Dataset Information

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.

ABSTRACT:

Background

Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies.

Patients and methods

Eligible patients (Eastern Cooperative Oncology Group performance status 0-1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review.

Results

From October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1-15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86-1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49-0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%).

Conclusions

The study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated.

Clinicaltrials.gov number

NCT02149108 (LUME-Colon 1).

SUBMITTER: Van Cutsem E

PROVIDER: S-EPMC6158765 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.

Van Cutsem E E Yoshino T T Lenz H J HJ Lonardi S S Falcone A A Limón M L ML Saunders M M Sobrero A A Park Y S YS Ferreiro R R Hong Y S YS Tomasek J J Taniguchi H H Ciardiello F F Stoehr J J Oum'Hamed Z Z Vlassak S S Studeny M M Argiles G G

Annals of oncology : official journal of the European Society for Medical Oncology 20180901 9

<h4>Background</h4>Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies.<h4>Patients and methods</h4>Eligible patients (Eastern Cooperative Oncology Group performance status 0-1, with hist ...[more]

PMID: 30010751

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Project description:BackgroundTreatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC.Materials and methodsThis was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1-14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety.ResultsA total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4-4.5) over placebo group (1.5 months; 95% CI, 1.4-1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27-0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8-9.7 vs. 7.2 months; 95% CI, 6.2-8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%).ConclusionAnlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients.Implications for practiceIn this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.

Project description:BackgroundNintedanib in combination with docetaxel is approved in the European Union and other countries for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) of adenocarcinoma histology after first-line chemotherapy, based on the overall survival findings of Phase III LUME-Lung 1 study. Change in target lesion size over time as a treatment effect was assessed in patients from this study.MethodsTumor size was evaluated using predefined tumor measurements. Mixed-effects models were used to quantify individual relationships between time from randomization and tumor burden, measured as the sum of longest diameter (SLD) of target lesions and assessed by an independent review (Response Evaluation Criteria In Solid Tumors [RECIST] v1.0). Exploratory analyses were conducted on the overall adenocarcinoma population, adenocarcinoma patients with time from start of first-line therapy <9 months (TSFLT <9), adenocarcinoma patients who had progressive disease as best response to first-line therapy (PD-FLT), and in squamous cell carcinoma patients.ResultsEstimated mean baseline SLD was 82.5 mm in the adenocarcinoma (n=658), 88.3 mm in the TSFLT <9 (n=405), 98.1 mm in the PD-FLT (n=117), and 94.3 mm in the squamous cell carcinoma (n=555) populations. Treatment with nintedanib/docetaxel showed a significant reduction in tumor size over time (P<0.0001) in patients with adenocarcinoma compared with placebo/docetaxel, and in patients with squamous cell carcinoma (P=0.0049). Treatment difference at 6 months was 9.7 mm in the overall adenocarcinoma population, 16.8 mm in the TSFLT <9 population, 19.7 mm in the PD-FLT population, and 6.8 mm in the squamous cell carcinoma population. SLD at 2 months post-randomization was identified as a surrogate endpoint for overall survival, in addition to progression-free survival, for all except the PD-FLT population.ConclusionTreatment with nintedanib/docetaxel significantly decreased tumor burden and decelerated tumor size over time compared with placebo/docetaxel in the overall adenocar-cinoma population, including in patients with the poorest prognosis due to aggressive tumor dynamics.

Project description:LESSONS LEARNED:Patients with metastatic colorectal cancer with good performance status or no liver metastasis could benefit from apatinib.Circulating tumor DNA abundance may be a predictor in serial monitoring of tumor load. BACKGROUND:Apatinib, an oral vascular endothelial growth factor (VEGF) receptor-2 inhibitor, has been approved as third-line treatment for metastatic gastric cancer in China. The aim of this study was to evaluate the efficacy and safety of apatinib, in the treatment of patients with refractory metastatic colorectal cancer after failure of two or more lines of chemotherapy. METHODS:In this open-label, single-arm, phase II study, patients with histological documentation of adenocarcinoma of the colon or rectum were eligible if they had received at least two prior regimens of standard therapies including fluoropyrimidine, oxaliplatin, and irinotecan. These patients were treated with apatinib in a daily dose of 500 mg, p.o., in the third-line or higher setting. Capture sequencing was dynamically performed to identify somatic variants in circulating tumor DNA (ctDNA) with a panel of 1,021 cancer-related genes. The primary endpoint was progression-free survival (PFS) and the tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Interim analysis was applied as predefined. RESULTS:From June 1, 2016 to December 31, 2017, 26 patients were enrolled. The median PFS of the whole group was 3.9 months (95% confidence interval [CI]: 2.1-5.9). The median overall survival (OS) was 7.9 months (95% CI: 4.6-10.1+). Patients with performance status (PS) 0-1 had longer PFS than those with PS 2 (4.17 months vs. 1.93 months, p = .0014). Patients without liver metastasis also had longer PFS than those who had live metastasis (5.87 months vs. 3.33 months, p = .0274). The common side effects of apatinib were hypertension, hand-foot syndrome, proteinuria, and diarrhea. The incidence of grade 3-4 hypertension, hand-foot syndrome, proteinuria, and diarrhea was 76.92%, 11.54%, 73.08%, and 23.08%, respectively. All of the patients received dose reduction because of adverse effect. Results of capture sequencing showed APC, TP53, and KRAS were most frequently mutant genes. ctDNA abundance increased before the radiographic assessment in ten patients. CONCLUSION:Apatinib monotherapy showed promising efficiency for patients with refractory colorectal cancer, especially in patients with PS 0-1 or no liver metastasis. ctDNA abundance may be a predictor in serial monitoring of tumor load.

Project description:BackgroundThe purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer.MethodsWe undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1:1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m(-2) as a 90-min infusion, leucovorin at 200 mg m(-2) as a 2-h infusion, and a bolus injection of 5-FU 400 mg m(-2) followed by a 46-h continuous infusion of 5-FU at 2400 mg m(-2). The XELIRI regimen consisted of irinotecan at 250 mg m(-2) as a 90-min infusion with capecitabine 1000 mg m(-2) twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity.ResultsBetween April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5-7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4-8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively).ConclusionsThe addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.

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Dataset Information

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.

Background

Patients and methods

Results

Conclusions

Clinicaltrials.gov number

Publications

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.

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