Ridaforolimus offers moderate maintenance benefit in advanced sarcoma

The investigational agent ridaforolimus reduced the risk for progression and death by 28% in previously treated patients with advanced sarcoma in a large phase III study.

Results of the SUCCEED (Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus) study showed that there was a small, but significant median progression-free survival (PFS) gain of 3.3 weeks vs. placebo (17.7 vs. 14.6 weeks, hazard ratio, 0.72; P less than .001) by independent review.

"The absolute magnitude of this statistically significant improvement in disease control was small because of the more rapid than expected progression in all patients in this study," said Dr. George D. Demetri of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, and his associates (J. Clin. Oncol. 2013;31:2485-92).

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy."

"To our knowledge, this is the first study demonstrating a statistically significant, although clinically small, impact on maintenance treatment on tumor progression in patients with sarcomas," the researchers said. "Future studies will build on these results in an effort to improve the outcomes of this rapidly progressive life-threatening disease."

The study was designed with the premise that the median time to progression would be around 6-9 months in the control arm. In fact, it was less than 4 months, and there was a 6-month PFS rate of 23% and average tumor growth of 10% in target lesions.

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy," the researchers said.

The SUCCEED trial was an international, randomized, double blind, placebo-controlled trial of 711 patients with advanced soft tissue or bone sarcomas who had achieved stable disease or a continued partial or complete response to immediately preceding cytotoxic chemotherapy Patients were randomized to receive either the mammalian target of rapamycin inhibitor ridaforolimus (n = 347), given at a dose of four 10 mg tablets/day for 5 days every week, or matching placebo tablets (n = 364).

Baseline patient characteristics were similar between the two study groups. The mean age of patients was 52 years in the ridaforolimus arm and 50 years in the placebo arm. The majority (89.3%) of patients had soft tissue sarcomas, with the remainder having bone sarcomas. Almost 75% of tumors were high grade, 66.6% of patients had metastatic disease involving the lung, 14.4% involving the liver, and 11.5% involving the bone. Around 40% of patients had received two or more prior cytotoxic chemotherapy regimens, and the best response to treatment had been stable disease in 74.4%, a partial response in 18.4%, and a complete response in 5.5%.

Investigator-assessed PFS showed slightly better median survival rates of 22.4 vs. 14.7 weeks (HR, 0.69; P less than .001). There was mean decrease in target lesion size of 1.3% in the ridaforolimus arm vs. a 10.3% increase in size in the placebo arm (P less than .001).

No overall survival benefit was observed in the trial. Based on 478 death events and a minimum of 2 years’ follow-up, median overall survival was 90.6 weeks vs. 85.3 weeks (HR, 0.93; P = .46). Dr. Demetri and his coworkers point out, however, that the study was not powered to determine an overall survival benefit.

Adverse effects of any grade occurred in 100% of ridaforolimus-treated and 93.6% of placebo-treated patients. Adverse effects of note that occurred to a greater extent in the active treatment arm included stomatitis, thrombocytopenia, infections, rash, hypertriglyceridemia, and anemia. Grade 3 or higher adverse events occurred in 64.1% of patients treated with ridaforolimus and 25.6% of those in the placebo arm.

This was an unselected patient population but no potential biomarkers or predictors for response have been identified. As ridaforolimus improved, the best target lesion response and the clinical benefit rate, it might contribute to tumor growth control, the researchers speculated. They therefore suggested that it might be better suited as an element of combination treatment with other tumor-signaling inhibitors.

The SUCCEED study was funded by Merck, Sharp, and Dohme. Dr. Demetri has received consultancy fees and research funding from Merck and ARIAD Pharmaceuticals. Several of his coauthors had also received honoraria from Merck or were employees of the company.

The investigational agent ridaforolimus reduced the risk for progression and death by 28% in previously treated patients with advanced sarcoma in a large phase III study.

Results of the SUCCEED (Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus) study showed that there was a small, but significant median progression-free survival (PFS) gain of 3.3 weeks vs. placebo (17.7 vs. 14.6 weeks, hazard ratio, 0.72; P less than .001) by independent review.

"The absolute magnitude of this statistically significant improvement in disease control was small because of the more rapid than expected progression in all patients in this study," said Dr. George D. Demetri of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, and his associates (J. Clin. Oncol. 2013;31:2485-92).

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy."

"To our knowledge, this is the first study demonstrating a statistically significant, although clinically small, impact on maintenance treatment on tumor progression in patients with sarcomas," the researchers said. "Future studies will build on these results in an effort to improve the outcomes of this rapidly progressive life-threatening disease."

The study was designed with the premise that the median time to progression would be around 6-9 months in the control arm. In fact, it was less than 4 months, and there was a 6-month PFS rate of 23% and average tumor growth of 10% in target lesions.

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy," the researchers said.

The SUCCEED trial was an international, randomized, double blind, placebo-controlled trial of 711 patients with advanced soft tissue or bone sarcomas who had achieved stable disease or a continued partial or complete response to immediately preceding cytotoxic chemotherapy Patients were randomized to receive either the mammalian target of rapamycin inhibitor ridaforolimus (n = 347), given at a dose of four 10 mg tablets/day for 5 days every week, or matching placebo tablets (n = 364).

Baseline patient characteristics were similar between the two study groups. The mean age of patients was 52 years in the ridaforolimus arm and 50 years in the placebo arm. The majority (89.3%) of patients had soft tissue sarcomas, with the remainder having bone sarcomas. Almost 75% of tumors were high grade, 66.6% of patients had metastatic disease involving the lung, 14.4% involving the liver, and 11.5% involving the bone. Around 40% of patients had received two or more prior cytotoxic chemotherapy regimens, and the best response to treatment had been stable disease in 74.4%, a partial response in 18.4%, and a complete response in 5.5%.

Investigator-assessed PFS showed slightly better median survival rates of 22.4 vs. 14.7 weeks (HR, 0.69; P less than .001). There was mean decrease in target lesion size of 1.3% in the ridaforolimus arm vs. a 10.3% increase in size in the placebo arm (P less than .001).

No overall survival benefit was observed in the trial. Based on 478 death events and a minimum of 2 years’ follow-up, median overall survival was 90.6 weeks vs. 85.3 weeks (HR, 0.93; P = .46). Dr. Demetri and his coworkers point out, however, that the study was not powered to determine an overall survival benefit.

Adverse effects of any grade occurred in 100% of ridaforolimus-treated and 93.6% of placebo-treated patients. Adverse effects of note that occurred to a greater extent in the active treatment arm included stomatitis, thrombocytopenia, infections, rash, hypertriglyceridemia, and anemia. Grade 3 or higher adverse events occurred in 64.1% of patients treated with ridaforolimus and 25.6% of those in the placebo arm.

This was an unselected patient population but no potential biomarkers or predictors for response have been identified. As ridaforolimus improved, the best target lesion response and the clinical benefit rate, it might contribute to tumor growth control, the researchers speculated. They therefore suggested that it might be better suited as an element of combination treatment with other tumor-signaling inhibitors.

The SUCCEED study was funded by Merck, Sharp, and Dohme. Dr. Demetri has received consultancy fees and research funding from Merck and ARIAD Pharmaceuticals. Several of his coauthors had also received honoraria from Merck or were employees of the company.

The investigational agent ridaforolimus reduced the risk for progression and death by 28% in previously treated patients with advanced sarcoma in a large phase III study.

Results of the SUCCEED (Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus) study showed that there was a small, but significant median progression-free survival (PFS) gain of 3.3 weeks vs. placebo (17.7 vs. 14.6 weeks, hazard ratio, 0.72; P less than .001) by independent review.

"The absolute magnitude of this statistically significant improvement in disease control was small because of the more rapid than expected progression in all patients in this study," said Dr. George D. Demetri of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, and his associates (J. Clin. Oncol. 2013;31:2485-92).

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy."

"To our knowledge, this is the first study demonstrating a statistically significant, although clinically small, impact on maintenance treatment on tumor progression in patients with sarcomas," the researchers said. "Future studies will build on these results in an effort to improve the outcomes of this rapidly progressive life-threatening disease."

The study was designed with the premise that the median time to progression would be around 6-9 months in the control arm. In fact, it was less than 4 months, and there was a 6-month PFS rate of 23% and average tumor growth of 10% in target lesions.

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy," the researchers said.

The SUCCEED trial was an international, randomized, double blind, placebo-controlled trial of 711 patients with advanced soft tissue or bone sarcomas who had achieved stable disease or a continued partial or complete response to immediately preceding cytotoxic chemotherapy Patients were randomized to receive either the mammalian target of rapamycin inhibitor ridaforolimus (n = 347), given at a dose of four 10 mg tablets/day for 5 days every week, or matching placebo tablets (n = 364).

Baseline patient characteristics were similar between the two study groups. The mean age of patients was 52 years in the ridaforolimus arm and 50 years in the placebo arm. The majority (89.3%) of patients had soft tissue sarcomas, with the remainder having bone sarcomas. Almost 75% of tumors were high grade, 66.6% of patients had metastatic disease involving the lung, 14.4% involving the liver, and 11.5% involving the bone. Around 40% of patients had received two or more prior cytotoxic chemotherapy regimens, and the best response to treatment had been stable disease in 74.4%, a partial response in 18.4%, and a complete response in 5.5%.

Investigator-assessed PFS showed slightly better median survival rates of 22.4 vs. 14.7 weeks (HR, 0.69; P less than .001). There was mean decrease in target lesion size of 1.3% in the ridaforolimus arm vs. a 10.3% increase in size in the placebo arm (P less than .001).

No overall survival benefit was observed in the trial. Based on 478 death events and a minimum of 2 years’ follow-up, median overall survival was 90.6 weeks vs. 85.3 weeks (HR, 0.93; P = .46). Dr. Demetri and his coworkers point out, however, that the study was not powered to determine an overall survival benefit.

Adverse effects of any grade occurred in 100% of ridaforolimus-treated and 93.6% of placebo-treated patients. Adverse effects of note that occurred to a greater extent in the active treatment arm included stomatitis, thrombocytopenia, infections, rash, hypertriglyceridemia, and anemia. Grade 3 or higher adverse events occurred in 64.1% of patients treated with ridaforolimus and 25.6% of those in the placebo arm.

This was an unselected patient population but no potential biomarkers or predictors for response have been identified. As ridaforolimus improved, the best target lesion response and the clinical benefit rate, it might contribute to tumor growth control, the researchers speculated. They therefore suggested that it might be better suited as an element of combination treatment with other tumor-signaling inhibitors.

The SUCCEED study was funded by Merck, Sharp, and Dohme. Dr. Demetri has received consultancy fees and research funding from Merck and ARIAD Pharmaceuticals. Several of his coauthors had also received honoraria from Merck or were employees of the company.