First Exploration of a TKI Combination in Frontline GIST Yields Encouraging Results

Ping Chi, MD

In a phase 2 clinical trial (NCT01991379), the combination of imatinib (Gleevec) and binimetinib (Mektovi) demonstrated efficacy and manageable toxicity as frontline treatment of patients with gastrointestinal stromal tumors (GIST). According to Ping Chi, MD, and fellow study investigators, findings from imatinib/binimetinib warrant further exploration of dual targeting in GIST using imatinib and a MEK inhibitor.

Of the 42 patients in the study, the combination of imatinib and binimetinib achieved confirmed partial responses (PRs) in 29 patients per RECIST. The best objective response rate observed in the study was 69.0% (95% CI, 52.9%-82.4%).

In terms of survival, the median PFS was 29.9 months (95% CI, 24.2 to not estimable [NE]), and the median OS was not reached (95% CI, 50.4 -NE).

No unexpected toxicities were observed during the study. Grade 3/4 adverse events did occur, including asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%).

In an interview with Targeted Oncology™, Chi, a medical oncologist, and the Geoffrey Beene Junior Faculty Chair at Memorial Sloan Kettering Cancer Center, discussed the novel strategy of combining KIT and MEK inhibition to treat patients with GIST treated in the frontline setting.

TARGETED ONCOLOGY: Can you discuss the dual targeting of GIST and what’s in the toolbox for this strategy?

Chi: This strategy is really based on preclinical data generated by my lab as well as other research labs, suggesting that the combination of targeting the KIT molecule, which is a master signaling molecule in GIST, as well as precursor interstitial cells and the master regulator ETV1, can be synergistic.

There are a variety of different KIT inhibitors out there but imatinib it is really 1 of the prototypes and was the first FDA-approved frontline therapy in GIST. There are a number of MEK inhibitors. This combination strategy has worked for all different KIT and MEK combinations.

What’s unique about the combination of imatinib and binimetinib? Why did you choose to explore these 2 agents specifically?

Well, imatinib is really 1 of the cornerstones of the first-line therapies and we still use it. It was initially FDA approved in 2001 for GIST, and it was sort of the poster child of targeted therapy in solid tumor at that time. Twenty years later, we're still using imatinib as the frontline therapy. It's effective for advanced GIST, but its efficacy is not indefinite, Most patients would develop resistance to imatinib within 2 years of therapy, and then they eventually would die from their disease. That’s why we asked, is there anything better than imatinib, or are there any strategies that we can use or leverage what we identified from the preclinical studies to improve the efficacy in the frontline setting?

What were the key goals of your phase 2 study of imatinib plus binimetinib in frontline GIST?

After we defined the recommended phase 2 dose, it was at the standard of care dose of imatinib 400 milligrams once daily and the binimetinib was defined as 45mg twice daily. In the phase 2 trial, we decided to use 30 mg twice daily for binimetinib for better, long-term tolerability after seeing some of the toxicities in the phase 1b study

The primary end point is objective response and then basically we have a statistical design using the exact binomial test and we wanted we define an absolute 20% improvement of the objective response over imatinib alone, based on the 1-sided type 1 error of 0.28 and type 2 errors of 0.1. We planned a sample size of 44 and if we have saw a PR or CR in more than 24 patients, the trial was considered positive.

Can you explain your study findings?

We accrued patients over the course of 6 years and the best objective response was 69%. We have seen 29 patients out of 42 evaluable patients with a confirmed RESIST PR. Now, we have fully accrued to the 44 patients and this objective response rate remains the same. I think this is a positive trial and the secondary end points included median progression-free survival and median overall survival. The median progression-free survival was 29.9 months, which compared to the historical controls is also very promising. The historical control for imatinib alone, either at the 400mg or 800mg daily dosing, is around 20 months to 24 months. So, an almost 30-months median progression-free survival is fairly promising in our minds. Other secondary end points also included pathological responses. We see significant response and with increased depth of response in some of the patients who eventually went to surgery. The median overall survival was not reached yet.

What about these results highlight the importance of GIST lineage dependence on ETV1 and KIT?

One of the things we think it validated from preclinical studies is that the combination can potentially be synergistic and has enhanced efficacy. A part of the efficacy is really through targeting downstream escape pathways and adaptive response pathways that are mediated by ETV1. Based on this trial, we've seen some promising enhancement of the results both from the perspective of the response rate as well as the median PFS, but also the pathological responses. I think it's more telling because in most of the cases, we see a deeper response. If you look at the swimmer plot, the majority of the patients would actually respond within 2 cycles of treatment, each cycle is about 4 weeks, so that also gives us a hint of the depth of response and the time to response.

This is the first study evaluated a TKI combination in this setting of GIST. What message do you have for other investigators on why they should continue to study this strategy?

It's 2 things. First, is that I think the efficacy signal is promising, and the second thing is that is that the combination is reasonably tolerable and has relatively safe toxicity profile. There were no unexpected toxicities, and the most common grade 3 of 4 toxicities included asymptomatic CPK elevation, there was hypophosphatemia, some level of neutrophil decrease, and also maculopapular rashes are more associated with the MEK binimetinib. There was also some low-grade anemia. The most bothersome, however, is these maculopapular rash and the increased peripheral edema, but those can all be managed with those modification or adjustment of symptomatic controls.

We have developed a way of managing these AES in patients, so I think in the grand scheme of things, we should consider testing the combination imatinib in combination with a MEK inhibitor in the frontline setting with a direct comparison to imatinib alone in a randomized trial to further compare the median progression-free survival and secondly, whether the combination can realty be tolerability is larger population of patients. Another trial would also show whether we can really change the frontline treatment landscape.

_REFERENCE:

_{Chi P, Qin L, Nguyen B, et al. Phase II trial of imatinib plus binimetinib in patients with treatment-naive advanced gastrointestinal stromal tumor. J Clin Oncol. 2022; 40(9):997-1008. doi: 10.1200/JCO.21.02029}