Abstract
The primary endpoint of the study was met with an objective response rate of 69%.
Major Finding: The primary endpoint of the study was met with an objective response rate of 69%.
Concept: Manageable toxicities over the long-term were demonstrated with this combination.
Impact: Further evaluation of this combination against imatinib alone for frontline treatment of GIST is necessary.
Gastrointestinal stromal tumors (GIST), one of the most common types of sarcoma, typically harbor activating mutations in KIT or PDGFRA. Imatinib, which targets both mutant KIT and PDGFRα, represents the first-line standard-of-care therapy for advanced GIST, but resistance continues to remain an issue with current subsequent therapies showing limited efficacy. As preclinical data have suggested binimetinib, a MEK inhibitor to target ETV1 protein stability, and imatinib are synergistic in inhibiting GIST tumor growth, Chi and colleagues conducted a phase II clinical trial to evaluate this combination in patients with treatment-naïve advanced GIST. Enrollment consisted of 50 patients with 42 of these being evaluable for efficacy. The first prespecified primary endpoint was met (>24 confirmed RECIST 1.1 partial response), with 69% being the best overall response rate. The median progression-free survival at data cutoff was 29.9 months, with 8 of the patients with locally advanced GIST achieving at least 70% pathologic response of their primary tumors, demonstrating a more robust treatment effect than conventional RECIST 1.1. Genetic analysis of patients who had progression of disease as compared to those who were denoted nonprogressors indicated an enrichment of CDKN2A inactivation in those with disease progression. Patients with disease progression also demonstrated emergent genomic alterations as compared to their matched pretreatment samples, and tumor mutational burden also increased in posttreatment samples of patients with disease progression. Investigation into the safety of this combination indicated manageable toxicities, with the most common grade 3 or 4 toxicities being asymptomatic creatine phosphokinase elevation, hypophosphatemia, decrease in neutrophils, anemia, and maculopapular rash. This study represents the first known trial of a tyrosine kinase inhibitor combination for frontline treatment of GIST and shows this combination is effective with manageable toxicities. Further evaluation of this combination strategy, especially in comparison to imatinib alone, for the treatment of advanced GIST is still required. ■
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
RSS Feeds