First-Line Binimetinib–Imatinib Shows Promise For Advanced GIST

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Phase II trial results support further investigation of the MEK inhibitor binimetinib given alongside the tyrosine kinase inhibitor imatinib as a first-line therapy for patients with advanced gastrointestinal stromal tumours (GIST). 

The study findings were presented at the virtual 2020 ASCO Annual Meeting by Ping Chi, from Memorial Sloan Kettering Cancer Center in New York, USA, who explained that preclinical research had indicated the treatment combination may have synergistic effects leading to growth inhibition. 

The investigators recruited 40 patients with advanced GIST who had received no more than 4 weeks of treatment with imatinib. As set per the phase Ib trial, participants received 2 weeks of imatinib followed by 28-day cycles of binimetinib 30 mg twice daily and imatinib 400 mg/day. 

The presenter described the combination regimen as “reasonably tolerated with manageable toxicity”, with the most common treatment-related adverse events being oedema, rash, diarrhoea and fatigue. Of note, binimetinib dose reduction or discontinuation reversed treatment-induced left ventricular ejection fraction decrease in three patients and dropped head syndrome in two patients. 

The primary endpoint of RECIST best objective response rate was designed to detect a 20.0% improvement on imatinib therapy alone; this was met with a confirmed partial response rate of 66.7% in the patient population, lasting for a median of 30 months, and a clinical benefit rate of 97.0%. 

Ten patients progressed, including one patient within 3 months who had primary resistance linked to activation of NF1. In addition, all six of the patients with primary exon 11 KIT mutations who were followed up developed secondary resistance mutations in KIT exon 17 or 13, while two patients with KIT exon 9 mutations developed resistance mutations affecting cell cycle regulators or chromatin structure regulators. 

Seven patients had unresectable disease at baseline, of whom six had localised tumours and one had a solitary liver metastasis; despite “modest” RECIST assessed responses, these patients had pathological response rates of 70–100%, and 85.7% were subsequently able to undergo surgery, “indicating that a treatment response by RECIST may be underestimating the depth of response”, the investigator commented. 

Median progression-free survival was 29.9 months and median overall survival was unreached at time of analysis, both of which compare well compared with historical medians of 18–24 months and 47–55 months, respectively, for imatinib alone, Ping Chi said. 

Describing the combination as “effective”, she concluded that “[w]ith these data, we believe the combination strategy is promising and warrants further evaluation in the first-line treatment of advanced GIST.” 

Reference 

Chi P, Qin L-X, Kelly CM, et al. A phase II study of MEK162 (binimetinib [BINI]) in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST). J Clin Oncol; 38: suppl abstr 11508. DOI: 10.1200/JCO.2020.38.15_suppl.11508.