Imatinib/Binimetinib Combo Shows Efficacy With Manageable Safety in Treatment-Naïve Advanced GIST

Ping Chi, MD, PhD

The combination of the TKI inhibitor imatinib (Gleevec) and the MEK inhibitor binimetinib (Mektovi) elicited encouraging responses in patients with treatment-naïve advanced gastrointestinal stromal tumors (GIST), according to data from a phase 2 trial (NCT01991379) published in the Journal of Clinical Oncology.¹

The novel combination elicited a best overall response rate (ORR) of 69.0% (2-sided 95% CI, 52.9%-82.4%) among 42 evaluable patients, meeting the primary end point of the research. The trial opened with a goal of improving ORR compared with historical ORRs achieved with imatinib monotherapy, which have ranged from 45% to 52%.²

At the time of data cutoff, 29 of these patients had confirmed partial responses (PRs) to treatment per RECIST v1.1 criteria, and 95.1% (95% CI, 83.5%-99.4%) experienced a Choi PR of approximately 8 weeks. Among 35 patients with PET scans evaluable by European Organization for Research and Treatment of Cancer (EORTC) at 4 weeks of combination treatment, 22.9% experienced a complete metabolic response, and 65.7% achieved partial metabolic response.

“This is 1 of the first clinical trials combining a TKI and an MEK inhibitor in the frontline treatment of GIST,” lead study author Ping Chi, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, and colleagues, wrote. “The combination of imatinib and binimetinib is effective in treatment-naïve advanced GIST. Deep and durable responses were noted.”

Imatinib monotherapy is currently the standard of care (SOC) in the frontline setting for patients with GIST. The TKI targets KIT and PDGFRa mutations, which the majority of these tumors harbor. Single-agent imatinib has been shown to result in a median progression-free survival (PFS) ranging from 18.0 to 20.4 months. Moreover, 10% to 17% of patients who receive imatinib in the frontline setting have been shown to not have disease progression for more than 9 years.^3,4

In addition to KIT, ETV1 is also known to be a well-established master regulator of GIST.⁵ Based on findings from preclinical models, investigators hypothesized that the dual targeting of KIT and ETV1 with the combination of imatinib and binimetinib could enhance therapeutic responses in patients with this disease.

The single-center, single-arm study enrolled patients who were at least 18 years of age, who had histologically confirmed advanced GIST and an ECOG performance status of 0 or 1. Patients were required to be treatment naïve, or at least 3 months removed from prior adjuvant imatinib therapy. Notably, patients who had started standard-of-care imatinib within 4 weeks and who had acceptable end-organ function were permitted.

All participants were given a 2-week lead-in of imatinib at a daily dose of 400 mg, followed by 400 mg daily plus binimetinib at a twice-daily at 30 mg continuously on every 28-day cycle.

Disease assessments were done via CT scans or MRIs, which were performed at baseline, every 8 weeks for the initial 32 weeks, and every 12 weeks until surgery, disease progression, death, or withdrawal. PET scans were also performed at baseline and at the end of the first cycle of treatment.

The primary end point of the trial was ORR per RECIST v.1.1 criteria, measured by complete response or PR. Key secondary end points included response rate by Choi and EORTC, progression-free survival (PFS), overall survival (OS), pathologic responses, and treatment-related adverse effects (AEs).

Between September 15, 2014, and November 15, 2020, a total of 54 patients were screened for the trial, and 50 were enrolled. A total of 43 patients received at least 2 doses of the combination, which made them evaluable for the safety, and 42 patients had at least 1 follow-up imaging study, which made them evaluable for efficacy.

Of those patients evaluated for efficacy, the median age was 60 years (range, 25-78), 71.4% were male, and 85.7% had an ECOG performance status of 0. The most common primary tumor locations included the stomach (38.1%), small bowel (35.7%), and rectum (11.9%). The primary driver mutation present in the population was KIT exon 11, and this was detected in 69.0% of patients.

Additional data showed that the 12-month clinical benefit rate achieved with the combination was 83.3% (95% CI, 68.6%-93.0%); at 24 months, this rate was 73.8% (95% CI, 58.0%-86.1%).

In an intention-to-treat analysis that was not stipulated in the trial protocol, which included 3 patients with intolerance to imatinib (n = 2) and binimetinib (n = 1), the best ORR with the doublet was 64.4% (n = 29/45; 95% CI, 48.8%-78.1%) per RECIST v1.1 criteria, and 88.6% (95% CI, n = 39/44; 95% CI, 75.4%-96.2%) by Choi.

The median PFS with the combination was 29.9 months (95% CI, 24.2–not reached [NR]). At 24 months, 69.7% (95% CI, 53.3%-91.2%) of patients continued to be free of disease progression; at 30 months, this rate was 47.8% (95% CI, 28.7%-79.6%). The median OS was NR (95% CI, 50.4 months-NR). At 30 and 48 months, 83.0% (95% CI, 70.4%-97.8%) and 72.8% (95% CI, 56.9%-93.1%) of patients, respectively, were alive.

Furthermore, 5 of 8 patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response.

No unexpected toxicities were observed during the trial. The most commonly reported AEs of any grade that were attributed as possibly, probably, or definitely associated with either imatinib and/or binimetinib per investigator assessment were peripheral (79.1%) and periorbital (69.8%) edema, acneiform (74.4%) and maculopapular (48.8%) rash, diarrhea (60.5%), asymptomatic creatinine phosphokinase elevation (100%), anemia (88.4%), white blood cell decrease (58.1%), platelet count decrease (51.2%), hypophosphatemia (46.5%), alanine aminotransferase increase (55.8%), and aspartate aminotransferase increase (86.1%).

Notably, 3 patients developed dropped head syndrome; this included 1 grade 3 effect. Two patients returned to baseline with dose reduction and 1 did so by discontinuing binimetinib. Additionally, 3 patients experienced a decrease in left ventricular ejection fraction (LVEF); 2 patients of these patients grade 3 effects and 1 patient had congestive heart failure exacerbation with LVEF decrease during the imatinib lead-in phase. The latter patient discontinued the trial after receiving 2 doses of combination due to intolerability to imatinib. Two of 3 patients had LVEF decrease that was attributed to binimetinib; these patients returned to their baseline cardiac function after a dose reduction of the agent and they continued on the trial.

No clinically significant grade 4 or 5 AEs determined to be at least possibly associated with study treatment were observed in this trial.

“Imatinib and binimetinib, or a similar combination, should be evaluated in a randomized trial in direct comparison with the SOC, imatinib alone, in the first-line treatment of [patients with] advanced GIST, with careful consideration of the efficacy end points and toxicity profiles,” the study authors concluded.

References

1. Chi P, Qin L-X, Nguyen B, et al. Phase II trial of imatinib plus binimetinib in patients with treatment-naive advanced gastrointestinal stromal tumor. J Clin Oncol. Published online January 18, 2022. doi:10.1200/JCO.21.02029
2. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26(4):626-632. doi:10.1200/JCO.2007.13.4452
3. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364(9440):1127-1134. doi:10.1016/S0140-6736(04)17098-0
4. Casali PG, Zalcberg J, Le Cesne A, et al. Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: Long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group intergroup phase III randomized trial on imatinib at two dose levels. J Clin Oncol. 2017;35(15):1713-1720. doi:10.1200/JCO.2016.71.0228
5. Chi P, Chen Y, Zhang L, et al. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature. 2010;467(7317):849-853. doi:10.1038/nature09409