Abstract
Background
Imatinib re-challenge is one of the available therapeutic options for patients with treatment-refractory gastrointestinal stromal tumours (GIST). Intermittent dosing of imatinib was suggested to delay outgrow of the imatinib-resistant clones in a preclinical study, and it could potentially reduce the adverse events.
Methods
A randomised phase 2 study was performed to evaluate the efficacy and safety of a continuous or intermittent imatinib schedule in GIST patients whose disease had progressed to at least imatinib and sunitinib.
Results
Fifty patients were included in the full analysis set. The disease control rate at 12 weeks was 34.8% and 43.5%, and median progression-free survival was 1.68 and 1.57 months in the continuous and intermittent groups, respectively. The frequency of diarrhoea, anorexia, decreased neutrophil, or dysphagia was lower in the intermittent group. The scores for global health status/quality of life was not significantly deteriorated over the 8 weeks in both groups.
Conclusions
The intermittent dosage did not improve the efficacy outcomes as compared to the continuous dosage, but showed slightly better safety profiles. Given the limited efficacy of imatinib re-challenge, intermittent dosage may also be considered in clinical circumstances where standard fourth-line agent is unavailable or all other viable treatments failed.
Subject terms: Gastric cancer, Outcomes research
Introduction
Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumour arising in the gastrointestinal tract. Since the landmark discoveries of the key oncogenic mutations in KIT and PDGFRA, molecularly targeted tyrosine kinase inhibitors (TKIs) have been the mainstay of GIST treatment. Imatinib is the robust standard first-line agent for patients with metastatic GIST, with efficacy against KIT and PDGFRA tyrosine kinases [1–3]. The first multicenter phase 2 trial (B2222) [4, 5] and the phase 3 SWOG [6] and EORTC [7] trials have shown an objective response rate (ORR) of 45–68%, a median progression-free survival (PFS) of 1.7–2.0 years and a median overall survival (OS) about 5 years. As treatment experiences with imatinib accumulate, it has become that survival outcomes with imatinib could be further improved. For example, the median PFS and OS of first-line imatinib treatment were reportedly up to 5.4 and 8.8 years, respectively, at a large volume centre, accompanied by the appropriate surgical interventions and management of adverse events [8]. This further highlights the importance of imatinib in the treatment of metastatic or unresectable GIST.
After clinical failure with imatinib, sunitinib [9] and regorafenib [10] are the standard second- and third-line agents, respectively. Recently, the INVICTUS study showed that a novel tyrosine kinase inhibitor ripretinib significantly improved PFS [11], which led to its Food and Drug Administration (FDA) approval as a fourth-line treatment. Another recent phase 3 study also showed that the HSP90 inhibitor pimitespib prolonged PFS in patients with refractory GIST [12].
One of the available treatment options for treatment-refractory GIST is the resumption of imatinib. In the phase 3 RIGHT study, we previously demonstrated a PFS benefit of imatinib re-challenge over placebo (median PFS 1.8 vs. 0.9 months) in advanced GIST patients whose disease had progressed at least on prior imatinib and sunitinib [13]. The rationale for the re-use of imatinib in a TKI-refractory setting is that GIST clones that retain sensitivity to imatinib may persist among the clones harbouring different sensitivities to different TKIs. This concept is supported by the spatial heterogeneity of secondary resistance mutations during polyclonal evolution [14–16] and differential sensitivity among the secondary mutations to subsequent treatments [17–19]. The clinical benefit seen in patients who resumed imatinib in the RIGHT study appears to be attributable to anti-tumour efficacy against imatinib-sensitive GIST clones.
While the standard imatinib administration schedule is once-daily 400 mg without drug holidays, another dosing schedule may be considered for heavily treated GIST. In a preclinical study by Grunewald et al., it was shown that imatinib might promote the growth of imatinib-resistant GIST clones with secondary mutations, whereas intermittent dosing of imatinib delayed the outgrow of the imatinib-resistant clones [20]. In that study, it was conceptually suggested that selective pressure by imatinib and partial KIT inhibition in the imatinib-resistant GIST clones may reduce the oncogenic stress of kinase hyperactivation, contributing to the overgrowth of tumours with a predominance of imatinib-resistant cells. These results support the concept that intermittent dosing of imatinib might delay the growth of tumours heterogeneously composed of imatinib-resistant and imatinib-sensitive clones. On the other hand, although imatinib is generally tolerable, some adverse events may negatively affect the clinical course of GIST patients receiving imatinib, which may be a particular issue for heavily treated GIST patients with a high tumour burden. Periodic resting from imatinib treatment may provide these patients with a chance for relief from adverse events.
In this randomised phase 2 study, we aimed to evaluate the efficacy and safety of continuous or intermittent imatinib dosing schemes in GIST patients who had progressed at least to imatinib and sunitinib.
Patients and methods
Study design and patients
This was a single-centre, randomised and open-label phase 2 clinical trial. The eligibility criteria were as follows: age 19 years or older; histologically confirmed metastatic or unresectable GIST that had been histologically confirmed by the detection of CD117 on immunohistochemical staining or genetically confirmed by the detection of a mutation in the KIT or PDGFRA genes on direct sequencing of tumour DNA; prior disease progression while being treated with imatinib (400 mg/day) and sunitinib sequentially; documented clinical benefit with previous first-line imatinib therapy, defined as a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months; expected life expectancy of greater than 12 weeks in the absence of any intervention; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2; and adequate bone marrow, liver, and renal function.
The protocol of this study was approved by the Institutional Review Board of Asan Medical Center and it was conducted in accordance with the ethical principles of the Declaration of Helsinki and within the Good Clinical Practice Guidelines, as defined by the International Conference on Harmonization. All patients provided written informed consent before enrolment. This study was registered with clinicaltrial.gov (NCT 02712112).
Procedure
Patients were randomly assigned to receive continuous or intermittent dosing of imatinib treatment (1:1) by an interactive web-response system that used a computer-generated random assignment list. Stratification factors for randomisation were ECOG performance status (0–1 vs. 2) and prior receipt of regorafenib treatment. Patients in the intermittent dosing group received 400 mg daily imatinib based on a 1-week-on and 1-week-off schedule (intermittent group), whereas those in the continuous dosing group (continuous group) received imatinib 400 mg daily without drug holidays. In both treatment arms, 4 weeks of treatment was considered one cycle. Imatinib dose modification or interruption was considered for grade 3–4 haematological toxicities (excluding anaemia) and grade 2–4 non-haematological toxicities. The study drug was provided by HK inno.N Corp (Seoul, Republic of Korea).
For response assessments, CT scans were performed every 4 weeks for the first 4 months of study and every 8 weeks thereafter. Additional imaging was done if clinically indicated. Tumour responses were determined by the investigators in accordance with modified RECIST v1.1. Toxicity was evaluated before each treatment cycle according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 4.03.
At the time of disease progression, patients were allowed to cross-over to receive the continuous dosing scheme of imatinib therapy at a 400 mg once-daily dose if they had been originally assigned to the intermittent dosing group, or to the intermittent dosing scheme of imatinib if they had been initially assigned to the continuous imatinib group. In both cases, cross-over was done at the discretion of the investigator in shared decision-making with the patient.
For exploratory analysis, we collected plasma samples from this study population and are planning to investigate the possible utility of circulating tumour DNA analysis in future studies.
Study endpoint
The primary endpoint was the disease control rate (DCR) rate at 12 weeks. The secondary endpoints included ORR, PFS and OS, as well as the safety profiles according to NCI-CTC v4.03.
Quality of life assessment
Health-related quality of life (QoL) was assessed as one of the secondary endpoints using the European Organization for Research and Treatment Quality of Life Questionnaire C30 (EORTC QLQ-C30), version 3.0 [21]. The EORTC QLQ-C30 questionnaire evaluates the global health status/QoL scale, five functional scales (physical, role, emotional, cognitive, and social) and nine symptom scales/items (fatigue, nausea/vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). QoL was assessed at baseline (before the start of study treatment) and every 4 weeks during study treatment.
Scores for each scale/item were linear transformed in a range from 0 to 100, in which a high score in global health status/QoL and functional scales represents high levels of QoL and functioning, respectively, whereas a high score in the symptom scales/items represents high levels of symptomatology/problems [21].
As previously described in the QoL analysis of the RIGHT study [22], the analysis was conducted during the first 8 weeks of study treatment, considering the possibility that the QoL analysis after this time-point may cause bias due to a substantial proportion of patients with disease progression.
Statistical analysis
Considering that the DCR rate at 12 weeks of the patients treated with continuous imatinib dosing was 30% in the RIGHT study [13], we assumed that a continuous or intermittent imatinib dosing scheme would also result in 30% of the DCR rate at 12 weeks. With a one-sided type I error of 5% and a power of 0.9, the required sample size by Fleming’s one-stage optimal design was 50. Efficacy and safety data were analysed based on the full analysis set (FAS), which included those patients who received at least one dose of the study drug. PFS was defined as the interval from randomisation to the date of disease progression (PD) or death. OS was defined as the time from randomisation to death from any cause. We used Kaplan–Meier curves to estimate PFS and OS. The chi-square test or Fisher’s exact test was used to compare the categorical variables among the subgroups. The baseline scores were compared using the t-test between two groups. Two-way analysis of variance (ANOVA) with repeated measures was used to compare the evolution of the QoL parameters with time between the two arms. Analysis of covariance (ANCOVA) was used to compare the QoL parameters between the two arms during each cycle of study treatment by adjusting for the baseline values. A P value of <0.05 was considered statistically significant. The statistical analyses were performed using R software version 3.6.2 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Study patients
Between May 2016 and October 2019, 51 patients were randomised. After excluding one patient who did not receive imatinib treatment as part of this study treatment because of rapid clinical deterioration, 50 patients were included in the FAS: 26 and 24 patients were allocated to the intermittent and continuous groups, respectively. The baseline patient characteristics are shown in Table 1. For both groups, the small bowel was the most frequent primary tumour site and KIT exon 11 mutation was the most common primary genotype. More than half of the patients had received first-line imatinib (400 mg daily) for at least 2 years. As third or later lines of treatment, most patients (n = 46) had received prior regorafenib and 40% of patients (n = 26) had received investigational treatments as part of clinical trials. As a subsequent treatment following the study treatment, 4 patients who had not previously received regorafenib were treated with regorafenib, 15 patients participated in clinical trials and received experimental treatments. The others were either treated with or without imatinib according to the clinical circumstances.
Table 1.
Clinical characteristics of the study patients.
| Variables | Continuous group (n = 24) | Intermittent group (n = 26) |
|---|---|---|
| Median age, years (range) | 60 (40–84) | 64.5 (32–91) |
| Male sex | 17 (70.8%) | 15 (57.7%) |
| ECOG PS | ||
| 0–1 | 21 (87.5%) | 23 (88.5%) |
| 2 | 3 (12.5%) | 3 (11.5%) |
| Primary tumour site | ||
| Stomach | 6 (25.0%) | 8 (30.8%) |
| Small bowel | 16 (66.7%) | 15 (57.7%) |
| Others | 2 (8.3%) | 3 (11.5%) |
| Prior third or later lines of therapy | ||
| Regorafenib | 23 (95.8%) | 23 (88.5%) |
| Investigational agent | 8 (33.3%) | 12 (46.2%) |
| Duration of previous first-line imatinib (400 mg/day) | ||
| ≤12 months and >6 months | 8 (33.3%) | 4 (15.4%) |
| ≤24 and >12 months | 4 (16.7%) | 7 (26.9%) |
| >24 months | 12 (50.0%) | 15 (57.7%) |
| Duration of previous second-line sunitinib | ||
| ≤6 months | 9 (37.5%) | 14 (53.8%) |
| >6 months | 15 (62.5%) | 12 (46.2%) |
| Duration of previous third-line regorafenib | (n = 23) | (n = 23) |
| ≤6 months | 11 (47.8%) | 10 (43.5%) |
| >6 months | 12 (52.2%) | 13 (56.5%) |
| Primary genotype | ||
| KIT exon 11 mutation | 13 (54.2%) | 17 (65.4%) |
| KIT exon 9 mutation | 8 (33.3%) | 6 (22.2%) |
| Others | 1 (4.2%)a | 3 (11.1%)b |
Data are presented as no. (%) or median (range).
ECOG Eastern Cooperative Oncology Group, PS performance status.
aWithout KIT or PDGFRA mutations (n = 1).
bWithout KIT or PDGFRA mutations (n = 2), KIT exon 13 mutation (n = 1).
Efficacy outcomes
The DCR rate at 12 weeks was 34.8 and 43.5% in the continuous and intermittent groups, respectively. The median PFS was 1.68 months (95% confidence interval [CI] 0.86–2.70) and 1.57 months (95% CI 0.89–3.58) in the continuous and intermittent groups, respectively (Fig. 1a). The median OS was 8.53 months (95% CI 5.16–11.77) and 8.81 months (95% CI 3.02–15.22) in the continuous and intermittent groups, respectively (Fig. 1b).
Fig. 1. Survival outcomes of patients in the continous and intermittent groups.
Progression-free survival a and overall survival b.
While there was one patient who achieved a PR in the intermittent group (ORR 4.3%), there was no patient who achieved a CR or PR in the continuous group (ORR 0%) (Table 2).
Table 2.
Response to continuous or intermittent imatinib treatment.
| Continuous group | Intermittent group | |
|---|---|---|
| Best response | ||
| Complete response | 0 (0.0%) | 0 (0.0%) |
| Partial response | 0 (0.0%) | 1 (4.3%) |
| Stable disease | 8 (34.8%) | 9 (39.1%) |
| Progressive disease | 15 (65.2%) | 13 (56.5%) |
| Overall response rate | 0 (0.0%) | 1 (4.3%) |
After disease progression was confirmed, 14 (58.3%) in the continuous group crossed over to the intermittent imatinib dosing scheme, while 15 (57.7%) patients in the intermittent group crossed over to the continuous imatinib dosing scheme. The median PFS of the corresponding patients were 1.46 months (95% CI 0.79–2.79) and 1.74 months (95% CI 1.01–not applicable), respectively (Supplementary Fig. 1). There was no difference in the survival outcomes between those with KIT exon 11 mutation and those without (P = 0.44 and P = 0.67 for PFS, and OS, respectively).
Safety outcomes
The profiles of the adverse events are summarised in Table 3. The most common adverse event of any grade was anaemia. Between the continuous and intermittent groups, there was no overall difference in the frequency of any grade (100% vs. 96.3%) or grade 3–4 adverse event (37.5% and 38.5%). Patients in the intermittent group showed a lower frequency of any grade adverse event (diarrhoea [3.8% vs. 20.8%], anorexia [0% vs. 16.7%], decreased neutrophil count [0% vs. 12.4%] and dysphagia [0% vs. 12.5%]) than those in the continuous group. On the other hand, the frequency of abdominal pain was higher in the intermittent group (46.2% vs. 25.0%). Two patients in the continuous group underwent dose modification, and there was no patient who discontinued the study treatment because of adverse events related to the study treatment.
Table 3.
Comparison of the frequency of adverse events.
| NCI-CTCAE v4.03 | Any grade | Grade 3–4 | ||
|---|---|---|---|---|
| Continuous group | Intermittent group | Continuous group | Intermittent group | |
| Any adverse events | 24 (100%) | 25 (96.3%) | 9 (37.5%) | 10 (38.5%) |
| Fatigue | 6 (25.0%) | 5 (19.2%) | – | – |
| Anorexia | 4 (16.7%) | 0 (0%) | 2 (8.3%) | 0 (0%) |
| Dysphagia | 3 (12.5%) | 0 (0%) | – | – |
| Pain (abdominal) | 6 (25.0%) | 12 (46.2%) | 1 (4.2%) | 2 (7.7%) |
| Nausea | 7 (29.2%) | 7 (26.9%) | – | – |
| Diarrhoea | 5 (20.8%) | 1 (3.8%) | 0 (0%) | 1 (3.8%) |
| Oedema | 8 (33.3%) | 9 (34.6%) | – | – |
| Bleeding | 1 (4.2%) | 4 (15.4%) | 1 (4.2%) | 3 (11.5%) |
| Dizziness | 2 (8.3%) | 3 (11.5%) | – | – |
| Abdominal distension | 1 (4.2%) | 3 (11.5%) | – | – |
| Anaemia | 21 (87.5%) | 22 (84.6%) | 4 (16.7%) | 5 (19.2%) |
| Neutrophil count decreased | 3 (12.5%) | 0 (0%) | 1 (4.2%) | 0 (0%) |
| Hypoalbuminaemia | 15 (62.5%) | 12 (46.2%) | 0 (0%) | 2 (7.7%) |
| AST increased | 10 (41.7%) | 11 (42.3%) | 0 (0.0%) | 3 (11.5%) |
| ALT increased | 6 (25.0%) | 8 (30.8%) | 0 (0%) | 3 (11.5%) |
| ALP increased | 13 (54.2%) | 10 (38.5%) | 1 (4.2%) | 0 (0%) |
| Bilirubin increased | 6 (25.0%) | 6 (23.1%) | 1 (4.2%) | 5 (19.2%) |
| Creatinine increased | 6 (25.0%) | 7 (26.9%) | – | – |
Adverse events occurring in ≥10% of patients of either of the group.
AST aspartate aminotransferase, ALT alanine aminotransferase, ALP alkaline phosphatase.
Quality of life
Among those who received the study treatment at each time (eligible for QoL analysis), most completed the QoL questionnaire (evaluable for QoL analysis) (Supplementary Table 1). At baseline, the scores for global health status/QoL and scales for functioning and symptoms were comparable between the intermittent and continuous groups (Supplementary Table 2).
When the EORTC QLQ-C30 parameters were longitudinally compared for the first 8 weeks of the study treatment, there was no significant deterioration in global heath/QoL, functional scales (Table 4 and Fig. 2), or symptom scales (Table 4 and Supplementary Fig. 2) in either group. The corresponding values, which were adjusted for baseline measures by ANCOVA, were also comparable between the two groups at 4 and 8 weeks after initiation of study treatment, respectively (Table 4).
Table 4.
Comparison of the quality of life parameters during study treatment.
| EORTC QLQ-C30 | Repeated measures ANOVA test for baseline–8 weeks | Scores at 4 weeks after baseline adjustment | Scores at 8 weeks after baseline adjustment | ||||
|---|---|---|---|---|---|---|---|
| P value | Continuous | Intermittent | P value | Continuous | Intermittent | P value | |
| LS mean (SE) | LS mean (SE) | LS mean (SE) | LS mean (SE) | ||||
| Global health status/QoL | 0.377 | 58.5 (4.54) | 48.0 (4.65) | 0.128 | 59.9 (6.07) | 56.5 (6.61) | 0.724 |
| Functioning | |||||||
| Physical | 0.469 | 66.5 (4.50) | 70.1 (4.71) | 0.587 | 72.6 (6.58) | 68.1 (7.13) | 0.452 |
| Role | 0.271 | 60.1 (5.40) | 64.4 (5.66) | 0.589 | 68.7 (8.03) | 62.9 (8.69) | 0.631 |
| Emotional | 0.551 | 73.5 (3.20) | 72.0 (3.27) | 0.743 | 70.8 (6.03) | 75.1 (6.52) | 0.636 |
| Cognitive | 0.967 | 75.5 (4.66) | 75.6 (4.76) | 0.993 | 76.7 (4.85) | 74.4 (5.25) | 0.759 |
| Social | 0.315 | 64.5 (5.08) | 72.2 (5.32) | 0.300 | 67.7 (6.12) | 65.5 (6.61) | 0.804 |
| Symptoms | |||||||
| Fatigue | 0.751 | 47.7 (4.16) | 40.3 (4.26) | 0.221 | 41.9 (7.21) | 39.1 (7.79) | 0.799 |
| Nausea/vomiting | 0.580 | 24.5 (4.75) | 25.2 (4.86) | 0.915 | 29.9 (6.39) | 22.1 (6.92) | 0.420 |
| Pain | 0.071 | 30.6 (4.94) | 32.4 (5.05) | 0.790 | 19.1 (7.10) | 40.3 (7.69) | 0.057 |
| Dyspnoea | 0.820 | 28.9 (5.67) | 28.9 (5.80) | 0.999 | 31.1 (6.20) | 24.8 (6.70) | 0.501 |
| Insomnia | 0.268 | 34.3 (6.11) | 43.0 (6.25) | 0.324 | 28.9 (7.95) | 46.9 (8.59) | 0.140 |
| Appetite loss | 0.603 | 31.4 (6.53) | 33.8 (6.68) | 0.798 | 36.4 (9.00) | 29.7 (9.72) | 0.616 |
| Constipation | 0.113 | 14.9 (4.95) | 28.4 (5.07) | 0.064 | 12.3 (5.59) | 19.0 (6.04) | 0.419 |
| Diarrhoea | 0.285 | 17.4 (5.08) | 29.6 (5.08) | 0.096 | 33.5 (5.89) | 19.2 (6.36) | 0.112 |
| Financial difficulties | 0.499 | 20.8 (5.33) | 28.3 (5.46) | 0.347 | 25.7 (6.10) | 28.4 (6.60) | 0.766 |
ANOVA analysis of variance, LS least squares, QoL quality of life, SE standard error.
Fig. 2.
Longitudinal assessment of EORTC QLQ-C30 parameters of global health and functional scales for the first 8 weeks of the study treatment.
Discussion
In this randomised phase 2 study, we assessed the efficacy and safety of continuous or intermittent imatinib treatment in TKI-refractory GIST patients who mostly received prior regorafenib. The DCR rate at 12 weeks was 34.8% and 43.5% in patients who received continuous and intermittent imatinib treatment, respectively, which was at least non-inferior to that reported in the RIGHT study (investigator-assessed, 32%). Intermittent imatinib dosing was generally tolerable, with a slightly better safety profile, compared to continuous imatinib dosing. Our results highlight that imatinib re-challenge on a continuous dosing scheme is as effective as in the RIGHT study, and an intermittent imatinib dosing scheme can be considered one of the therapeutic options for patients with GIST refractory to standard TKIs.
Given the widespread use of regorafenib in clinical practice and clinical trials of novel agents since the RIGHT study, the efficacy of imatinib re-challenge needed to be confirmed in this clinical context. Indeed, only about 40% of patients received third or later lines of treatment including regorafenib in the RIGHT study, whereas most patients had received regorafenib and about 40% of patient had received other investigational treatment as part of clinical trials in our study. The slightly shorter median PFS (1.68 and 1.57 months for intermittent and continuous groups, respectively) compared to the historical data of the RIGHT trial (1.8 months) [13] appears to be attributable to the inclusion of more heavily treated patients. Nevertheless, the median OS (8.53 and 8.81 months for the continuous and intermittent groups, respectively) was comparable with the median OS of 8.2 months of the imatinib group in the RIGHT study. In addition, the DCR at 12 weeks of the continuous (34.8%) and intermittent (43.5%) groups were higher than that of the placebo group in the RIGHT study (5%). These results suggest that, as demonstrated in the RIGHT study, imatinib resumption either in a continuous or intermittent dosing scheme provided clinical benefit, although the benefit was still limited.
With ripretinib being the global standard fourth-line treatment based on the INVICTUS trial, the role of imatinib re-challenge, either continuously or intermittently, would be less clinically relevant than previously. However, despite the approval of ripretinib by the FDA and European Medicines Agency, the actual access to ripretinib is still limited in many areas. Also, the financial burden of this novel agent may preclude its routine use according to various clinical situations. Therefore, in areas without access to ripretinib, our findings may be still clinically relevant when there is no available treatment option. Therefore, although imatinib re-challenge is not a global standard fourth-line treatment in the era of ripretinib, it may be considered for GIST patients who failed to all other available treatment options including ripretinib.
Intermittent dosing of anti-cancer treatment has been classically considered to reduce treatment-related toxicities when at least a non-inferior therapeutic efficacy was expected [23–26]. In a retrospective analysis of patients with chronic myeloid leukaemia, an intermittent dosage of imatinib was tested in an attempt to prevent serious haematologic toxicities, and it was associated with a sustained cytogenetic response [27]. We designed this study based on a notion that the intermittent dosing scheme may be acceptable even though this may not necessarily be associated with superior efficacy outcomes, given the probability that the intermittent dosing scheme may have an advantage in terms of the toxicity profiles. The standard-treatment control arm (continuous group) served as a reference to recapitulate the historical control patients in this clinical setting where regorafenib was more prevalently used. Therefore, this study was not designed to directly compare the continuous versus intermittent imatinib treatment and a statistical comparison is not possible, but our results suggest that the clinical efficacy of an intermittent imatinib dosing scheme was at least non-inferior to that of a continuous imatinib dosing scheme in heavily treated GIST patients. An intermittent imatinib dosing schedule was also generally tolerable with a similar overall frequency of any grade or grade 3–4 adverse events between the two groups. Of note, the intermittent dosing scheme was associated with a lower proportion of any grade anorexia, dysphagia, diarrhoea and neutropenia, which appears to be attributable to the resting period from imatinib. On the other hand, a higher frequency of abdominal pain was observed in the intermittent group. This is in line with the symptom aggravation during the resting period of TKIs reported in previous GIST studies [28, 29]. Nevertheless, it can be said that intermittent imatinib dosing was overall well tolerated with a slightly better safety profile in heavily treated GIST patients. Together with its efficacy and safety profiles, the safety profiles of intermittent imatinib dosage also support its clinical use in this clinical context. In particular, intermittent imatinib dosage may be not only a tolerable but also a financially feasible option, especially in circumstances in which imatinib resumption is not reimbursed or is financially burdensome.
In a previous analysis of the RIGHT study, QoL was not impaired over the course of the resumption of imatinib despite increased frequencies of grade 3–4 adverse events such as oedema, fatigue, nausea and vomiting compared to placebo [13, 22]. Similarly, the measures of QoL were not significantly impaired with either continuous or intermittent imatinib re-challenge in the current analysis. These results suggest that the benefit of imatinib may outweigh its toxicities and supports the clinical relevance of these therapeutic approaches in a heavily pretreated clinical setting for GIST patients.
Given the distinct patterns of polyclonal evolution of GIST when acquiring clinical resistance [14, 16], intermittent treatment with imatinib was suggested to have beneficial aspects of delaying the outgrow of mixed populations of imatinib-sensitive and imatinib-resistant clones in a preclinical study [20]. However, this concept of potentially better tumour control by an intermittent-dosing schemed was not well-supported by our data. Currently, it remains unknown whether intermittent administration of imatinib indeed differentially affects the growth of imatinib-sensitive and imatinib-resistant GIST clones. Considering the comparable efficacy between an intermittent and continuous imatinib dosage, we assume that periodic inhibition of imatinib-sensitive clones may be sufficient to achieve a clinically relevant delay in tumour growth in this regard. Studying the dynamic changes in the proportion of imatinib sensitive- and resistant- clones using circulating tumour DNA in future studies may help to understand better the complex dynamics in this clinical setting. In this regard, we collected plasma samples from this study population and are planning to address this issue by circulating tumour DNA analysis in future studies. Also, the impact of the imatinib dosing schedule on the growth kinetics of tumour nodules harbouring different proportions of imatinib-sensitive and imatinib-resistant clones should be further explored.
There are some limitations to be discussed in this study: the number of patients included in the current study was relatively small and this study was based on a single centre, which somewhat limits the generalisability of our findings. As this study did not aim to directly compare the continuous versus intermittent dosing schemes, the results would be primarily for hypothesis generating, rather than drawing a definite conclusion.
In conclusion, an intermittent dosing schedule did not improve the efficacy outcomes as compared to continuous dosing schedule. Given the limited efficacy of imatinib re-challenge, the slightly better safety profiles of the intermittent imatinib dosage suggest that it may also be considered in TKI-refractory GIST patients in clinical circumstances in which ripretinib is unavailable or all other viable treatments including ripretinib failed.
Supplementary information
Acknowledgements
The study drug was supplied by HK inno.N Corp. This study was presented in part at the ASCO Annual Meeting 2022.
Author contributions
Study concepts: YKK; data acquisition: H-DK, CY, M-HR and Y-KK; quality control of data and algorithms: H-DK, CY, M-HR and Y-KK; data analysis and interpretation: H-DK, CY, M-HR and Y-KK; statistical analysis: H-DK, CY, M-HR and YKK; manuscript preparation: H-DK and Y-KK; manuscript editing: H-DK, CY, M-HR and Y-KK; manuscript review: H-DK, CY, M-HR and Y-KK.
Funding
None.
Data availability
Not applicable.
Competing interests
There are no competing interests directly related to this work. Out of this work, Y-KK has served as a consultant for ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics, Daehwa, Blueprint, Surface Oncolgy, BMS, Merck (MSD). M-HR received honoraria from DAEHWA Pharmaceutical, Bristol Myers Squibb, Lilly, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, Daiichi Sankyo and AstraZeneca, and served as a consultant for DAEHWA Pharmaceutical, Bristol Myers Squibb, Lilly and Ono Pharmaceutical. CY received honoraria from Servier, Bayer, AstraZeneca, Merck Sharp & Dohme, Eisai, Celgene, Bristol Myers Squibb, Debiopharm, Ipsen, Kyowa Kirin, Novartis, Boryung Pharmaceuticals, Merck Serono, Mundipharma, Roche, and Janssen, and received research grants from Servier, Bayer, AstraZeneca, Ono Pharmaceuticals, Celgene, Ipsen, Boryung Pharmaceuticals, Ildong Pharmaceuticals, CKD Pharmaceuticals, and HK inno.N.
Ethics approval and consent to participate
The protocol of this study was approved by the Institutional Review Board of Asan Medical Center and it was conducted in accordance with the ethical principles of the Declaration of Helsinki and within the Good Clinical Practice Guidelines, as defined by the International Conference on Harmonization. All patients provided written informed consent before enrolment. This study was registered with clinicaltrial.gov (NCT 02712112).
Consent for publication
Not applicable.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Hyung-Don Kim, Changhoon Yoo.
Supplementary information
The online version contains supplementary material available at 10.1038/s41416-023-02269-z.
References
- 1.Casali PG, Blay JY, Abecassis N, Bajpai J, Bauer S, Biagini R, et al. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021. 10.1016/j.annonc.2021.09.005. [DOI] [PubMed]
- 2.NCCN. National Comprehensive Cancer Network guideline, gastrointestinal stromal tumors (GISTs) (version 1.2021). Plymouth Meeting, PA: NCCN; 2021.
- 3.Koo DH, Ryu MH, Kim KM, Yang HK, Sawaki A, Hirota S, et al. Asian Consensus Guidelines for the Diagnosis and Management of Gastrointestinal Stromal Tumor. Cancer Res Treat. 2016;48:1155–66. doi: 10.4143/crt.2016.187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–80. doi: 10.1056/NEJMoa020461. [DOI] [PubMed] [Google Scholar]
- 5.Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620–5. doi: 10.1200/jco.2007.13.4403. [DOI] [PubMed] [Google Scholar]
- 6.Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26:626–32. doi: 10.1200/jco.2007.13.4452. [DOI] [PubMed] [Google Scholar]
- 7.Casali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner LH, et al. Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group Intergroup Phase III Randomized Trial on Imatinib at Two Dose Levels. J Clin Oncol. 2017;35:1713–20. doi: 10.1200/jco.2016.71.0228. [DOI] [PubMed] [Google Scholar]
- 8.Kim JH, Ryu MH, Yoo C, Chae H, Na H, Beck M, et al. Long-term survival outcome with tyrosine kinase inhibitors and surgical intervention in patients with metastatic or recurrent gastrointestinal stromal tumors: a 14-year, single-center experience. Cancer Med. 2019;8:1034–43. doi: 10.1002/cam4.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329–38. doi: 10.1016/s0140-6736(06)69446-4. [DOI] [PubMed] [Google Scholar]
- 10.Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:295–302. doi: 10.1016/s0140-6736(12)61857-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Blay JY, Serrano C, Heinrich MC, Zalcberg J, Bauer S, Gelderblom H, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:923–34. doi: 10.1016/s1470-2045(20)30168-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Honma Y, Kurokawa Y, Sawaki A, Naito Y, Iwagami S, Baba H, et al. Randomized, double-blind, placebo (PL)-controlled, phase III trial of pimitespib (TAS-116), an oral inhibitor of heat shock protein 90 (HSP90), in patients (pts) with advanced gastrointestinal stromal tumor (GIST) refractory to imatinib (IM), sunitinib (SU) and regorafenib (REG). J Clin Oncol. 2021;39:11524.
- 13.Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013;14:1175–82. doi: 10.1016/s1470-2045(13)70453-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006;12:1743–9. doi: 10.1158/1078-0432.Ccr-05-1211. [DOI] [PubMed] [Google Scholar]
- 15.Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008;216:64–74. doi: 10.1002/path.2382. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Desai J, Shankar S, Heinrich MC, Fletcher JA, Fletcher CD, Manola J, et al. Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res. 2007;13:5398–405. doi: 10.1158/1078-0432.Ccr-06-0858. [DOI] [PubMed] [Google Scholar]
- 17.Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008;26:5352–9. doi: 10.1200/jco.2007.15.7461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.George S, Wang Q, Heinrich MC, Corless CL, Zhu M, Butrynski JE, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol. 2012;30:2401–7. doi: 10.1200/jco.2011.39.9394. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Serrano C, Mariño-Enríquez A, Tao DL, Ketzer J, Eilers G, Zhu M, et al. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J Cancer. 2019;120:612–20. doi: 10.1038/s41416-019-0389-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Grunewald S, Mühlenberg T, Rubin B, Schuler MH, Fletcher JA, Bauer S. Effect of secondary KIT mutations on growth of GIST cells in the absence of selective pressure by imatinib in isogenic models of imatinib resistance. J Clin Oncol. 2014;32:10555.
- 21.Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–76. doi: 10.1093/jnci/85.5.365. [DOI] [PubMed] [Google Scholar]
- 22.Yoo C, Ryu MH, Nam BH, Ryoo BY, Demetri GD, Kang YK. Impact of imatinib rechallenge on health-related quality of life in patients with TKI-refractory gastrointestinal stromal tumours: Sub-analysis of the placebo-controlled, randomised phase III trial (RIGHT) Eur J Cancer. 2016;52:201–8. doi: 10.1016/j.ejca.2015.10.071. [DOI] [PubMed] [Google Scholar]
- 23.Shah MA, Wainberg ZA, Catenacci DV, Hochster HS, Ford J, Kunz P, et al. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS ONE. 2013;8:e54014. [DOI] [PMC free article] [PubMed]
- 24.Dréno B, Kunstfeld R, Hauschild A, Fosko S, Zloty D, Labeille B, et al. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol. 2017;18:404–12. doi: 10.1016/s1470-2045(17)30072-4. [DOI] [PubMed] [Google Scholar]
- 25.Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368:1314–25. doi: 10.1056/NEJMoa1212299. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Algazi AP, Othus M, Daud AI, Lo RS, Mehnert JM, Truong TG, et al. Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial. Nat Med. 2020;26:1564–8. doi: 10.1038/s41591-020-1060-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Faber E, Nausová J, Jarosová M, Egorin MJ, Holzerová M, Rozmanová S, et al. Intermittent dosage of imatinib mesylate in CML patients with a history of significant hematologic toxicity after standard dosing. Leuk Lymphoma. 2006;47:1082–90. doi: 10.1080/10428190600565057. [DOI] [PubMed] [Google Scholar]
- 28.Son MK, Ryu MH, Park JO, Im SA, Kim TY, Lee SJ, et al. Efficacy and safety of regorafenib in korean patients with advanced gastrointestinal stromal tumor after failure of imatinib and sunitinib: a multicenter study based on the management access program. Cancer Res Treat. 2017;49:350–7. doi: 10.4143/crt.2016.067. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Raut C, Van Den Abbeele A, Ramaiya N, Morgan J, George S, Quigley M, et al. Patterns of PET response after long-term sunitinib therapy in patients (pts) with imatinib (IM)-resistant gastrointestinal stromal tumors (GIST). J Clin Oncol. 2006;24:9547.
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