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Masitinib plus gemcitabine shows promise in vulnerable pancreatic cancer subgroups
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The addition of masitinib to gemcitabine significantly prolonged OS in patients with advanced pancreatic cancer who overexpressed ACOX1 or had baseline pain, according to the results of a randomized phase 3 study.
However, the combination failed to demonstrate improved outcomes in the overall population compared with gemcitabine alone.
“Pancreatic cancer continues to be a disease with high unmet medical need, requiring new active agents,” Gaёl Deplanque, MD, PhD, of the department of medical oncology at Saint Joseph Hospital in Paris, and colleagues wrote. “For over a decade, single-agent gemcitabine has been the standard first-line treatment for unresectable, locally advanced or metastatic pancreatic ductal adenocarcinoma. … Numerous gemcitabine-based combination regimens evaluated in randomized trials have either failed to demonstrate significant improvement in OS or have shown statistically significant but rather modest survival benefits compared with gemcitabine alone.”
However, masitinib (AB Science) — a selective oral tyrosine kinase inhibitor — has shown promise when combined with gemcitabine in preclinical and clinical studies, according to study background.
Deplanque and colleagues evaluated data from 353 patients with inoperable, chemotherapy-naive advanced pancreatic ductal adenocarcinoma. Patients were treated at one of 73 centers, most of which were located in France, the Czech Republic and the United States.
All patients received 1,000 mg/m2 of gemcitabine plus 9 mg/kg of masitinib (n = 175) or placebo (n = 178) daily. Treatment continued until disease progression or the development of intolerable adverse events.
OS in the modified intent-to-treat population served as the primary endpoint. Researchers sought to identify patient subgroups with poor prognoses while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit as a secondary endpoint.
Median follow-up was 26 months.
Overall, median OS rates were comparable in the masitinib and placebo arms (7.7 months vs. 7.1 months; HR = 0.89; 95% CI, 0.7-1.13).
The secondary endpoint analysis identified two subgroups with significantly reduced survival rates: patients with an overexpression of acyl–CoA oxidase-1 (ACOX1) in their blood and patients with a baseline pain intensity above a threshold of 20 mm on a 100 mm visual analog scale (VAS). Patients in these subgroups — which represented an estimated 63% of patients — displayed a median OS of 5.5 months when treated with gemcitabine alone and, thus, represent a critical unmet medical need population, according to the researchers.
Patients in these subgroups displayed a significant OS improvement when treated with masitinib plus gemcitabine. Patients with an overexpression of ACOX1 achieved a median OS of 11.7 months (HR = 0.23; 95% CI, 0.1-0.51) and patients with baseline pain achieved a median OS of 8 months (HR = 0.62; 95% CI, 0.43-0.89) with the combination.
Severe hematological adverse events were more common in the masitinib cohort (63% vs. 42%; P < .001) and more patients treated with masitinib discontinued study treatment (42% vs. 23%; P = .003). Anemia, nausea, vomiting, thrombocytopenia and neutropenia occurred more frequently in the masitinib cohort; however, back pain, constipation and pulmonary embolism were more common in the placebo cohort.
Despite a higher incidence of adverse events among the active-agent cohort, the instances were generally manageable, according to the researchers.
“The survival benefit observed for advanced pancreatic ductal adenocarcinoma patients with overexpression of ACOX1 in blood or reporting baseline pain of VAS > 20 mm when treated with masitinib plus gemcitabine, coupled with manageable toxicity suggests a positive benefit–risk ratio,” Deplanque and colleagues concluded. “This has led to the initiation of a confirmatory study that may support the use of masitinib plus gemcitabine as a new treatment option for these two subgroups of patients.” – by Cameron Kelsall
Disclosure: The study was funded by AB Science and Acobiom. Researchers report consultant and employment roles with and stock ownership in AB Science.
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