Combination therapy using conformation-specific KIT inhibitors associated with clinical benefit in patients with advanced gastrointestinal stromal tumors

1. The use of a type I KIT inhibitor, such as PLX9486, in combination with a type II inhibitor, such as sunitinib, was associated with clinical benefit and well tolerated in drug-naïve patients with advanced refractory gastrointestinal stromal tumors.

2. This combination therapy achieved better global disease control and allowed treatment to target a broader spectrum of conformationally distinct oncogenic-resistant mutations.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Gastrointestinal stromal tumors (GISTs) and its mutant subtypes, including KIT-mutant forms, are frequently caused by the activation of tyrosine kinase mutations. As such, treatment using kinase inhibitors often provide effective short-term therapy before relapse occurs due to the proliferation of heterogeneous subclones with resistant mutations. In recent years, conformation-specific KIT inhibitors have been used to target advanced GISTs. However, their mechanism of action in targeting these cancer subtypes as well as the clinical benefits of various monotherapy dosing and combination therapies are not well understood. This two-part phase 1b/2a nonrandomized clinical trial sought to evaluate whether PLX9486, a type I KIT inhibitor, could be combined with a type II KIT inhibitor, such as sunitinib, to target a broad spectrum of oncogenic mutations and achieve global disease control. The main outcomes and measures of the analysis were pharmacokinetics, safety, and tumor responses. In addition, clinical efficacy end points assessed via progression-free survival and clinical benefit rate were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA. From 39 PLX9486-naïve patients with refractory GIST, PLX9486 (a selective type I KIT inhibitor targeting activation-loop mutations) use together with sunitinib (a type II inhibitor targeting adenosine triphosphate-binding pocket mutations) achieved the highest median progression-free survival of 12.1 months and the highest clinical benefit rate of 80% among various uses and dosages of the agents. These results suggested that the use of a type I KIT inhibitor, such as PLX9486, in combination with a type II inhibitor, such as sunitinib, was well tolerated in drug-naïve patients with advanced refractory GIST. Furthermore, this combination therapy achieved better global disease control and allowed treatment to target a broader spectrum of conformationally distinct oncogenic-resistant mutations. A limitation of this study was the small sample size and heterogeneity present throughout disease progression that can produce residual confounding effects when attempting to study the outcomes of specific combinations of drug-resistant subclones. Long-term randomized clinical trials comparing PLX9486 monotherapy to combination therapy with sunitinib are needed to evaluate specific inhibitory mechanisms of drug-resistance and overall clinical outcomes.

Click to read the study in JAMA

Relevant Reading: A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors

In-Depth [randomized controlled trial]: This two-part phase 1b/2a nonrandomized clinical trial tested a highly selective type I inhibitor of KIT, PLX9486, by enrolling 39 PLX9486-naïve patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST). The initial part of the trial (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors while the second part (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Data was collected from March 2015 to February 2019 with analysis completed by July 2020. In part 1, patients received 250, 350, 500, and 1000mg of PLX9486 monotherapy. In part 2, the recommended dose of PLX9486 was 500 and 1000mg combined with 25 or 37.5mg daily of sunitinib continuously administered in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal. Patients with GIST who received PLX9486 at a dose of 500mg or less had a median progression-free survival of 1.74 (95%CI, 1.54-1.84) months along with a clinical benefit rate of 14% (95%CI, 0%-58%). Patients who received PLX9486 at the recommended phase 2 dose had a median progression-free survival of 5.75 (95%CI, 0.99-11.0) months along with a clinical benefit rate of 50% (95%CI, 21%-79%). Lastly, PLX9486 use together with sunitinib had a median progression-free survival of 12.1 (1.34-NA) months and a clinical benefit rate of 80% (95%CI, 52%-96%).

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