In the population with unresectable locally advanced tumors with pain, the masitinib treatment-arm showed a significant improvement in overall survival (OS) relative to the control arm. The between group difference in median OS was 1.8 months (p=0.007) in favor of masitinib (13.0 months in masitinib arm versus 11.2 months in control group), with a 0.46 hazard ratio (HR) of death, which represents a reduction in risk of death of 54% for masitinib-treated patients relative to control. Results on the primary endpoint were consistent with secondary analysis in progression free survival (PFS), which measures the time to tumor progression or death (whichever occurs first) from the start of treatment. The between group difference in median PFS was 1.8 months (p=0.039) in favor of masitinib (7.4 months in masitinib arm versus 5.6 months in control group), with a 0.47 hazard ratio representing a reduction in risk of having a progression or death of 53%.

Masitinib also reduced pain relative to the control arm in patients with unresectable locally advanced tumors, as demonstrated by a between group difference that reached statistical significance or approached significance at each timepoint. In pancreatic cancer, there is evidence that pain is a clinical predictor of poor prognosis [1]. Study AB12005 demonstrated that mast cells are associated with pain and that blocking mast cells, as masitinib does, is able to reverse the poor prognosis of patients with unresectable locally advanced tumors with pain.

• 96.3% of patients had at least one adverse event in masitinib arm versus 99.3% in the control arm
• 18.7% of patients had one fatal adverse event in masitinib arm versus 19.1% in the control arm
• 19.1% of patients had at least one serious adverse event (non-fatal) in masitinib arm versus 21.3% in the control arm
• 74.8% of patients had at least one adverse event with Grade 3 or 4 in masitinib arm versus 83.1% in the control arm

Julien Taieb, MD, PhD, Head of the Gastroenterology and Gastrointestinal Oncology Department at the Georges Pompidou European Hospital said: "Masitinib is not a cytotoxic agent but a targeted drug blocking two cells of the innate immune system, mast cells and macrophages. Study AB12005 demonstrated for the first time that this targeted approach is beneficial in a targeted population, made of patients with unresectable locally advanced tumors with pain".

Prof. Olivier Hermine, president of the Scientific Committee of AB Science and member of the Académie des Sciences in France, said: "This study is particularly important as it confirms the relevance of targeting mast cells and macrophages in oncology. We had previously observed the benefit of masitinib targeting mast cells and macrophages in cancer through in vitro and in animal assays in my laboratory. This study validates the benefit of masitinib in humans in the most difficult-to-treat cancer. We can now state that masitinib is an anti-metastatic drug that could be useful in patients at high risk of developing metastases. In addition, it validates the role of mast cells in pain and the acceptable safety profile of masitinib even in combination with chemotherapy."

The pre-specified primary endpoint was overall survival. The primary analysis was pre-specified both in the overall population and also in patients with unresectable locally advanced tumors, with a 5% alpha spending split, which corresponds to the chance factor threshold below which the statistical test is considered significant by regulatory authorities, of 2.5% for the overall population and 2.5% for the locally advanced subgroup. The distinction between unresectable locally advanced or metastatic disease status was a stratification factor, thereby ensuring that treatment-arms were unbiased for this known prognostic factor. Secondary endpoints included progression free survival according to central RECIST criteria and change in pain from baseline.

The study enrolled 383 patients (randomization 2:1 between masitinib and placebo) with i) histologically or cytologically confirmed adenocarcinoma of the pancreas, unresectable locally advanced or metastatic stage, ii) pain related to the disease (Visual Analogue Scale > 20 mm or opioid analgesics at a dose ≥ 1 mg/kg/day), and iii) chemotherapy naïve for the advanced/metastatic disease. 92 patients had unresectable locally advanced with pain criteria.

Efficacy analysis was performed in the modified intent-to-treat (mITT) population, which included all randomized patients who took at least one dose of study treatment (masitinib/placebo) and with pain criteria (VAS > 20 and/or patients treated with opioid analgesics dose ≥ 1 mg/kg/day at baseline). There was a difference of 4 patients between the ITT population and the mITT population, with 1 patient receiving no study treatment and 3 patients without pain criteria.

A first phase 2/3 study (AB07012) enabled the identification of a subgroup based on the level of pain at baseline where survival was statistically increased (+2.6 months, p=0.012, Hazard Ratio=0.62). Pain intensity was assessed via a visual analog scale (VAS) at baseline. This linear scale provides a visual representation of pain as perceived by the patient. Pain intensity was represented by a 100 mm long, continuous line free of any internal reference marks. One extremity indicated an absence of pain (0-value) and the other extremity indicated very severe pain (100-value). The VAS threshold for the ‘pain' subgroup was set to VAS ≥20 mm, which is consistent with established precedent from the scientific literature [3-6]. 

There is evidence from the scientific literature in support of biological plausibility for the observed masitinib treatment-effect in patients with baseline pain (VAS ≥ 20). The presence of pain in pancreatic cancer is thought to flag an increased mast cell activity within the tumor microenvironment, which promotes disease progression. Masitinib's highly selective inhibition of mast cell activation is expected to be of therapeutic benefit by modulating mast cell related remodeling of the tumor microenvironment.

The estimated prevalence of people living with pancreatic cancer is 21 per 100,000 [7]. At the time of diagnosis, most patients with pancreatic ductal adenocarcinoma present with locally advanced or metastatic disease and only 10-20% of cases are candidates for curative surgery. Median overall survival is between 6 to 7 months and 1-year survival rates range between 17 to 25% [8;9]. As such, population with unresectable pancreatic cancer in first line is around 100,000 in the EU and 60,000 in the USA.

[1] Okusaka T, et al. Abdominal pain in patients with resectable pancreatic cancer with reference to clinicopathologic findings. Pancreas. 2001;22(3):279-284.
[2] Deplanque 2015, Ann Oncol. doi: 10.1093/annonc/mdv133. http://annonc.oxfordjournals.org/content/26/6/1194

[3] Balaban EP, et al. Locally Advanced Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. 2017 Apr;13(4):265-269. doi: 10.1200/JOP.2016.017376.
[3] Khazaie K, Blatner NR, Khan MW, et al. The significant role of mast cells in cancer. Cancer Metastasis Rev. Mar 2011;30(1):45-60.
[4] Theoharides TC. Mast cells and pancreatic cancer. N Engl J Med. Apr 24 2008;358(17):1860-1861.
[5] Maltby S, Khazaie K, McNagny KM. Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta. Aug 2009;1796(1):19-26.
[6] Christy AL, Brown MA. The multitasking mast cell: positive and negative roles in the progression of autoimmunity. J Immunol. Sep 1 2007;179(5):2673-2679

About masitinib
Masitinib is a new orally administered tyrosine kinase inhibitor that targets mast cells and macrophages, important cells for immunity, through inhibiting a limited number of kinases. Based on its unique 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. In oncology due to its immunotherapy effect, masitinib can have an effect on survival, alone or in combination with chemotherapy. Through its activity on mast cells and microglia and consequently the inhibition of the activation of the inflammatory process, masitinib can have an effect on the symptoms associated with some inflammatory and central nervous system diseases and the degeneration of these diseases.

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