Interruption of imatinib in advanced gastrointestinal stromal tumor after prolonged imatinib maintenance in the absence of gross tumor lesions.

BACKGROUND: Current guidelines recommend indefinite imatinib treatment for advanced gastrointestinal stromal tumor (GIST) patients. Imatinib-refractory progression-free survival (PFS) and overall survival were previously reported not to differ between GIST patients who interrupted imatinib and those who did not. METHODS: Clinical outcomes of 77 consecutive patients with recurrent or metastatic GIST who interrupted imatinib treatment after maintaining years of imatinib treatment in the absence of gross tumor lesions were retrospectively analyzed. Associations between clinical factors and progression-free survival (PFS) following imatinib interruption were analyzed. RESULTS: The median time from the absence of gross tumor lesions to imatinib interruption was 61.5 months. Since imatinib interruption, the median PFS was 19.6 months, and 4 patients (26.3%) remained progression-free for longer than 5 years. Among the patients who had progressive disease following the interruption, imatinib re-introduction led to an 88.6% objective response rate and a 100% disease control rate. Complete removal of the initial gross tumor lesion(s) and complete removal of the residual gross tumor lesion(s) by local treatment (vs. no local treatment or residual lesions after local treatment) were independently associated with favorable PFS. CONCLUSION: Interruption of imatinib following prolonged maintenance in the absence of gross tumor lesions led to disease progression in the majority of cases. However, re-introduction of imatinib resulted in effective tumor control. Unmaintained remission seems to be possible in some patients with metastatic or recurrent GIST after a prolonged remission with imatinib if there is complete removal of any gross tumor lesions.

Systemic Steroid Treatment for Imatinib-Associated Severe Skin Rash in Patients with Gastrointestinal Stromal Tumor: A Phase II Study.

BACKGROUND: To achieve optimal clinical outcomes in patients with gastrointestinal stromal tumor (GIST), it is crucial to maintain sufficient dosing of imatinib. Skin rash is a common imatinib-associated adverse event and may affect compliance. This phase II study was conducted to evaluate whether imatinib-associated severe skin rash can be managed with systemic steroids without dose reduction or interruption of imatinib. This study is registered at ClinicalTrials.gov, number NCT03440515. PATIENTS AND METHODS: Between 2014 and 2016, 29 patients with imatinib-associated severe skin rash were enrolled. Skin rash of grade 2 with grade ≥2 pruritus or of grade 3 was considered severe. Oral prednisolone was administered 30 mg/day for 3 weeks, then tapered off over 12 weeks. The primary endpoint was treatment success rate (TSR). Treatment success was defined as maintaining imatinib for more than 15 weeks after completion of the steroid administration schedule without skin rash that led to additional steroid treatment or dose reduction or interruption of imatinib. RESULTS: Of the 29 patients enrolled, 22 patients with skin rash were treated successfully (TSR, 75.8%), 2 (6.9%) were evaluated as treatment failures, and 5 (17.2%) were not evaluable. The 2-year rash-free and imatinib reduction-free interval rate was 67.2% with median follow-up of 22.0 months (range, 0.4-30.3). Recurrence of severe skin rash occurred in seven patients (24.1%). Systemic steroids were well tolerated except in one patient who experienced pneumocystis pneumonia. CONCLUSION: This study demonstrated that imatinib-associated severe skin rash can be effectively controlled by systemic steroid treatment without interruption or dose reduction of imatinib in patients with GIST. IMPLICATIONS FOR PRACTICE: Imatinib has been the standard treatment of gastrointestinal stromal tumor in both adjuvant and palliative settings. It is crucial to maintain sufficient dosing of imatinib to achieve optimal clinical outcomes. Imatinib commonly causes imatinib-associated skin rash, which may worsen drug compliance. This phase II study demonstrated that systemic steroids could help maintaining the efficacy of imatinib by preventing interruption or dose reduction of imatinib. The present study provides a new administration strategy of systemic steroids and its efficacy and safety data. Thus, this study can be a cornerstone to establish treatment guidelines for imatinib-associated skin rash.

Phase II Trial of Continuous Regorafenib Dosing in Patients with Gastrointestinal Stromal Tumors After Failure of Imatinib and Sunitinib.

BACKGROUND: Regorafenib at the standard intermittent dosing schedule proved effective in the GRID trial for refractory gastrointestinal stromal tumors (GISTs). However, this dosing schedule requires frequent dose reduction, and the progression of GISTs or tumor-related symptoms during the off-treatment period has also been noted in some patients. Therefore, we conducted this phase II trial to evaluate the efficacy and safety of regorafenib at a lower dose on a continuous dosing schedule. METHODS: Patients with measurable, metastatic, or recurrent GISTs who failed to respond to both imatinib and sunitinib were eligible for this study. Regorafenib 100 mg p.o. daily was administered continuously. The primary endpoint was disease control rate (DCR: complete response plus partial response [PR] plus stable disease [SD]) lasting for at least 12 weeks using RECIST version 1.1. RESULTS: The best response was PR in 2 (8%), SD in 16 (64%), and progressive disease in 6 (24%) patients. DCR lasting for at least 12 weeks was 64% (16 of 25). The median progression-free survival was 7.3 months (95% confidence interval, 5.9-8.6), and the 1-year survival rate was 64.5%. Ten patients (40%) experienced grade 3-4 toxicities, including hand-foot skin reaction (n = 4, 16%) and elevation of alanine aminotransferase (n = 2, 8%). Only six patients (24%) needed dose modification with a relative dose intensity of 95.0% for eight cycles in all patients. CONCLUSION: Regorafenib at a lower dose on a continuous schedule might be an alternative treatment in patients with GISTs after failure of imatinib and sunitinib. Clinical trial identification number. NCT02889328 IMPLICATIONS FOR PRACTICE: Regorafenib at the standard intermittent dosing schedule proved effective in the GRID trial for refractory gastrointestinal stromal tumors (GISTs). However, this dosing schedule requires frequent dose reduction, and the progression of GISTs or tumor-related symptoms during the off-treatment period has been noted in some patients. This study was to evaluate the efficacy and safety of regorafenib at a lower dose on a continuous dosing schedule. With good efficacy and acceptable safety profiles, regorafenib at a lower, continuously administered dose might be an alternative treatment in patients with GISTs after imatinib and sunitinib. Rechallenge of regorafenib may slow the disease progression.

Severe Imatinib-Associated Skin Rash in Gastrointestinal Stromal Tumor Patients: Management and Clinical Implications.

PURPOSE: This study evaluated the incidence of imatinib-associated skin rash, the interventional outcomes of severe rash, and impact of severe rash on the outcomes of imatinib treatment in gastrointestinal stromal tumor (GIST) patients. MATERIALS AND METHODS: A total of 620 patients were administered adjuvant or palliative imatinib for GIST at Asan Medical Center between January 2000 and July 2012. This analysis focused on a group of 42 patients who developed a severe rash requiring major interventions, defined as dose interruption or reduction of imatinib or systemic steroid use. RESULTS: Of the 620 patients treated with imatinib, 148 patients (23.9%) developed an imatinib-associated skin rash; 42 patients (6.8%) developed a severe rash requiring major intervention. Of these, 28 patients (66.8%) successfully continued imatinib with interventions. Serial blood eosinophil levels during imatinib treatment were associated with skin rash and severity. A significant association was observed between successful intervention and blood eosinophil level at the time of intervention initiation. In metastatic settings, patients with severe rash requiring major interventions tended to show poorer progression-free survival than patients who did not require major intervention and patients with no rash, although this finding was not statistically significant (p=0.326). CONCLUSION: By aggressive treatment of severe rash through modification of imatinib dose or use of systemic steroid, the majority of patients can continue on imatinib. In particular, imatinib dose intensity can be maintained with use of systemic steroid. Measuring the blood eosinophil levels may be helpful in guiding the management plan for skin rash regarding the intensity and duration of interventions.

Association of ABCG2 polymorphism with clinical efficacy of imatinib in patients with gastrointestinal stromal tumor.

PURPOSE: Imatinib is a substrate of drug transporters and metabolizing enzymes, including members of the cytochrome P450 (CYP) system. Differences in imatinib pharmacokinetics among individuals might be influenced by genetic polymorphisms and be associated with variable clinical imatinib efficacy. This study sought to test how genetic polymorphisms can affect the clinical efficacy of imatinib and its blood levels in GIST patients. METHODS: A total of 209 GIST patients who had received imatinib 400 mg daily were genotyped for six single-nucleotide polymorphisms in three genes (CYP3A5 6986A>G; ABCB1 1236C>T, 2677G>A/T, and 3435C>T; and ABCG2 34G>A and 421C>A) via blood samples. Progression-free survival (PFS) and imatinib plasma trough levels were evaluated and compared according to genotypes. RESULTS: With a median follow-up of 39.6 months (range 16.7-97.5 months), the estimated 5-year PFS rate was 67.5 % (95 % CI 59.9-75.1). Among the CYP3A5, ABCB1, and ABCG2 genotypes, ABCG2 421C>A was associated with PFS. The 5-year PFS rate in patients with the AA variant of ABCG2 421C>A (92.3 %; 95 % CI 77.8-100.0) was significantly superior to that of patients with CC/CA genotypes (65.0 %; 95 % CI 56.9-73.1; p = 0.047). For the imatinib trough levels, there were no statistically significant differences when comparing polymorphisms among all genotypes, even after adjusting for clinical factors, including sex, age, body surface area, hemoglobin, albumin, and creatinine clearance. CONCLUSIONS: The ABCG2 421C>A genetic variation could influence clinical efficacy in terms of PFS in patients with advanced GIST undergoing imatinib therapy.

Imatinib plasma monitoring-guided dose modification for managing imatinib-related toxicities in gastrointestinal stromal tumor patients.

Imatinib, the first-line treatment in patients with advanced gastrointestinal stromal tumors (GIST), is generally well tolerated, although some patients have difficulty tolerating the standard dose of 400 mg/day. Adjusting imatinib dosage by plasma level monitoring may facilitate management of patients who experience intolerable toxicities due to overexposure to the drug. We present two cases of advanced GIST patients in whom we managed imatinib-related toxicities through dose modifications guided by imatinib plasma level monitoring. Imatinib blood level testing may be a promising approach for fine-tuning imatinib dosage for better tolerability and optimal clinical outcomes in patients with advanced GIST.

Efficacy, safety, and pharmacokinetics of imatinib dose escalation to 800 mg/day in patients with advanced gastrointestinal stromal tumors.

Imatinib dose escalation has been suggested as an effective therapy for advanced gastrointestinal stromal tumors (GIST) after progression on the standard dose. We evaluated the efficacy, tolerability, and pharmacokinetics of imatinib dose escalation. Eighty-four patients with GIST who received imatinib 800 mg/day as second-line therapy were reviewed. In 66 patients, imatinib plasma trough level (Cmin) at 800 mg/day was measured. The relationships between imatinib exposure and therapeutic efficacy or toxicity were examined by grouping patients into quartiles according to Cmin and its percent change after dose escalation. Disease control was achieved in 56 % of patients. The median progression-free survival (PFS) was 5.1 months. There was a strong tendency for better PFS in patients with KIT exon 9 mutations compared to patients with other genotypes (median PFS 11 vs 4 months, p=0.051). The common grade 3-4 toxicities were anemia (26 %), neutropenia (11 %), and hemorrhage (5 %). Mean ± standard deviation imatinib Cmin at 800 mg/day and percent Cmin change was 3,552 ± 1,540 ng/mL and 160 ± 101 %, respectively. Body surface area, hemoglobin, and absolute neutrophil count were independent covariates of Cmin at 800 mg/day. Neither Cmin nor its percent change associated with efficacy. The upper three quartiles of percent Cmin change associated with more frequent severe toxicities (56 %) than the lowest quartile (10 %; p=0.01). Dose escalation to 800 mg/day was active and feasible in GIST after progression on the standard dose. Imatinib Cmin monitoring may help to manage the patients with standard dose-resistant GIST that may require dose escalation.

Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors: correlation between changes in covariates and imatinib exposure.

A pharmacokinetic study in patients with gastrointestinal stromal tumors (GIST) suggested that imatinib plasma concentration may decrease following long-term exposure. We assessed changes in imatinib plasma trough levels (C(min)) during long-term treatment. Follow-up (FU) imatinib C(min) was measured in 65 patients who received the same dose of imatinib for at least 9 months after previous (initial) tests. After exclusion of 7 patients who had been treated with imatinib for over 2 years at the time of initial testing, 58 patients were included in this analysis. The median intervals from initiation of imatinib to initial testing and from initial to FU testing were 5.5 months (range, 0.5-24.0 months) and 13.0 months (range, 9.6-17.9 months), respectively. Mean inter- and intra-subject variability values were 47.7% and 20.9%, respectively, at initial measurements, and 45.2% and 19.4%, respectively, at FU. Mean FU imatinib C(min) (1,370 ± 661 ng/mL) was significantly higher than mean initial C(min) (1,171 ± 573 ng/mL; p = 0.003). Compared with initial C(min), FU C(min) was decreased in 22 patients and increased in 36, with median changes of 13% and 32%, respectively. Multivariate analysis showed a significant correlation between the ratio of FU to initial imatinib C(min) and that of albumin (r = -0.39, p = 0.003). During long-term treatment, imatinib C(min) did not decrease significantly but remained stable or increased in most patients. Changes in imatinib C(min) were associated with changes in albumin concentration. Monitoring of imatinib C(min) only for concerns about time-dependent increases in imatinib clearance is not necessary.

Nilotinib in patients with GIST who failed imatinib and sunitinib: importance of prior surgery on drug bioavailability.

PURPOSE: To evaluate the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors (GISTs) resistant or intolerant to both imatinib and sunitinib and to explore the potential relationship between nilotinib pharmacokinetics and clinical outcomes. PATIENTS AND METHODS: We analyzed the efficacy, tolerability and pharmacokinetic parameters of nilotinib (400 mg twice daily) in 17 GIST patients with histories of prior gastrointestinal surgery. RESULTS: Median patient age was 59 years (range, 35-71 years), 14 of 17 patients (82.4%) were male, and mean body weight was 59.4 kg. Of the 17 patients, 2 (11.8%) had partial responses (PR), 10 (58.8%) had stable disease (SD), and 5 (29.4%) had progressive disease (PD), with a clinical benefit rate (CR + PR + SD) at 24 weeks of 47.0%. Median progression-free survival (PFS) and overall survival (OS) were 23.6 weeks (95% confidence interval [CI] 0.0-50.6 weeks) and 74.0 weeks (95% CI 27.4-120.6 weeks), respectively. Most observed adverse events were mild (grade 1, 41.2%; grade 2, 52.9%), with no grade 3/4 events. Pharmacokinetic parameters of nilotinib were as follows: C (max) of 1,754 ± 970 µg/L, T(1/2) of 13.4 ± 8.94 h and AUC (0-12 h) of 14,190 ± 6,853 h µg/L. The AUC (0-12 h) of nilotinib was significantly lower in the 4 patients with prior major (total or subtotal) gastrectomy than in the other 13 patients (8,526 ± 7,869 h µg/L vs. 15,930 ± 5,759 h µg/L, P = 0.014). Of the 4 gastrectomized patients, two (50%) showed markedly decreased nilotinib exposure (AUC (0-12 h) of 1,914 and 3,194 h µg/L) and rapid disease progression (PFS of 4.6 and 7.1 weeks). CONCLUSION: Nilotinib was active and safe in patients with advanced GIST resistant to both imatinib and sunitinib. Major gastrectomy decreased the bioavailability of nilotinib and, in some patients, lowered its clinical activity.

Cross-sectional study of imatinib plasma trough levels in patients with advanced gastrointestinal stromal tumors: impact of gastrointestinal resection on exposure to imatinib.

PURPOSE: Imatinib plasma trough levels (C(min)) have been reported to correlate with treatment outcomes in patients with gastrointestinal stromal tumors (GISTs). We therefore have evaluated the correlation between imatinib C(min) and the clinical characteristics of patients with GIST. PATIENTS AND METHODS: Steady-state imatinib C(min) in 107 patients with GIST who were taking imatinib 300 to 800 mg/d was measured. RESULTS: In patients treated with imatinib 400 (n = 92), 300 (n = 7), 600 (n = 2), or 800 (n = 11) mg/d, imatinib C(min) was 1,305 +/- 633 ng/mL, 1,452 +/- 830 ng/mL, 1,698 +/- 725 ng/mL, and 3,330 +/- 1,592 ng/mL, respectively. Of the 92 patients treated with 400 mg/d imatinib, 59 patients (63%) were men; the median age was 55 years (range, 28 to 76 years), and the median duration of imatinib use before sampling was 8.8 months (range, 0.5 to 67.6 months). The mean inter- and intrapatient variability rates were 44.7% and 26.5%, respectively. In univariate analyses, high C(min) was correlated with advanced age (P = .02), low creatinine clearance (P = .001), low hemoglobin (P = .03), and low albumin (P < .001) concentrations. Imatinib C(min) was also significantly lower in patients with (n = 18; 942 +/- 330 ng/mL) than without (n = 74; 1,393 +/- 659 ng/mL) major (ie, total or subtotal) gastrectomy (P = .002). In multivariate analysis, albumin (P = .001) concentrations, creatinine clearance (P = .002), and major gastrectomy (P = .003) were significantly correlated with C(min). CONCLUSION: In patients with GIST, imatinib C(min) at steady state was significantly associated with albumin concentration, creatinine clearance, and previous major gastrectomy. Although its clinical impact is unclear at present time, monitoring of imatinib C(min) might be particularly important for optimal treatment with imatinib in patients who have undergone major gastrectomy.