Masitinib Shows Advanced Pancreatic Cancer Promise for Select Patients

Masitinib plus gemcitabine increases overall survival for two subgroups of patients with pancreatic ductal adenocarcinoma compared with gemcitabine alone

medwireNews: Combining the Tyrosine kinase inhibitor (TKI) masitinib with gemcitabine may help some groups of patients with advanced pancreatic ductal adenocarcinoma (PDAC), suggest phase III trial results published in the Annals of Oncology.

The median overall survival (OS) results for the 173 patients randomly assigned to receive gemcitabine 1000 mg/m2 plus masitinib 9 mg/kg per day did not significantly differ from the 175 patients given gemcitabine plus placebo, at 7.7 and 7.0 months, respectively.

However, Gaël Deplanque, from Saint Joseph Hospital, Paris in France, and co-authors identified two patient subgroups that had “particularly poor survival” on gemcitabine plus placebo and showed these populations derived significant benefit from masitinib.

Of the 40 patients who had overexpression of acyl-CoA oxidase-1 (ACOX1) in their blood, median OS was 11.7 months with combined therapy versus 5.6 months for gemcitabine plus placebo, giving a significant hazard ratio of 0.23.

In addition, 137 patients had a baseline pain intensity threshold greater than 20 mm on a 100 mm visual analogue scale. Median OS was 8.0 months for the patients given masitinib plus gemcitabine versus 5.4 months for those given gemcitabine plus placebo, with a significant hazard ratio of 0.62.

“[I]t is thought that the presence of baseline pain… or an overexpression of ACOX1 effectively identifies those patients with a pro-tumoral T-helper cell type-2 immune response, a condition caused in part by increased mast cell activity in the tumor microenvironment or by transcriptional or physiological alterations favoring M2-polarization of tumor-associated Macrophages”, the authors explain.

They note that preclinical research also suggests that masitinib may be associated with a reduced mast cell count and reduced tumour vascularisation and innervation, as well as increased recruitment of anti-tumour macrophages.

Masitinib was associated with an increase in grade 3 and 4 adverse events and treatment interruption, reduction or discontinuation, with a significantly increased rate of severe haematological adverse events.

Nevertheless, the TKI did not significantly accelerate decline in patient quality of life compared with gemcitabine plus placebo, prompting the researchers to write that the survival gain when “coupled with manageable toxicity suggests a positive benefit–risk ratio.”

Emphasising the need for further research, Gaël Deplanque and team conclude that a confirmatory study has been initiated to examine the use of masitinib plus gemcitabine in these two PDAC patient subgroups.

Reference

Deplanque G, Demarchi M, Hebbar M, et al. A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer. Ann Oncol 2015; Advance online publication 9 April. doi: 10.1093/annonc/mdv133

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