Masitinib is an oral inhibitor of both the KIT and PDGFRA receptors. It may have greater activity than imatinib against wild-type GIST and juxta-membrane KIT mutations in exon 11.
Manufaturer: Masitinib is under development by AB Science. For information at the manufacturer’s website see http://www.ab-science.com/ Masitinib has been approved in Europe for use in dogs for mast cell tumors, as shown on the website http://www.masivet.com
NCI drug dictionary definition: The orally bioavailable mesylate salt of masatinib, a multi-targeted protein tyrosine kinase inhibitor with potential antineoplastic activity. Masitinib selectively binds to and inhibits both the wild-type and mutated forms of the stem cell factor receptor (c-Kit; SCFR); platelet-derived growth factor receptor (PDGFR); fibroblast growth factor receptor 3 (FGFR3); and, to a lesser extent, focal adhesion kinase (FAK). As a consequence, tumor cell proliferation may be inhibited in cancer cell types that overexpress these receptor tyrosine kinases (RTKs).
Phase II Results on GIST as first-line treatment
A Phase II trial of first-line masitinib on inoperable patients never treated with imatinib has been published as follows (link for abstract)
Le Cesne A, Blay JY, Bui BN, Bouché O, Adenis A, Domont J, Cioffi A, Ray-Coquard I, Lassau N, Bonvalot S, Moussy A, Kinet JP, Hermine O.
Phase II study of oral masitinib mesilate in imatinib-naïve patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST).
Eur J Cancer. 2010 Mar 6. [Epub ahead of print] PubMed PMID: 20211560
This is a small study with only 30 subjects accrued in 2005-2007 in France. Two of the 30 subjects were later discovered to have been misdiagnosed (they did not have GIST) but continued on the trial. Four patients dropped out before 4 months of treatment. Analyses included all these subjects. Regarding the mutation status of the subjects, LeCesne et al stated “Sufficient biopsy material was available to perform mutational analysis for 15/30 patients (50%): 10/30 patients (33.3%) had a GIST harbouring a c-kit exon 11 mutation, 1/30 patient (3.3%) had double c-kit exon 11 and 13 mutations, 3/30 patients (10%) had a WT c-Kit, and 1/30 patient (3.3%) had a GIST harbouring the PDGFRA mutation (D842V).” Mutation status for the other GIST subjects is unknkown. No exon 9 mutation subjects were identified.
Masitinib is taken orally in two doses per day, with the dose for an individual based on body weight (7.5 mg per kilogram of patient weight).
By RECIST definition the best response was: 3.3% complete response (CR), 50% partial response (PR), 43.3% stable disease (SD), and 3.3% progressive disease. The overall response rate (CR + PR) was 16/30 (53.3%) patients with a disease control rate (CR + PR + SD) of 29/30 (96.7%) patients. The median time to first objective response was 5.6 months (range: 0.8–23.8 months). Progression-free survival was 89% at 6 months, 77% at one year, 64% at 18 months, 60% at 2 years, and 55% at three years. You can also see some earlier preliminary data on this trial in a 2009 presentation at ASCO (see link below) and some later data described next.
Adverse effects were more common during the early months of treatment and decreased over time. Le Cesne et al reported “The most frequent treatment-related toxicities per patient were: asthenia (83%), diarrhoea (57%), eye oedema (47%), nausea (47%), muscle spasms (40%), cutaneous rash (40%), abdominal pain (33%), pruritus (33%), vomiting (23%), upper abdominal pain (23%) and peripheral oedema (20%). Treatment-related oedemas (all types) were experienced by 21/30 patients (70%).”
Additional followup data:
An update for the Phase II masitinib trial was reported in a poster at the 2011 GI Cancers Symposium (link on title below to read the abstract):
Overall survival benefit with masitinib mesylate in imatinib-naive, locally advanced, or metastatic gastrointestinal stromal tumor (GIST): 4-years follow-up of the French Sarcoma Group phase II trial.
Blay et al, J Clin Oncol 29: 2011 (suppl 4; abstr 85)
The abstract states “At the cut-off date (31 August 2010), 9 patients are still under treatment with a median treatment duration of 41 months (min=33, max=52). Two additional progressions have been reported for a total of 14 events (13 progressions and 1 death). Updated median PFS is 41 months (95% CI: [17.5; NR]) with PFS rates of 60% [39; 77], 56% [35; 73] and 45% [24; 64] respectively at 2, 3 and 4 years. With 8 patients dead, median OS is not yet reached with OS rates of 90% [72; 97], 87% [68; 95] and 74% [52; 87], respectively, at 2, 3, and 4 years.”
For comparison, the MetaGIST analysis of two large imatinib Phase III trials indicated 30-34% progression-free survival (PFS) at 3 years (less than the 56% reported in this small trial of masitinib), and the median PFS duration for imatinib was 19-23 months (reference Gleevec prescribing information). Therefore, the duration of response to masitinib looks good in this trial, but these results may be skewed by the unknown mutation status of half of the subjects. The Phase III trial (see below) will have a larger subject base and will provide a direct comparison to imatinib.
Current Phase III Trial Recruiting
A new Phase III trial comparing masitinib to imatinib opened in December 2008. Link to the trial description at NCT00812240. The following GIST patients are eligible:
- Histologically proven, metastatic or locally advanced non resectable, or recurrent post surgery GIST
- Naïve patient or patient previously treated with imatinib as neoadjuvant/adjuvant who relapsed after imatinib discontinuation.
Previous results using this drug against GIST have been reported as shown below:
Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Castéran N, Borge L, Hajem B, Lermet A, Sippl W, Voisset E, Arock M, Auclair C, Leventhal PS, Mansfield CD, Moussy A, Hermine O.
Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.
PLoS One. 2009 Sep 30;4(9):e7258.
PubMed PMID: 19789626; PubMed Central PMCID: PMC2746281 free access!
Masitinib mesylate in imatinib-naive locally advanced or metastatic gastrointestinal stromal tumor (GIST): Results of the French Sarcoma Group phase II trial. Presentation at the 2009 ASCO meeting, Abstract No: 10507. Author(s): A. Le Cesne, J. Blay, N. B. Bui, O. Bouché, A. Adenis, J. Domont, A. Cioffi, A. Moussy, O. Hermine.
Bui BN, Blay J, Duffaud F, Hermine O, Le Cesne A.
Preliminary efficacy and safety results of Masitinib administered, front line in patients with advanced GIST.
A phase II study.
Journal of Clinical Oncology. 2007; 25: No.18S:10025 (abstract).
Second-line trial in imatinib-resistant patients
In early February 2012 AB Science issued a press release asserting that a Phase II trial underway in France (NCT01506336) will demonstrate superiority of masitinib to sunitinib as second-line therapy for imatinib-resistant patients. The press release did not include supporting details but indicated that the study would be reported at the June 2012 ASCO meeting. Patients are cautioned that the press release seems premature without the full details of the trial results. If full details are presented at ASCO then it should be possible to draw firmer conclusions then.
In response to a request from SPAEN (Sarcoma Patient Euro-Net) the French expert committee (Dr. Axel Le Cesne, Prof. Dr. Jean-Yves Blay and Prof. Dr. Antoine Adenis) made this statement:
“For reasons beyond our control, a press release announcing the superiority of one therapeutic arm compared to the other was published 48 hours ago. This press release should not be considered, at any point, as a scientific statement, and the conclusions reported in this document should be interpreted with caution. This trial consisted in of a small phase II study (44 patients) comparing the administration in a metastatic setting of Masitinib versus Sunitinib – which is the current standard treatment in patients resistant/refractory to Imatinib. The reported overall survival results can potentially be explained by the fact that a majority of the patients who developed secondary resistance to Masitinib successively received Sunitinib, whereas on progression on the Sunitinib arm, cross-over was not provided or performed.”