Binimetinib Added to Standard of Care Elicits Responses in Advanced GIST

Through preclinical research, clinical investigators have found that ETV1 aides in generating adaptive responses to KIT and PDGFRA inhibition. This research eluded to a possible synergy between the MEK inhibitor binimetinib (Mektovi) and the tyrosine kinase inhibitor (TKI) imatinib (Gleevac). Ping Chi, MD, PhD, and colleagues conducted a phase 2 clinical trial based on this hypothesis, which enrolled patients with treatment-naïve gastrointestinal stromal tumors (GIST).

In 38 evaluable patients, the best objective response rate was 68.4% (2-sided 95% CI, 51-83%; 1-sided 90% CI, 57-100%), which included partial responses in 26 patients. This met the primary end point of the study. Additionally, there was 1 patient with stable disease and 1 patient with progressive disease. The median duration of response was 30 months (95% CI, 19 months-not evaluable [NE]). The survival data shows a median progression-free survival of 29.9 months (95% CI, 24.2 months-NE), and the median overall survival was not evaluated.

Chi et al assessed the resectability conversion rate (RCR) in patients following treatment with binimetinib plus imatinib and observed an RCR of 88.9% (95% CI, 52-100%), meaning most patients who were unresectable at baseline became resectable after treatment with the combination.

The safety analysis showed that the combination was well-tolerated in patients with no unexpected toxicities observed. The grade 3 and 4 toxicities included asymptomatic creatine phosphokinase elevation (61%), neutrophil decrease (11%), maculopapular rash (8%), and anemia (8%). Toxicities did not lead to treatment discontinuation, but 9 patients did discontinue treatment due to disease progression.

In an interview with Targeted Oncology, Chi, medical oncologist, Geoffrey Beene Junior Faculty chair, Memorial Sloan Kettering Cancer Center, discussed the phase 2 study of binimetinib in combination with imatinib in patients with untreated advanced GIST and the next steps following the data she presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

TARGETED ONCOLOGY: In terms of targeted therapies, what does the treatment landscape look like for patients with GIST?

Chi: For targeted therapy, GIST is the poster child for solid tumors. It started in 1998 or early 1999 with imatinib, and imatinib has been the first-line targeted therapy for the majority of GIST treatment since the year of 2000 when it was initially FDA-approved. Since that time, there has been second-line sunitinib (Sutent) and third-line regorafenib (Stivarga) that were FDA-approved subsequently. More recently, we have seen avapritinib (Ayvakit) receive FDA approval for PDGFRA exon 18-mutant GIST, which is the subset that is imatinib-resistant. Now, we also have ripretinib (Qinlock), which is FDA-approved for the fourth-line treatment of GIST.

TARGETED ONCOLOGY: Can you explain the synergy between binimetinib and imatinib observed in early studies?

Chi: Binimetinib and imatinib have not been combined in any other settings. Our study was probably the first to show that the combination of a TKI and MEK inhibitor is relatively safe and tolerable in this setting. Also, the synergy was previously defined, by us and others,

to specifically target both of the upstream KIT and PDGFRA signaling master regulator as well as the downstream regulator ETB-1 in preclinical models.

Our study is the first proof-of-concept phase 1 and 2 study to show the safety, tolerability and early efficacy of this combination.

TARGETED ONCOLOGY: What results did you present for this combination at ASCO?

Chi: This is the first time to present the phase 2 data. The phase 2 primary end point is objective response rate. It's a single-arm, single-institution study of patients in the frontline setting of treatment-naïve GIST.

When we combined the standard of care imatinib at 400 mg once daily with binimetinib 30 mg twice daily, we found that the combination has met our predetermined end point with a statistically significant response rate of approximately 67%. Based on our statistical design, we've seen 26 confirmed responses, even prior to the complete accrual of the predetermined patients cohort.

TARGETED ONCOLOGY: What do you find most interesting about this study?

Chi: There are a few things. First, on top of the primary end point of objective response, I think the resectability was quite high in a select subset of patients. There were 7 patients who were considered unresectable, and later, 6 of them were resectable.

In our presentation, we also noted that some of the pathological responses in these patients were deeper compared to the traditional RECIST responses. Moving forward, we need to look at how to evaluate response beyond the traditional methods of evaluation. Should we be using more of a combination of the volumetric imaging studies as well as pathological responses. I think that will be a meaningful next step.

TARGETED ONCOLOGY: What are the nest steps for this study?

Chi: Initially when we designed the trial, we included a follow-up play for if the trial was successful. Our next strategy is to combine either imatinib with another MEK inhibitor or use a newer generation of KIT infusion in combination with a MEK inhibitor to further elicit the synergy, which would be useful in the frontline setting.

TARGETED ONCOLOGY: Could you also highlight the correlative analyses for this study?

Chi: There are additional correlative studies that were preplanned with the pretreatment, on treatment, and progression biopsies. We have only generated a part of the data, but I think once the full set of correlative studies have been evaluated, it will give us additional information on resistance mechanisms are involved.

_Reference:

_{Chi P, Qin LX, Kelly CM, et al. A phase II study of MEK162 (binimetinib [BINI]) in combination with imatinib in patients with untreated advanced gastrointestinal stromal tumor (GIST). J Clin Oncol. 2020:38 (suppl; abstr 11508). doi: 10.1200/JCO.2020.38.15_suppl.11508}