In a single-center phase II trial reported in the Journal of Clinical Oncology, Chi et al found that the combination of the MET inhibitor binimetinib and the KIT inhibitor imatinib produced a high response rate in patients with previously untreated advanced gastrointestinal stromal tumor.

As stated by the investigators, “Dual targeting of the gastrointestinal stromal tumor lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy.”

Study Details

The study enrolled 50 adult patients at Memorial Sloan Kettering Cancer Center between September 2014 and November 2020. Patients received a 2-week lead-in of imatinib at 400 mg once daily alone followed by imatinib at 400 mg once daily and binimetinib at 30 mg twice daily in 28-day cycles. The primary endpoint was objective response rate on Response Evaluation Criteria in Solid Tumors version 1.1.

The trial was designed to detect a 20% improvement in response rate vs imatinib alone (unacceptable rate of 45%, acceptable rate of 65%) with a planned sample size of 44 patients. The trial was to be considered positive if objective response were achieved in more than 24 patients.

Responses

Overall, 43 patients who received at least two doses of study treatment were evaluable for safety and 42 who had at least one follow-up imaging study were evaluable for efficacy.

Objective responses (all partial) were achieved in 29 (69.0%, 95% confidence interval [CI] = 52.9%–82.4%) of 42 evaluable patients. The clinical benefit rate was 83.3% (95% CI = 68.6%–93.0%) at 12 months and 73.8% (95% CI = 58.0%–86.1%) at 24 months. On Choi criteria, partial response (≥ 10% reduction in tumor size or ≥ 15% reduction in density) was observed in 39 (95.1%) of 41 evaluable patients at approximately 8 weeks.

At data cutoff, median follow-up among survivors was 35.6 months (range = 2.4–73.8 months).

Median progression-free survival was 29.9 months (95% CI = 24.2 months–not estimable), with 69.7% and 47.8% of patients remaining progression-free at 24 and 30 months. Median overall survival was not reached (95% CI = 50.4 months–not estimable), with 83.0% and 72.8% of patients remaining alive at 30 and 48 months.

Among eight patients with locally advanced disease who underwent surgery after treatment, all achieved at least 70% confirmed pathologic response of the primary tumors, and significant pathologic response (≥ 90% treatment effect) was observed in five.

Adverse Events

The most common adverse events of any grade considered at least possibly related to treatment were asymptomatic creatinine phosphokinase (CPK) elevation (100%), anemia (88.4%), increased aspartate aminotransferase (86.1%), peripheral edema (79.1%) and acneiform rash (74.4%). The most common grade 3 and 4 events were asymptomatic CPK elevation (79.1%), hypophosphatemia (14.0%), decreased neutrophils (9.3%), anemia (7.0%), and maculopapular rash (7.0%). No treatment-related deaths were reported.

The investigators concluded, “The study met the primary endpoint. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of gastrointestinal stromal tumor.”

Ping Chi, MD, PhD, of the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Cancer Institute, Array BioPharma/Pfizer, and others. For full disclosures of the study authors, visit ascopubs.org.