Date: 2012-06-05
Type of information:
phase: 2
Announcement: results
Company: AB Science (France)
Product: masitinib
Action
mechanism: Masitinib is a 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.
Disease: Gleevec®-resistant gastrointestinal stromal tumors (GIST)
Therapeutic area: Cancer Oncology
Country: France
Trial details: Patients with inoperable, locally advanced or metastatic GIST and showing disease progression while treated with imatinib 400 mg/day received either masitinib or sunitinib until progression. Primary endpoint was PFS evaluated with RECIST with OS as a secondary endpoint. Based upon an 80% power to detect with a Fleming design a median PFS ?3 months (alpha 10%, unilateral), a population of 44 patients (22 per arm) was required. Stratification was applied based on mutation status.
Latest
news: * On June 5, 2012, AB Science has announced that this trial studied efficacy and safety of masitinib at 12 mg/kg/day and sunitinib at 50 mg/day for the treatment of imatinib-resistant GIST. 44 patients (exon 11 [66%], exon 9 [11%], wild-type or other [5%], not done at baseline [18%]) were randomized into masitinib (n=23) or sunitinib (n=21) treatment-arms from 9 centers between 02/2009 and 09/2011. After a median follow-up of 14 months, median PFS was 3.9 months (95%CI [2.6;8.1]) for masitinib vs 3.8 months [1.9;11] for sunitinib. Of those patients progressing under masitinib, 88% received sunitinib in third line. AB Science has also announced that data from the development program of masitinib in gastrointestinal stromal tumors (GIST) have been presented as part of three presentations delivered at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, 1-5 June in Chicago, Illinois. These presentations were as follows: I. Masitinib in second-line treatment of advanced GIST
Median OS was not reached (NR) (95%CI [21;NR]) for masitinib vs 15 months [9.4;22] for sunitinib. The 18-month and 24-month OS rates for masitinib vs sunitinib were 79% (95%CI [53;92]) vs 20% [1.5;55], and 53% (95%CI [9.5;84]) vs 0%, respectively. Similar results were seen in the exon 11 subpopulation with median OS for masitinib NR (95%CI [NR;NR]) vs 15 months [9.6;22] for sunitinib.
The safety profile of masitinib was better than sunitinib with a lower occurrence of severe related adverse events (AEs) (17% vs 52%) and related AEs leading to discontinuation (0% vs 9.5%). In masitinib treated patients, nausea, diarrhea and asthenia were the most common related AEs.
Although PFS curves looked similar, this study apparently showed a longer survival in the masitinib treatment-arm with a better safety profile than sunitinib. Masitinib may potentially offer patients a new active compound for advanced GIST in the second-line setting.
I. Oral presentation “Masitinib mesylate in imatinib-resistant advanced GIST: A randomized phase II trial” (Abstract #10007, Sarcoma Oral Abstract Session) was delivered by Professor Adenis on June 4th)
II. Poster presentation “Masitinib in imatinib-naive advanced gastrointestinal stromal tumor (GIST): Five-year follow-up of the French Sarcoma Group phase II trial” (Abstract #10089, Sarcoma General Poster Session), was delivered by Dr Le Cesne on June 3rd)
III. Poster presentation “Masitinib in comparison to imatinib as first line therapy of patients with advanced gastrointestinal stromal tumor (GIST): A randomized phase III trial” (Abstract # TPS10102, Sarcoma General Poster Session, Trials in progress), was delivered by Professor Adenis on June 3rd)
The oral presentation “Masitinib mesylate in imatinib-resistant advanced GIST: A randomized phase II trial“, delivered by Professor Antoine Adenis (Centre Oscar Lambret, Lille, France), reported encouraging data from a phase II study of masitinib in Gleevec®-resistant gastrointestinal stromal tumors (GIST).
Masitinib significantly improved overall survival in patients with Gleevec®-resistant GIST as compared to Sutent® (sunitinib), which is currently the standard of care for second-line treatment of GIST. In this study, 44 patients with inoperable, locally advanced or metastatic GIST and showing disease progression while treated with Gleevec® (imatinib) (400 to 800 mg/day) received either masitinib (23 patients) at 12 mg/kg/day or sunitinib (21 patients) until progression.
After a median follow-up of 17 months, the updated median overall survival was not reached for masitinib versus 16 months for sunitinib (Hazard Ratio: 0.27 [0.09; 0.78]). This is an improvement from the previous data disclosed after a median follow-up of 14 month, at which time the Hazard Ratio was: 0.32 [0.11; 0.91].
After 18 months, 82% [59%; 93%] of patients treated with masitinib were still alive, versus 33% [8%; 62%] for patients treated with sunitinib.
Masitinib was well tolerated, with 17% of patients reporting non-hematological grade 3 related adverse events, as compared with 62% of patients in the sunitinib treatment-arm. No patients receiving masitinib reported any related serious adverse events compared with 19% of patients in the sunitinib treatment-arm. A phase III study has been initiated in this indication on the basis of these results, with recruitment of the first patient announced on 15th May 2012.
II. Masitinib as first-line treatment of advanced GIST
Two other presentations were also delivered, one reporting on the 5-year follow-up data from a phase II clinical study of masitinib in the first-line treatment of locally advanced or metastatic GIST, and a related presentation describing the ongoing phase III study for this indication.
The poster communication “Masitinib in imatinib-naive advanced gastrointestinal stromal tumor (GIST): Five-year follow-up of the French Sarcoma Group phase II trial”, delivered by Dr Axel Le Cesne (Institut Gustave Roussy, Villejuif, France), reported on the latest data from a multicenter, open label, phase II study, evaluating efficacy and safety of masitinib as a first-line treatment of advanced GIST.
With a median follow-up of 72 months, the updated overall survival data for the KIT exon 11 mutation subpopulation (N=10) had not yet been reached (NR [64 months; NA]), whilst the median progression free survival was 45 months [20; NA]. These data compare favorably to historical imatinib data of 60 months and 27 months, respectively. Results for the overall study population (N=30) were equally encouraging, with updated median overall survival and progression free survival at 65 months [53; NA] and 41 months [18; 51], respectively. These data compare favorably to historical imatinib data of 55 months and 18 months, respectively.
III. About the phase III study in Gleevec®-naïve GIST (first-line) - trial in progress
The poster communication “Masitinib in comparison to imatinib as first line therapy of patients with advanced gastrointestinal stromal tumor (GIST): A randomized phase III trial”, delivered by Professor Antoine Adenis (Centre Oscar Lambret, Lille, France), reported on the progress and characteristics of this phase III study. On May 11th 2012, an Independent Data Monitoring Committee gave its positive opinion to continue this study.
This prospective, multicenter, randomized, open-label, active-controlled, 2-parallel group, phase III study compares efficacy and safety of masitinib (7.5 mg/kg/day) to the active control of imatinib (400 or 600 mg/day) in first-line treatment of patients with advanced GIST. This study will recruit around 200 patients from sites around the world, randomized with a 1:1 ratio between masitinib and imatinib. The primary endpoint is progression free survival, defined as the delay between the date of randomization to the date of documented progression or any cause of death during the study. Overall survival will be the main secondary endpoint.
* On January 2012, AB Science has announced encouraging results from a phase 2 study with its investigational drug, masitinib, in Gleevec®-resistant gastrointestinal stromal tumors (GIST). Masitinib significantly improved overall survival in patients with Gleevec®-resistant gastrointestinal stromal tumors (GIST) as compared to Sutent® (sunitinib) from Pfizer, a drug approved for second-line treatment of GIST, currently the standard of care for these patients. In this study, 44 patients with inoperable, locally advanced or metastatic GIST and showing disease progression while treated with Gleevec® (imatinib) (400 to 800 mg/day) received either masitinib (23 patients) at 12 mg/kg/day or Sutent® (21 patients) until progression. After a median follow-up of 14 months, median overall survival was not reached for masitinib versus 15 months for Sutent® (p=0.022 HR:3.2). After 18 months, 79% of patients treated with masitinib were still alive, versus 20% for patients treated with Sutent®. After 2 years, 53% of patients treated with masitinib were still alive, versus 0% for the patients treated with Sutent®.
The study also demonstrated that masitinib was significantly better tolerated than Sutent®. The safety profile of masitinib was better than that of sunitinib, with a significantly longer Safety Event Free Survival (p=0.002), and a lower occurrence of severe adverse events. In masitinib treated patients, nausea, diarrhea and asthenia were the most common related adverse events.
Full data has been submitted for publication to the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting.
