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

ABSTRACT: 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.

SUBMITTER: Kim EJ

PROVIDER: S-EPMC7648351 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Kim Eo Jin EJ Ryu Min-Hee MH Park Sook Ryun SR Beck Mo Youl MY Lee Woo Jin WJ Lee Mi Woo MW Kang Yoon-Koo YK

The oncologist 20200712 11

<h4>Background</h4>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. ...[more]

PMID: 32589310

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Project description:PurposeDual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST.MethodsIn this trial (NCT01991379), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in > 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity.ResultsBetween September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response (≥ 90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%).ConclusionThe study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.

Project description:PurposeThis phase Ib trial was designed to evaluate the safety and early efficacy signal of the combination of imatinib and binimetinib in patients with imatinib-resistant advanced gastrointestinal stromal tumors (GISTs).Patients and methodsThis trial used a standard 3 + 3 design to determine the recommended phase II dose (RP2D). Additional patients were enrolled on an expansion cohort at the RP2D enriching for succinate dehydrogenase (SDH)-deficient GISTs to explore potential efficacy.ResultsThe trial enrolled nine patients in the dose-escalation cohort and 14 in the dose-expansion cohort including six with SDH-deficient GISTs. Imatinib 400 mg daily with binimetinib 45 mg twice daily was established as the RP2D. Dose-limiting toxicity (DLT) was asymptomatic grade 4 creatinine phosphokinase (CPK) elevation. The most common non-DLT grade 3/4 toxicity was asymptomatic CPK elevation (69.6%). Other common ≥grade 2 toxicities included peripheral edema (17.4%), acneiform rash (21.7%), anemia (30.4%), hypophosphatemia (39.1%), and aspartate aminotransferase (AST) increase (17.4%). Two serious adverse events occurred (grade 2 dropped head syndrome and grade 3 central retinal vein occlusion). No unexpected toxicities were observed. Limited clinical activity was observed in KIT-mutant GIST. For SDH-deficient GISTs, one of five had confirmed RECIST1.1 partial response (PR). The median progression-free survival (mPFS) in patients with SDH-deficient GIST was 45.1 months [95% confidence interval (CI), 15.8-not estimable (NE)]; the median overall survival (mOS) was not reached (95% CI, 31.6 months-NE). One patient with a refractory metastatic SDH-deficient GIST had an exceptional pathologic response and durable clinical benefit.ConclusionsThe combination of imatinib and binimetinib is safe with manageable toxicity and has encouraging activity in SDH-deficient but not imatinib-refractory KIT/PDGFRA-mutant GISTs. The observed clinical benefits provide a motivation for a larger trial of the combination strategy in SDH-deficient GISTs.

Dataset Information

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

Publications

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

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