Dataset Information

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study.

ABSTRACT:

Objectives

Regorafenib improved overall survival in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies in two randomised, phase III trials, but has not been evaluated in Turkey. REGARD evaluated the safety and efficacy of regorafenib in Turkish patients with treatment-refractory mCRC.

Design

Open-label, single-arm, phase IIIb study conducted between July 2013 and April 2015.

Setting

11 tertiary centres in Turkey.

Participants

Eligible patients were adults with mCRC who had disease progression within 3 months after receiving their last dose of approved standard therapies and who had an Eastern Cooperative Oncology Group performance status ≤1. Patients were excluded if they had previously received regorafenib. Of 139 patients screened, 100 were treated and completed the study, and all 100 were analysed. Fifty-eight per cent were male.

Interventions

Patients received oral regorafenib, 160 mg once daily, for the first 3 weeks of each 4-week cycle until disease progression, death or unacceptable toxicity.

Primary and secondary outcome measures

The primary endpoint was safety, assessed by incidence of treatment-emergent adverse events (TEAEs). Progression-free survival (PFS) per investigator was the primary efficacy endpoint. There were no secondary endpoints.

Results

The median treatment duration was 2.5 months (range 0.1 to 20.6). Ninety-six per cent of patients had at least one TEAE and 77% had a grade ≥3 TEAE. The most common grade ≥3 regorafenib-related TEAEs were hypophosphataemia (11%), fatigue (8%), hyperbilirubinaemia (6%), hand-foot skin reaction (5%), hypertension (5%), anorexia (5%) and increased alanine aminotransferase (5%). TEAEs led to dose reduction in 30% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 17% of patients. Median PFS was 3.1 months (95% CI 2.9 to 3.8).

Conclusion

The regorafenib safety profile and PFS in REGARD were consistent with the results of previous trials of regorafenib in mCRC. Regorafenib is an option for patients in Turkey with treatment-refractory mCRC.

Trial registration number

NCT01853319, ClinicalTrials.gov.

SUBMITTER: Dane F

PROVIDER: S-EPMC7170555 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study.

Dane Faysal F Ozgurdal Kirhan K Yalçın Şuayib Ş Benekli Mustafa M Aykan Nuri Faruk NF Yücel İdris İ Özkan Metin M Evrensel Turkkan T Sevinç Alper A Coskun Hasan Şenol HŞ Sanli Ulus Ali UA Kara Ismail Oguz IO Yumuk Perran Fulden PF

BMJ open 20200326 3

<h4>Objectives</h4>Regorafenib improved overall survival in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies in two randomised, phase III trials, but has not been evaluated in Turkey. REGARD evaluated the safety and efficacy of regorafenib in Turkish patients with treatment-refractory mCRC.<h4>Design</h4>Open-label, single-arm, phase IIIb study conducted between July 2013 and April 2015.<h4>Setting</h4>11 tertiary centres in Turkey.<h4>Participants</h4>Eligible ...[more]

PMID: 32220908

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Project description:BackgroundRegorafenib confers an overall survival benefit in patients with refractory metastatic colorectal cancer; however, the adverse event profile of regorafenib has limited its use. Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. This study evaluated the safety and activity of two regorafenib dosing schedules.MethodsIn this randomised, multicentre, open-label, phase 2 study done in 39 outpatient cancer centres in the USA, adults aged 18 years or older with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy, including EGFR inhibitors if KRAS wild-type, were enrolled. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had no previous treatment with regorafenib. Patients were randomly assigned (1:1:1:1) into four groups with two distinct regorafenib dosing strategies and two clobetasol usage plans, stratified by hospital. Regorafenib dosing strategies were a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib) if no significant drug-related adverse events occurred and a standard-dose strategy (160 mg/day orally) for 21 days of a 28-day cycle. Clobetasol usage plans (0·05% clobetasol cream twice daily applied to palms and soles) were either pre-emptive or reactive. After randomisation to the four preplanned groups, using the Pocock and Simon dynamic allocation procedures stratified by the treating hospitals, we formally tested the interaction between the two interventions, dosing strategy and clobetasol usage. Given the absence of a significant interaction (p=0·74), we decided to pool the data for the pre-emptive and reactive treatment with clobetasol and compared the two dosing strategies (dose escalation vs standard dose). The primary endpoint was the proportion of evaluable patients (defined as those who were eligible, consented, and received any protocol treatment) initiating cycle 3 and was analysed per protocol. Superiority for dose escalation was declared if the one-sided p value with Fisher's exact test was less than 0·2. This trial is registered with ClinicalTrials.gov, number NCT02368886. This study is fully accrued but remains active.FindingsBetween June 2, 2015, and June 22, 2017, 123 patients were randomly assigned to treatment, of whom 116 (94%) were evaluable. The per-protocol population consisted of 54 patients in the dose-escalation group and 62 in the standard-dose group. At data cutoff on July 24, 2018, median follow-up was 1·18 years (IQR 0·98-1·57). The primary endpoint was met: 23 (43%, 95% CI 29-56) of 54 patients in the dose-escalation group initiated cycle 3 versus 16 (26%, 15-37) of 62 patients in the standard-dose group (one-sided p=0·043). The most common grade 3-4 adverse events were fatigue (seven [13%] patients in the dose-escalation group vs 11 [18%] in the standard-dose group), hand-foot skin reaction (eight [15%] patients vs ten [16%] patients), abdominal pain (nine [17%] patients vs four [6%] patients), and hypertension (four [7%] patients vs nine [15%] patients). 14 patients had at least one drug-related serious adverse event: six patients in the dose-escalation group and eight patients in the standard-dose group. There was one probable treatment-related death in the standard-dose group (myocardial infarction).InterpretationThe dose-escalation dosing strategy represents an alternative approach for optimising regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data.FundingBayer HealthCare Pharmaceuticals.

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Project description:BackgroundAnti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer.MethodsThis single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months' follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733.FindingsBetween 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4-15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0-not evaluable) and 1.8 months (95% CI 1.8-2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity.InterpretationFurther studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab.FundingBayer/Bristol Myers Squibb.

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Dataset Information

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study.

Objectives

Design

Setting

Participants

Interventions

Primary and secondary outcome measures

Results

Conclusion

Trial registration number

Publications

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study.

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