Background
Since the introduction of imatinib mesylate (IM) [
1], the outcome of metastatic gastrointestinal stromal tumour (GIST) has improved considerably [
2]. IM is an inhibitor of receptor tyrosine kinases, including the stem cell factor receptor
KIT and the platelet-derived growth factor receptor alpha (
PDGFRA), the main drivers of tumour development in GIST [
3]. Several clinical trials have demonstrated the efficacy and safety of IM, and it has become the treatment of choice for the majority of patients with metastatic GIST [
2,
4,
5]. The median duration of response to IM in metastatic GIST is 29 months [
2], with approximately 20% of the responses lasting 10 years or more [
6]. Still, most patients eventually progress on IM, requiring second- and third-line therapy with other tyrosine kinase inhibitors such as sunitinib and regorafinib [
7].
In patients with chronic myeloid leukaemia (CML) and GIST, pharmacokinetic (PK) studies have shown that IM has >90% bioavailability following oral administration [
8]. IM plasma concentration is influenced by various factors such age, body weight, body surface area (BSA), previous major gastric resection, white blood cell (WBC) count, haemoglobin, creatinine clearance, albumin, and alpha glycoprotein (AGP) levels [
9‐
15]. A retrospective sub-study from the B2222 trial [
4], the first trial showing safety and efficacy of IM in metastatic GIST patients, presented a significantly shorter time to progression in patients with IM trough levels (C
min) below 1110 ng/mL at day 29 [
16]. Additionally, a retrospective study in patients with CML in chronic phase reported that C
min of IM could predict clinical outcome [
13]. However, the optimal threshold value of IM C
min has yet to be determined; both in patients with GIST and CML. A prospective PK study showed a significant decrease of approximately 30% in plasma IM concentration after 90 days of treatment [
17], indicating that drug monitoring should preferentially be done after 3 months. This finding was recently supported by a study in real-life practice, where C
min was analysed after more than 3 months of treatment, and concentrations above 760 ng/mL were associated with longer progression-free survival (PFS) [
18].
Although considerable inter-patient variability in IM plasma concentrations (40–60%) has been observed in several studies [
15,
16], a fixed dose of 400 mg IM is the standard of care in patients with metastatic GIST [
7]. Patients that progress on 400 mg/day and patients with KIT exon 9 mutations may benefit from increasing the dose to 800 mg/day [
2,
19,
20]. Treatment with 400 mg IM is generally well tolerated, but patients still experience side effects such as anaemia, periorbital oedema, muscle cramps, and diarrhoea [
2,
4,
5]. Several of these can be ameliorated with supportive measures, but some patients need dose modifications [
21]. Compliance, i.e. adherence to self-administered drugs, is a general challenge for patients on any long-term treatment, as also reported for patients with GIST [
22]. However, the extent of non-compliance is often not known and might be a larger problem than expected. Altogether, there are several situations where IM plasma concentration measurements might have a considerable clinical impact in patients with metastatic GIST. However, at present, therapeutic drug monitoring (TDM) is not yet a part of routine clinical practice.
The aim of this study was to assess IM plasma concentration repeatedly over several years in a group of patients with metastatic GIST and thereby revealing scenarios where such measurements might have clinical implications.
Discussion
The role of IM C
min measurements in optimizing therapeutic efficacy in GIST is still investigational, despite preliminary estimates of IM blood levels that are associated with improved clinical outcomes (C
min > 1110 ng/mL) [
16]. In this study, we assessed C
min in a group of patients over several years trying to determine whether there are clinical scenarios where measurements of IM C
min could be advantageous. To the best of our knowledge this is the first study in metastatic GIST with repeated measurements of C
min plasma concentrations including samples at the time of documented progression.
Low IM C
min was associated with major gastrectomy in both univariate and multivariate analysis, which is consistent with previous findings [
14]. IM tablets dissolve more rapidly at pH 5.5 or less [
8], and lack of gastric acid secretion may explain the lower concentration in such patients. Many patients with metastatic GIST have previously undergone surgery for a primary gastric GIST and one might speculate that such patients could possess an increased risk of sub-therapeutic IM plasma levels and subsequently a less favourable disease outcome. In our cohort, only eight patients had disease progression, of which three had undergone gastric resection. Thus, analysing the prognostic impact of gastric surgery is impossible due to small patient numbers. Still, a more individualized drug dosage based on IM plasma concentrations may be beneficial in patients with prior gastric surgery.
Interestingly, in the current study patients with liver metastases had low IM C
min compared to patients without liver metastases. A previous study has shown that IM clearance is not affected by low volume liver disease [
17], and it thus seems unlikely that the liver metastases per se affect IM metabolism in our patients. We are not aware of studies that have reported differences in IM plasma concentration in patients with or without liver metastases, and this issue could be of interest for further studies.
Older patients had higher plasma concentrations in our cohort. The well-known decline of organ functions and increased prevalence of comorbidity and concomitant medication among elderly patients may influence the pharmacokinetics and pharmacodynamics of IM. We did not prospectively register concomitant medications or co-occurring medical conditions, and are thus not able to discern the role of these factors separately. Our results could suggest that individual dosing supported by IM plasma concentration measurement could be even more useful in elderly patients, to balance side effects and anti-tumour efficacy more precisely.
Although there were no serious adverse events in our study, dose reduction due to subjective side effects were mandatory in seven patients. Two of these patients had relatively high C
min on 200 mg, suggesting that for some patients this dose is enough to ensure optimal therapeutic plasma levels of IM. The four other patients had low levels suggesting that patient-reported side effects are not necessarily associated with high plasma concentrations. Few studies have explored the relationship between IM plasma concentration and side effects. One study showed that the occurrence and number of side effects correlated with IM total and free plasma concentrations in GIST patients [
27], but further studies on relations between concentration and toxicity are warranted. Unfortunately, we did not register side effects in a formal and prospective manner. However, measuring C
min concentrations in patients experiencing subjective side effects (e.g. muscle cramps, dizziness, fatigue etc.) that limit daily activity may help to determine whether it is safe to modify the dose of IM.
The relatively large inter- and interpatient variability in our study compared to other real-life cohorts [
14,
18] could be explained by lack of compliance. Although oral cancer therapies offer patients the convenience of self-administration at home, evidence show that adherence to these therapies is far from optimal [
28,
29]. The BFR14 Study evaluated the effect of IM interruption in responding patients (complete response, partial response, or stable disease) after different periods of treatment (1, 3 and 5 years), and results from the study indicated that discontinuation of IM is associated with rapid progression [
30‐
32]. Therefore, maintaining proper adherence may be of great significance and drug monitoring could potentially improve compliance to therapy.
Interestingly, we found a decrease in C
min plasma concentration at the time of disease progression, which might explain loss of disease control in certain patients. Measurements of IM C
min in case of progressive disease could therefore be indicated if lack of patient compliance has been ascertained. A sub-therapeutic drug level at the prescribed dose could suggest that increasing the dose would be of clinical benefit, in particular in the absence of secondary KIT or PDGFRA mutations. Studies comparing 400 with 800 mg IM daily in advanced disease showed no clinical benefit of IM 800 mg daily, except for tumours with KIT exon 9 mutations [
33]. Despite this, dose escalation to 800 mg can be beneficial in up to 30% of patients upon disease progression on 400 mg [
2,
19,
20]. IM plasma concentration measurements have not been performed in dose escalation studies, and perhaps only patients with sub-therapeutic IM levels will benefit from this strategy, whereas the remainder should be offered second-line therapy.
Total IM plasma concentration was measured in our study. Another option is to measure free drug concentrations; i.e. the pharmacologically active fraction not bound by albumin or AGP. The area under the PK curve (AUC) for IM, which can either be measured directly or as the correction of the total drug concentration for binding to AGP, may provide a better surrogate for cellular drug exposure than total IM concentration [
15,
26]. Furthermore, IM concentration measurement in the cytoplasm of the tumour cells could even more precisely predict target inhibition and clinical efficacy. A new approach to measurement of intracellular levels of IM in an in vivo setting has been developed, and there were large variation in IM concentrations between plasma, adipose tissue, and different sites within a given tumour [
34]. Although only three patients were included in the latter study, this highlights the importance of further clinical investigations on measurements of intracellular IM levels in GIST tissues to understand their possible impact on patient outcome.
Among the limitations of this study are the retrospective registration of the majority of the clinical data and side effects. We neither did review of the radiology nor the pathology, but experienced sarcoma radiologists and pathologists at a major reference centre had already confirmed the diagnostic work-up at start of IM, including analyses of KIT and PDGFRA mutations that were found in all patients except three. Furthermore, patients with <3 plasma samples were excluded, and median treatment duration of IM before inclusion was 25 months. Even though patients were not excluded due to progressive disease, a bias towards patients without progression could have occurred. Moreover, the plasma samples were not drawn at trough time, but a validated method to extrapolate the samples to trough was used [
25]. Even though these issues in general would be considered as shortcomings, they reflect well a routine oncology practice, and our findings could therefore easily be transferred to a routine clinical setting.
In conclusion, our results do not support repeated monitoring of IM levels on a routine basis in all patients. However, we have revealed clinical scenarios where drug measurement could be beneficial, such as for patients who have undergone gastric resection, suspicion of non-compliance, subjectively reported side effects, in elderly patients and at the time of disease progression. Whether dose escalation could be beneficial at disease progression for patients with low IM plasma concentration should be further studied.
Authors’ contributions
IH, OSB and KB were responsible for the concept and design of the study. IH, OSB and KB collected and assembled the clinical data and the plasma samples. KU and JB analysed the plasma IM concentrations. IH and KB analysed the final data. All authors read and approved the final manuscript.