Correlation between imatinib trough concentration and efficacy in patients with advanced GIST with different genotypes.

Abstract

e23515 Background: Imatinib (IM) has significantly enhanced the prognosis of patients (pts) with advanced gastrointestinal stromal tumors (GISTs). The clinical outcomes may correlate with IM exposure. However, the efficacy threshold, particularly based on different primary KIT mutant, remains undefined. This study aimed to establish the efficacy threshold of IM plasma trough concentration (Cmin) at steady-state in Chinese pts with advanced GIST, additionally to define subgroup thresholds based on various primary KIT mutations. Methods: This was a single-center, prospective, observational cohort study. Pts with histologically confirmed recurrent/metastatic GIST who received regular IM treatment and had undergone at least two measurements of steady-state IM Cmin were enrolled from Jul 2017 to Jun 2022. Clinical outcomes including objective response rate (ORR), survival, and IM Cmin were assessed. Results: A total of 168 pts with a median age of 52y were enrolled. The primary lesion locations comprised stomach, small intestine, rectum and others. Metastatic lesions were found in the liver, peritoneum, both liver and peritoneum and others. Median sum of longest diameter of target lesions was 10.7cm. Of 168 pts, 117 (69.6%) harbored KIT 11, 27 (16.1%) harbored KIT 9, 5 (3.0%) harbored PDGFRA, and 9 (5.4%) were KIT/PDGFRA wild type. During IM response period, 104 pts combined with surgical treatment (surgery or interventional therapy). After a median follow-up duration was 50.6m (range, 16.3–189.8), 72 pts had disease progression and 20 died. Estimated median progression-free survival (mPFS) for all patients was 79.4m (95%CI 55.7–103.1). The median overall survival was not reached. A Cmin threshold of ≥738ng/ml defined by log-rank test was associated with longer PFS for the whole population (P = 0.002) irrespective of other clinical characteristics. Pts with an IM Cmin below 738ng/ml exhibited a shorter mPFS (25.3m, 95%CI 41.9–97.1) compared to those surpassing this threshold (96.7m, 95%CI 65.8–127.6). The ORR for the whole population was 73.0% (CR 2.2%, PR 70.8%), with no significant difference observed between pts with IM Cmin below and above 738ng/ml. For pts with KIT 11 and KIT 9 mutations, the efficacy thresholds for IM Cmin were ≥680ng/ml and ≥1877ng/ml, respectively. Multivariate Cox regression analysis revealed that IM Cmin ≥738ng/ml, primary gastric origin, liver-only metastasis, sum of target lesions diameter ≤5cm, KIT 11 mutation, and combined with surgical treatment were favorable prognostic factors. Conclusions: IM exposure significantly correlates with clinical benefits in advanced GISTs, with an IM Cmin above 738ng/ml associated with a longer PFS in Chinese population. Considering different primary KIT mutant, a threshold of 680 ng/ml could be considered for efficacy in KIT 11 mutations, while a higher Cmin of 1877 ng/ml was necessary for KIT 9 mutation.