Date: 2015-04-09
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in the Annals of Oncology
Company: AB Science (France)
Product: masitinib
Action
mechanism: Masitinib is a new orally administered tyrosine kinase inhibitor that targets mast cells, important cells for immunity, as well as a limited number of kinases that play key roles in various cancers. Owing to its novel mechanism of action, masitinib can be developed in a large number of conditions in oncology, in inflammatory diseases, and in certain diseases of the central nervous system. Through its activity of inhibiting certain kinases that are essential in some oncogenic processes, masitinib may have an effect on tumor regression, alone or in combination with chemotherapy. Through its activity on the mast cell and certain kinases essential to the activation of the inflammatory cells and fibrosing tissue remodeling, masitinib can have an effect on the symptoms associated with some inflammatory and central nervous system diseases.
Disease: pancreatic cancer
Therapeutic area: Cancer - Oncology
Country:
Trial
details: In this prospective, international, randomized, double-blinded clinical trial, 348 patients received either masitinib in combination with Gemzar®, or placebo in combination with Gemzar®. A planned ancillary pharmacogenomic study, based on RNA extracted from whole blood samples before treatment start, was also conducted to identify genetic expression patterns predictive for overall survival and/or treatment benefit.
Latest
news: * On April 9, 2015, AB Science announced the publication of results from the first randomized phase 3 study of masitinib in treatment of advanced pancreatic ductal adenocarcinoma (PDAC). Entitled, ‘A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer’ this article has been published in the peer-reviewed journal Annals of Oncology. A phase 3 confirmatory study is currently ongoing. * On October 30, 2012, AB Science announced the results from a phase 3 study evaluating the effect of masitinib in combination with Gemzar® (gemcitabine, Eli Lilly) on overall survival (OS) in patients with pancreatic cancer. Masitinib in combination with Gemzar® significantly extended median OS by 6 and 2.7 months in two independent patient populations, representing 65% and 45% of the overall population; namely, patients with a genetic biomarker - collected from simple blood sample - indicative of aggressive disease progression, and patients with cancer pain. Pain intensity and the discovered genetic biomarker were shown to be of prognostic value for survival under Gemzar® alone and at the same time predictive of increased survival with masitinib in combination with Gemzar® for those patients identified as having a poor prognosis with Gemzar® alone.
• Findings revealed that the markers of acyl-CoA oxidase-1 (ACOX1) expression in blood and baseline pain intensity may have prognostic value, with patients from these subgroups experiencing aggressive disease progression while receiving Gemzar® (gemcitabine, from Eli Lilly and Company).
• In patients with over-expression of ACOX1 in blood, administration of masitinib in combination with Gemzar® produced a statistically significant overall survival advantage of +6.1 months (Hazard Ratio=0.23[0.10;0.51]) when compared with placebo administered in combination with Gemzar®.
• In the pain subgroup, administration of masitinib in combination with Gemzar® produced a statistically significant overall survival advantage of +2.6 months (Hazard Ratio=0.62[0.43;0.89]) when compared with placebo administered in combination with Gemzar®.
• Safety of the combination remained acceptable with no overall detrimental effect on quality of life.
• A new confirmatory phase 3 trial of masitinib in advanced pancreatic cancer has been initiated, with an objective to replicate these promising results in a prospective manner.
Reported in this article are results of a phase 3 study conducted by Professor Gaël Deplanque (Saint Joseph Hospital, Paris, France) and colleagues from 73 active centers located predominantly in France, United States and Czech Republic. In this study, 353 patients with inoperable, chemotherapy-naïve, PDAC received gemcitabine in combination with either masitinib or placebo until progression. The primary endpoint was overall survival (OS).
Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of whether masitinib generated therapeutic benefit in these subgroups.
While median OS was similar between treatment-arms for the overall population, secondary analyses identified two subgroups having significantly poor survival when receiving single-agent gemcitabine. One subgroup was defined by an over-expression of acyl-CoA oxidase-1 (ACOX1) in blood, and the other subgroup was defined by patients exceeding a pain intensity threshold assessed via a visual analog scale (VAS) at baseline. These subgroups represent a critical unmet medical need as evidenced from a shorter median OS of approximately 5.5 months, and comprise an estimated 63% of PDAC patients.
In these subgroups, a significant treatment effect was observed for masitinib with median OS of 11.7 months in the ‘ACOX1’ subgroup (HR=0.23[0.10;0.51],P=0.001), and 8.0 months in the ‘pain’ subgroup (HR=0.62[0.43;0.89],P=0.012). Despite increased toxicity of the combination compared with single-agent gemcitabine, side-effects remained manageable.
AB Science also announced that the European Medicines Agency (EMA) has accepted to review a Marketing Authorization Application (MAA) for conditional approval of masitinib in combination with Gemzar® in the treatment of pancreatic cancer, following filing of this dossier.
Full data has been submitted for presentation at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium (24-26 January 2013, in San Francisco, California).
Filing for the conditional approval of masitinib in combination with Gemzar® in the treatment of non resectable, advanced adenocarcinoma pancreatic cancer was accepted by EMA on the basis of results from a phase 3 study that showed masitinib in combination with Gemzar® significantly extends overall survival in two independent patient populations having the worst prognosis. These populations consisted of patients with a gene expression profile (or genetic biomarker) indicative of aggressive disease progression (65% of pancreatic cancer patients), and patients with cancer pain (45% of pancreatic cancer patients).
AB Science made two important discoveries based on data from these studies.
• First, pancreatic cancer patients characterized by the discovered genetic biomarker (approximately 65% of all patients) reported very poor survival when receiving placebo plus Gemzar®, with a median OS of 5 months. However, this same genetic biomarker was highly predictive of significantly extended survival in patients receiving masitinib in combination with Gemzar®, with a median OS increased by 6.0 months to 11.0 months, corresponding to a hazard ratio of 0.29 (p=0.000038). OS rates at 12 and 18 months were respectively, 41.4% and 18.5% in the masitinib plus Gemzar® treatment arm versus 11.1% and 4.2% in the placebo plus Gemzar® arm.
• Second, patients presenting with a certain threshold of pain intensity at the time of study entry (approximately 45% of all patients) were revealed to have a very poor prognosis when receiving placebo plus Gemzar®, with a median OS of 5.4 months. In these patients, the combination therapy of masitinib plus Gemzar® showed a statistically significant extended survival, with median OS increased by 2.7 months to 8.1 months, corresponding to a hazard ratio of 0.61 (p=0.010). OS rates at 12 and 18 months were respectively, 32.2% and 18.2% in the masitinib plus Gemzar® treatment arm versus 17.8% and 7.8% in the placebo plus Gemzar® arm.
Besides being predictive for masitinib plus Gemzar® treatment efficacy, these two factors were also of prognostic value for overall survival in patients treated with Gemzar® as a single agent. Regarding the genetic biomarker, patients harboring this ‘aggressive genetic fingerprint’ had a median OS of 5.0 months whilst patients without this fingerprint had a median OS of 14.3 months. Regarding the prognostic factor of ‘pain intensity’, patients exceeding a certain threshold of pain at baseline had a median OS of 5.4 months versus 15.4 months in patients without pain.
Results in the overall study population did not show a significant advantage for masitinib in combination with Gemzar® as compared with Gemzar® treatment alone. Median OS was 7.7 months in the masitinib plus Gemzar® treatment arm versus 7.0 months in the placebo plus Gemzar® treatment arm (p=0.74; hazard ratio=0.90). This finding of a non significant survival improvement in the overall population is explained by the fact that masitinib is not indicated when Gemzar® is highly efficient; namely, the situation defined by an absence of both pain and genetic biomarker detecting “aggressiveness”.
Masitinib received orphan drug designation in the treatment of pancreatic cancer from both FDA and EMA.
