Merck known outside the United States and Canada as MSD, and ARIAD Pharmaceuticals, Inc., announced the presentation of detailed results from the phase III Succeed clinical trial. Succeed evaluated oral ridaforolimus, an investigational mTOR inhibitor, in patients with metastatic soft-tissue or bone sarcomas who previously had a favourable response to chemotherapy. In this patient population, ridaforolimus improved Progression-Free Survival (PFS) compared to placebo, the primary endpoint of the study. The complete study results were presented by Sant P Chawla, MD, director, Sarcoma Oncology Centre, Santa Monica, CA, during the 2011 American Society of Clinical Oncology (ASCO) annual meeting in Chicago.
Based on these results, Merck plans to submit a New Drug Application (NDA) for ridaforolimus to the US Food and Drug Administration (FDA) and a marketing application in the European Union this year. “These data bring us one step closer to making ridaforolimus available to patients with metastatic sarcoma who need it and reinforces our ongoing commitment to developing innovative therapies to treat cancer,” said Eric Rubin, MD, vice president of clinical oncology research at Merck.
The Succeed (Sarcoma Multi-Centre Clinical Evaluation of the Efficacy of Ridaforolimus) trial was a randomized (1:1), placebo-controlled, double-blind study of oral ridaforolimus administered at 40 mg/day (five of seven days per week) in patients with metastatic soft-tissue or bone sarcomas who previously had a favourable response to chemotherapy. Oral ridaforolimus was granted a Special Protocol Assessment (SPA) by the FDA for the Succeed trial.
Based on 552 Progression-Free Survival (PFS) events in 711 patients,(ridaforolimus(N=347), placebo (N=364))determined by an independent radiological review committee, the study achieved its primary endpoint of improvement in PFS, with a statistically significant (p=0.0001) 28 percent reduction in the risk of progression or death observed in those treated with ridaforolimus compared to placebo (hazard ratio=0.72).
Median PFS was 17.7 weeks for those treated with ridaforolimus compared to 14.6 weeks in the placebo group. Furthermore, based on the full analysis of PFS determined by investigator assessment, there was a statistically significant (p<0.0001) 31 percent reduction by ridaforolimus in the risk of progression or death compared to placebo (hazard ratio=0.69). In the investigator assessment analysis, median PFS was 22.4 weeks for those treated with ridaforolimus compared to 14.7 weeks in the placebo group.
The independent radiological committee review analysis showed that the proportion of patients alive and free from disease progression in the ridaforolimus group compared to placebo was greater after three months (70 percent versus 54 percent), and six months (34 percent versus 23 percent).
Secondary endpoints were trends in Overall Survival (OS), best target lesion response, assessment of cancer-related symptoms, and safety and tolerability. Follow-up for OS is ongoing, and the current trend favours ridaforolimus: results at the most recent data cut-off (386 OS events) showed a median OS of 21.4 months for the oral ridaforolimus group compared to 19.2 months for the placebo arm (hazard ratio=0.88, p=0.2256).
For the best target lesion response, the oral ridaforolimus group showed an average target tumour lesion size reduction of 1.3 percent; whereas the placebo group showed an average target tumour lesion size increase of 10.3 percent (p<0.0001). No conclusions could be drawn from the exploratory analysis of cancer-related symptoms based on patient questionnaires about pain, cough and shortness of breath due to incomplete questionnaire data.
The most common severe (Grade greater-than or equal to 3) adverse events occurring at an incidence greater-than or equal to 7 percent in the ridaforolimus group compared to placebo were thrombocytopenia (10 percent versus 1 percent), stomatitis (9 percent versus < 1 percent), anemia (7 percent versus 3 percent), and hyperglycaemia (7 percent versus < 1 percent). The most common side effects observed in the study were consistent with the known safety profile of ridaforolimus. The most common adverse events (all Grades) occurring at an incidence greater-than or equal to 30 percent in the ridaforolimus group compared to placebo were stomatitis (e.g. mouth sores) (61 percent versus 18 percent), infections (all sites included) (52 percent versus 26 percent), fatigue (36 percent versus 22 percent), thrombocytopenia (34 percent versus 4 percent), diarrhoea (32 percent versus 18 percent) and cough (31 percent versus 16 percent). For adverse events that led to death, there were 6 deaths (1.8 percent) due to pulmonary disorders in the ridaforolimus treatment group and no deaths (0 percent) due to pulmonary disorders in the placebo group.
“Patients with metastatic soft-tissue and bone sarcomas have limited treatment options available to them. Data from the Succeed trial show that ridaforolimus maintained the benefit of prior conventional chemotherapy,” said Dr Chawla. “The study met the primary endpoint of PFS, showing a clinically meaningful and statistically significant improvement in PFS in those patients treated with oral ridaforolimus.”
“These updated data illustrate how challenging metastatic sarcomas can be, even in patients who have responded favourably to chemotherapy,” said Harvey J Berger, MD, chairman and chief executive officer of ARIAD. “We are pleased with the results of the Succeed trial and look forward to Merck filing for marketing approval of ridaforolimus.”
As part of an exclusive license agreement with ARIAD, Merck is responsible for the development and worldwide commercialization of ridaforolimus in oncology.
Sarcomas are a group of cancers of connective tissue of the body for which there are currently limited treatment options. Sarcomas can arise anywhere in the body and are divided into two main groups - bone tumours and soft-tissue sarcomas.
Ridaforolimus is an investigational targeted and potent small-molecule inhibitor of the protein mTOR, a protein that acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival, integrating signals from proteins, such as PI3K, AKT and PTEN known to be important to malignancy.
Merck is known as MSD outside the United States and Canada and through its prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, deliver innovative health solutions.
ARIAD's vision is to transform the lives of cancer patients with breakthrough medicines. The company's mission is to discover, develop and commercialize small-molecule drugs to treat cancer in patients with the greatest and most urgent unmet medical need - aggressive cancers where current therapies are inadequate.