplatin, because it’s such a well-tolerated regimen. The rationale is that there hasn’t been really good data to show a benefit from the more toxic protocols."

Cisplatin is known to sensitize tumor cells to radiation, he noted. "When you’re looking at just radiosensitization, and you’re looking at just local outcomes and not trying to affect the distant metastasis rate, then let’s try to use a therapy that’s less toxic, so that patients don’t have to break therapy."

In all, 92 patients had surgery with limb-preservation attempt, and the majority (88%) had disease-free surgical margins (R0 resections); rates of R0 resections did not differ among the treatment groups.

The overall 3-year local control rate was 87%, distant metastasis-free survival was 69%, and overall survival was 68%. Patients who received a neoadjuvant therapy had higher rates of wound complications, which occurred in 11% of surgery-only patients, compared with 50% of patients who received chemoradiotherapy (P = .003) and 42% of those who received radiation (P = .02). There was no significant difference in wound complications between the two neoadjuvant therapy types, however, and no factors predicted these complications.

The Johns Hopkins Experience

Dr. Raval and colleagues from Johns Hopkins reported on 16 patients with high-grade soft-tissue sarcomas treated with interdigitated neoadjuvant chemotherapy and radiation, surgery, and adjuvant chemotherapy.

The therapy consists of three cycles of chemotherapy, with 44 Gy radiation divided into 22 fractions, 11 of which are delivered following the first chemotherapy cycle, and 11 following the second cycle. Surgery is performed about 80 days after the start of therapy, and an additional 11 Gy or radiation is given if an R0 resection was not achieved. If the patient can tolerate it, three additional adjuvant chemotherapy cycles are given.

Estimated 3-year overall survival was 66%, disease-free survival was 58%, and the local control rate was 100%. No local recurrences had been seen at the longest follow-up of 160 months.

The Hopkins investigators compared their results with those from a pilot study using the same protocol at Massachusetts General Hospital in Boston. The MGH investigators had an 87% 5-year overall survival rate, 70% disease-free survival rate, and 92% local-control rate. Among MGH historical controls treated with surgery only, the respective rates were 58%, 42%, and 86%.

"This combined-modality approach to high grade soft-tissue sarcoma continues to play a role in the treatment of patients with this rare soft tissue neoplasm," the investigators concluded.

Both studies were internally funded. Dr. Ashman and Dr. Raval reported that they had no relevant financial disclosures.

MIAMI BEACH – Preoperative chemotherapy or radiation – take your pick or both – improves overall survival of patients with large, soft-tissue sarcomas of the extremities, retrospective studies from two cancer centers suggest.

Looking at a cohort of 112 patients, investigators at the Mayo Clinic in Scottsdale, Ariz., saw no significant differences by treatment type in local control rates or overall survival.

But among patients with tumors measuring longer than 5 cm, the 3-year overall survival rate was 63% for those who had neoadjuvant radiation and surgery and 70% for those who had chemoradiotherapy and surgery, versus 40% with surgery alone (P = .03), radiation oncologist Jonathan B. Ashman and colleagues reported at the annual meeting of the American Society for Radiation Oncology.

"We found that patients who are treated with either neoadjuvant strategy – either radiation or chemotherapy/radiation – have bigger tumors, so they’re more aggressive tumors, but the local control is the same, so we think that the neoadjuvant therapy is helping more than we would expect from surgery alone," Dr. Ashman said in an interview.

In a separate study, Johns Hopkins Hospital investigators reported excellent local control and good overall survival rates for patients with large sarcomas of the extremities that were treated with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy.

The estimated 3-year overall survival rate was 66%, the estimated disease-free survival rate 58%, and estimated the local control rate 100% among 16 patients treated with interdigitated neoadjuvant chemotherapy and radiation using the MAID protocol (mesna, doxorubicin, ifosfamide and dacarbazine), reported radiation oncologist Dr. Raju Raval and colleagues from Johns Hopkins Hospital in Baltimore.

The Mayo Experience

The Mayo investigators retrospectively looked at whether adding chemotherapy to external beam radiation therapy and limb-sparing surgery added benefit for patients with stage II or III soft-tissue sarcomas of the extremities. The center’s sarcoma team recommends either neoadjuvant radiation or chemoradiotherapy for patients who have high-grade tumors and are likely to have narrow resection margins based on preoperative MRI imaging showing large tumor size or unfavorable location of the tumor relative to bone or to neurovascular structures.

"We found that patients who are treated with either neoadjuvant strategy – either radiation or chemotherapy/ radiation – have bigger tumors."

The investigators reviewed the charts of 91 patients treated for primary disease, and 21 treated for tumor recurrence from 1998 through 2009. Median follow-up was 22.1 months. Overall, 39 of the patients received neoadjuvant chemoradiotherapy, 37 neoadjuvant radiation, and 36 surgery alone. The majority of tumors in each treatment group were pathologic grade 3 or 4, and most were 5 cm or greater in their longest dimension.

Of the 39 patients who received some form of chemotherapy, 20 had concurrent weekly cisplatin 20-40 mg/m2, with the remainder receiving other protocols, including MAID and MAP (methotrexate, doxorubicin, and cisplatin).

Dr. Ashman said that although there is no clear evidence to support the use of weekly cisplatin in sarcoma, "our practice has been over the last 5-8 years to have patients who have large and high-risk tumors but otherwise have good performance status, with good renal function and no other contraindications to receive weekly cisplatin, because it’s such a well-tolerated regimen. The rationale is that there hasn’t been really good data to show a benefit from the more toxic protocols."

Cisplatin is known to sensitize tumor cells to radiation, he noted. "When you’re looking at just radiosensitization, and you’re looking at just local outcomes and not trying to affect the distant metastasis rate, then let’s try to use a therapy that’s less toxic, so that patients don’t have to break therapy."

In all, 92 patients had surgery with limb-preservation attempt, and the majority (88%) had disease-free surgical margins (R0 resections); rates of R0 resections did not differ among the treatment groups.

The overall 3-year local control rate was 87%, distant metastasis-free survival was 69%, and overall survival was 68%. Patients who received a neoadjuvant therapy had higher rates of wound complications, which occurred in 11% of surgery-only patients, compared with 50% of patients who received chemoradiotherapy (P = .003) and 42% of those who received radiation (P = .02). There was no significant difference in wound complications between the two neoadjuvant therapy types, however, and no factors predicted these complications.

The Johns Hopkins Experience

Dr. Raval and colleagues from Johns Hopkins reported on 16 patients with high-grade soft-tissue sarcomas treated with interdigitated neoadjuvant chemotherapy and radiation, surgery, and adjuvant chemotherapy.

The therapy consists of three cycles of chemotherapy, with 44 Gy radiation divided into 22 fractions, 11 of which are delivered following the first chemotherapy cycle, and 11 following the second cycle. Surgery is performed about 80 days after the start of therapy, and an additional 11 Gy or radiation is given if an R0 resection was not achieved. If the patient can tolerate it, three additional adjuvant chemotherapy cycles are given.

Estimated 3-year overall survival was 66%, disease-free survival was 58%, and the local control rate was 100%. No local recurrences had been seen at the longest follow-up of 160 months.

The Hopkins investigators compared their results with those from a pilot study using the same protocol at Massachusetts General Hospital in Boston. The MGH investigators had an 87% 5-year overall survival rate, 70% disease-free survival rate, and 92% local-control rate. Among MGH historical controls treated with surgery only, the respective rates were 58%, 42%, and 86%.

"This combined-modality approach to high grade soft-tissue sarcoma continues to play a role in the treatment of patients with this rare soft tissue neoplasm," the investigators concluded.

Both studies were internally funded. Dr. Ashman and Dr. Raval reported that they had no relevant financial disclosures.

MIAMI BEACH – Preoperative chemotherapy or radiation – take your pick or both – improves overall survival of patients with large, soft-tissue sarcomas of the extremities, retrospective studies from two cancer centers suggest.

Looking at a cohort of 112 patients, investigators at the Mayo Clinic in Scottsdale, Ariz., saw no significant differences by treatment type in local control rates or overall survival.

But among patients with tumors measuring longer than 5 cm, the 3-year overall survival rate was 63% for those who had neoadjuvant radiation and surgery and 70% for those who had chemoradiotherapy and surgery, versus 40% with surgery alone (P = .03), radiation oncologist Jonathan B. Ashman and colleagues reported at the annual meeting of the American Society for Radiation Oncology.

"We found that patients who are treated with either neoadjuvant strategy – either radiation or chemotherapy/radiation – have bigger tumors, so they’re more aggressive tumors, but the local control is the same, so we think that the neoadjuvant therapy is helping more than we would expect from surgery alone," Dr. Ashman said in an interview.

In a separate study, Johns Hopkins Hospital investigators reported excellent local control and good overall survival rates for patients with large sarcomas of the extremities that were treated with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy.

The estimated 3-year overall survival rate was 66%, the estimated disease-free survival rate 58%, and estimated the local control rate 100% among 16 patients treated with interdigitated neoadjuvant chemotherapy and radiation using the MAID protocol (mesna, doxorubicin, ifosfamide and dacarbazine), reported radiation oncologist Dr. Raju Raval and colleagues from Johns Hopkins Hospital in Baltimore.

The Mayo Experience

The Mayo investigators retrospectively looked at whether adding chemotherapy to external beam radiation therapy and limb-sparing surgery added benefit for patients with stage II or III soft-tissue sarcomas of the extremities. The center’s sarcoma team recommends either neoadjuvant radiation or chemoradiotherapy for patients who have high-grade tumors and are likely to have narrow resection margins based on preoperative MRI imaging showing large tumor size or unfavorable location of the tumor relative to bone or to neurovascular structures.

"We found that patients who are treated with either neoadjuvant strategy – either radiation or chemotherapy/ radiation – have bigger tumors."

The investigators reviewed the charts of 91 patients treated for primary disease, and 21 treated for tumor recurrence from 1998 through 2009. Median follow-up was 22.1 months. Overall, 39 of the patients received neoadjuvant chemoradiotherapy, 37 neoadjuvant radiation, and 36 surgery alone. The majority of tumors in each treatment group were pathologic grade 3 or 4, and most were 5 cm or greater in their longest dimension.

Of the 39 patients who received some form of chemotherapy, 20 had concurrent weekly cisplatin 20-40 mg/m2, with the remainder receiving other protocols, including MAID and MAP (methotrexate, doxorubicin, and cisplatin).

Dr. Ashman said that although there is no clear evidence to support the use of weekly cisplatin in sarcoma, "our practice has been over the last 5-8 years to have patients who have large and high-risk tumors but otherwise have good performance status, with good renal function and no other contraindications to receive weekly cisplatin, because it’s such a well-tolerated regimen. The rationale is that there hasn’t been really good data to show a benefit from the more toxic protocols."

Cisplatin is known to sensitize tumor cells to radiation, he noted. "When you’re looking at just radiosensitization, and you’re looking at just local outcomes and not trying to affect the distant metastasis rate, then let’s try to use a therapy that’s less toxic, so that patients don’t have to break therapy."

In all, 92 patients had surgery with limb-preservation attempt, and the majority (88%) had disease-free surgical margins (R0 resections); rates of R0 resections did not differ among the treatment groups.

The overall 3-year local control rate was 87%, distant metastasis-free survival was 69%, and overall survival was 68%. Patients who received a neoadjuvant therapy had higher rates of wound complications, which occurred in 11% of surgery-only patients, compared with 50% of patients who received chemoradiotherapy (P = .003) and 42% of those who received radiation (P = .02). There was no significant difference in wound complications between the two neoadjuvant therapy types, however, and no factors predicted these complications.

The Johns Hopkins Experience

Dr. Raval and colleagues from Johns Hopkins reported on 16 patients with high-grade soft-tissue sarcomas treated with interdigitated neoadjuvant chemotherapy and radiation, surgery, and adjuvant chemotherapy.

The therapy consists of three cycles of chemotherapy, with 44 Gy radiation divided into 22 fractions, 11 of which are delivered following the first chemotherapy cycle, and 11 following the second cycle. Surgery is performed about 80 days after the start of therapy, and an additional 11 Gy or radiation is given if an R0 resection was not achieved. If the patient can tolerate it, three additional adjuvant chemotherapy cycles are given.

Estimated 3-year overall survival was 66%, disease-free survival was 58%, and the local control rate was 100%. No local recurrences had been seen at the longest follow-up of 160 months.

The Hopkins investigators compared their results with those from a pilot study using the same protocol at Massachusetts General Hospital in Boston. The MGH investigators had an 87% 5-year overall survival rate, 70% disease-free survival rate, and 92% local-control rate. Among MGH historical controls treated with surgery only, the respective rates were 58%, 42%, and 86%.

"This combined-modality approach to high grade soft-tissue sarcoma continues to play a role in the treatment of patients with this rare soft tissue neoplasm," the investigators concluded.

Both studies were internally funded. Dr. Ashman and Dr. Raval reported that they had no relevant financial disclosures.