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Circulating tumor cells and palbociclib treatment in patients with ER-positive, HER2-negative advanced breast cancer: results from a translational sub-study of the TREnd trial.
Galardi, F, De Luca, F, Biagioni, C, Migliaccio, I, Curigliano, G, Minisini, AM, Bonechi, M, Moretti, E, Risi, E, McCartney, A, et al
Breast cancer research : BCR. 2021;(1):38
Abstract
BACKGROUND Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation. METHODS Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood samples were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. Samples with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR. RESULTS All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 (n = 26) had a worse PFS than those with 0 CTCs (n = 16) (p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, (p = 0.004). Finally, patients with ≥ 5 CTCs at T2 (n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF (p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels. CONCLUSIONS CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied sample size.
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Edoxaban versus warfarin in vitamin K antagonist experienced and naïve patients from the edoxaban versus warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF) randomised trial.
Kozieł, M, Al-Saady, N, Hjortshøj, SP, Goudev, A, Huber, K, Cohen, A, Jin, J, Melino, M, Winters, SM, Goette, A, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2020;(8):1018-1024
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Abstract
BACKGROUND In ENSURE-AF study, edoxaban had similar efficacy and safety profile versus enoxaparin-warfarin (enox-warf) in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. OBJECTIVES To evaluate the efficacy and safety of edoxaban versus enox-warf in patients who were vitamin K antagonists (VKA) naïve or experienced at time of randomisation into ENSURE-AF trial. METHODS The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular death during the overall study period, 28 days on study drug after cardioversion and 30 days follow-up. The primary safety endpoint was the composite of major and clinically relevant nonmajor bleeding during the on-medication period from time of first dose to last dose of study drug taken + 3 days. RESULTS Of 2199 patients enrolled in ENSURE-AF, 1095 were randomised to edoxaban and 1104 to enox-warf. There were numerically fewer primary efficacy endpoint events with edoxaban than enox-warf irrespective of whether VKA experienced or naïve (0.5% vs. 0.9%, 0.3% vs. 1.4%, respectively). There were no significant differences in the primary safety endpoint [odds ratio (OR) 2.09, 95% confidence interval (CI) 0.72-6.81 in anticoagulant experienced patients, OR 0.77, 95% CI 0.15-3.60 in anticoagulant naïve patients] and in major bleeding rates regardless of treatment or VKA experience (OR 0.69, 95%CI 0.06-6.04, OR 0.48, 95% CI 0.01-9.25, respectively). CONCLUSIONS Edoxaban had comparable efficacy and safety to optimized anticoagulation with enox-warf. The primary efficacy and safety endpoint outcomes were broadly similar between VKA experienced or naïve patients.
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Cardiovascular- and Bleeding-Related Hospitalization Rates With Edoxaban Versus Warfarin in Patients With Atrial Fibrillation Based on Results of the ENGAGE AF-TIMI 48 Trial.
Vilain, K, Li, H, Kwong, WJ, Antman, EM, Ruff, CT, Braunwald, E, Cohen, DJ, Giugliano, RP, Magnuson, EA, ,
Circulation. Cardiovascular quality and outcomes. 2020;(11):e006511
Abstract
Background The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) demonstrated noninferiority of once-daily 60 mg (30 mg dose-reduced) edoxaban compared with warfarin for prevention of stroke/systemic embolism in patients with atrial fibrillation. No previous analysis has explored the impact of treatment with edoxaban versus warfarin on rates of hospitalizations. Methods Detailed healthcare resource utilization data from ENGAGE AF-TIMI 48 for the 14 024 randomized patients who received at least one dose of study drug were used to compare the rates of bleeding- and cardiovascular-related hospitalizations for edoxaban versus warfarin. Hospitalization rates were calculated for each treatment group, and relative rates were estimated using Poisson regression. The influence of patient characteristics on the impact of edoxaban versus warfarin was evaluated through the inclusion of interaction terms. Results The overall rate of cardiovascular- or bleeding-related hospitalization was significantly lower for edoxaban than warfarin (relative rate [RR], 0.91 [95% CI, 0.85-0.97], P=0.003). Rates of hospitalizations for cardiovascular reasons (RR, 0.91 [95% CI, 0.85-0.97], P=0.004), stroke (RR, 0.80 [95% CI, 0.72-0.88], P<0.0001), and for each stroke subtype (ischemic: RR, 0.89 [95% CI, 0.81-0.99], P=0.03; hemorrhagic: RR, 0.60 [95% CI, 0.54-0.68], P<0.0001) were also lower for edoxaban. Notably, significantly greater reductions with edoxaban versus warfarin were seen for ischemic stroke-related hospitalizations in vitamin K antagonist naive patients and patients with CHADS2 scores 4 to 6, previous stroke or transient ischemic attack, age ≥75, and no previous coronary artery disease. For nonstroke bleeding-related hospitalizations, greater reductions with edoxaban were seen in vitamin K antagonist naive patients, patients with CHADS2 scores 4 to 6, and patients with moderate renal dysfunction. Conclusions Edoxaban 60 mg (30 mg dose-reduced) was associated with a significantly lower overall rate of cardiovascular- or bleeding-related hospitalization and significant reductions in the subcategories of cardiovascular-related, stroke-related, bleed-related, and nonstroke cardiovascular-related hospitalizations, when compared with warfarin. These results suggest the potential for cost offsets with edoxaban, with even greater reductions in higher-risk patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.
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Effect of concomitant antiplatelet agents on clinical outcomes in the edoxaban vs warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF) randomized trial.
Goette, A, Merino, JL, De Caterina, R, Huber, K, Heidbuchel, H, Jin, J, Lip, GYH
Clinical research in cardiology : official journal of the German Cardiac Society. 2020;(11):1374-1380
Abstract
AIMS: In ENSURE-AF (NCT02072434), the oral Factor Xa inhibitor edoxaban showed similar efficacy and safety vs enoxaparin-warfarin in patients undergoing electrical cardioversion of nonvalvular atrial fibrillation (AF). This ancillary analysis compares primary efficacy and safety end points for patients receiving vs not receiving concomitant antiplatelet therapy (APT) in ENSURE-AF. METHODS The primary efficacy end point was a composite of stroke, systemic embolic events, myocardial infarction, and cardiovascular death during 28 days on study drug after cardioversion plus 30 days of follow-up. The primary safety end point was the composite of major and clinically relevant non-major bleeding occurring between the first and the last dose of study drug. RESULTS Of 2199 patients enrolled, 1095 were randomized to edoxaban and 1104 to enoxaparin-warfarin. Patients receiving concomitant APT were older; more naïve to vitamin K antagonist; had lower creatinine clearance; and more likely to have history of coronary artery disease, hypertension, diabetes, or ischemic stroke/transient ischemic attack. In patients receiving vs not receiving concomitant APT, primary efficacy event rate was numerically higher (0.92% vs 0.60%, p = 0.64) and primary safety event rate was significantly higher (3.21% vs 0.92%, p = 0.0096). Stepwise logistic regression analysis identified age and APT as covariates correlated with bleeding. There was a trend toward increased bleeding risk in elderly patients receiving vs not receiving concomitant APT. CONCLUSION In ENSURE-AF, thromboembolic events were rare and absolute bleeding event rates were higher with concomitant APT. These findings may be relevant for AF-patients considered for dual therapy; even for a short treatment duration of 1 month.
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Performance of the ABC Scores for Assessing the Risk of Stroke or Systemic Embolism and Bleeding in Patients With Atrial Fibrillation in ENGAGE AF-TIMI 48.
Berg, DD, Ruff, CT, Jarolim, P, Giugliano, RP, Nordio, F, Lanz, HJ, Mercuri, MF, Antman, EM, Braunwald, E, Morrow, DA
Circulation. 2019;(6):760-771
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BACKGROUND The ABC (age, biomarker, clinical history)-stroke and ABC-bleeding risk scores incorporate clinical variables and cardiovascular biomarkers to estimate risk of stroke or systemic embolic events and bleeding, respectively, in patients with atrial fibrillation. These scores have been proposed for routine clinical use, but their performance in external cohorts remains uncertain. METHODS ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS2 score ≥2. We performed a nested prospective biomarker study in 8705 patients, analyzing baseline high-sensitivity troponin T (hsTnT), NT-proBNP (N-terminal B-type natriuretic peptide), and growth differentiation factor-15 (GDF-15), as well as in serial samples after 12 months. The ABC-stroke (age, prior stroke/transient ischemic attack, hsTnT, NT-proBNP) and ABC-bleeding (age, prior bleeding, hemoglobin, hsTnT, and GDF-15) scores were tested. Hazard ratios were adjusted for estimated glomerular filtration rate and the components of the CHA2DS2-VASc and HAS-BLED scores, respectively. Discrimination and reclassification were compared with these established scores. RESULTS Median baseline hsTnT, NT-proBNP, and GDF-15 levels were 13.7 ng/L (25th-75th percentiles, 9.6-20.4 ng/L), 811 pg/mL (386-1436 pg/mL), and 1661 pg/mL (1179-2427 pg/mL), respectively. Elevated hsTnT, NT-proBNP, and GDF-15 were independently associated with higher rates of stroke or systemic embolic events, and elevated hsTnT and GDF-15 were independently associated with higher rates of major bleeding ( P<0.001 for each). The ABC-stroke and ABC-bleeding scores were well calibrated and yielded higher c indexes than the CHA2DS2-VASc score for stroke or systemic embolic events (0.67 [95% CI, 0.65-0.70] versus 0.59 [95% CI, 0.57-0.62]; P<0.001) and HAS-BLED score for major bleeding (0.69 [95% CI, 0.66-0.71] versus 0.62 [95% CI, 0.60-0.64]; P<0.001), respectively. The ABC-stroke and ABC-bleeding scores stratified patients within CHA2DS2-VASc and HAS-BLED risk categories ( P<0.001 for both). Patients with ABC-bleeding scores predicting a high 1-year risk of bleeding (>2%) derived greater benefit from treatment with edoxaban compared with warfarin. CONCLUSIONS The ABC-stroke and ABC-bleeding scores evaluated in this anticoagulated clinical trial cohort were well calibrated and outperformed the CHA2DS2-VASc and HAS-BLED scores, respectively. These scores may help identify patients most likely to derive a benefit from treatment with non-vitamin K antagonist oral anticoagulants. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.
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Edoxaban in atrial fibrillation patients with established coronary artery disease: Insights from ENGAGE AF-TIMI 48.
Zelniker, TA, Ruff, CT, Wiviott, SD, Blanc, JJ, Cappato, R, Nordio, F, Mercuri, MF, Lanz, H, Antman, EM, Braunwald, E, et al
European heart journal. Acute cardiovascular care. 2019;(2):176-185
Abstract
BACKGROUND The relative efficacy and safety profile of the oral Factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation and established coronary artery disease (CAD) has not been analyzed. MATERIALS AND METHODS In the ENGAGE AF-TIMI 48 trial, two edoxaban regimens were compared with warfarin in 21,105 patients with atrial fibrillation and CHADS2 ⩾2. We analyzed the primary trial endpoints (efficacy: stroke or systemic embolic event, safety: International Society on Thrombosis and Haemostasis major bleeding) in patients with versus without CAD, and used interaction testing to assess for treatment effect modification. RESULTS The 4510 patients (21.4%) with known CAD were older, more likely male, on aspirin, with lower creatinine clearance and higher CHADS2 and HAS-BLED scores ( p <0.001 for each). Treatment with the higher-dose edoxaban regimen (versus warfarin) in patients with known CAD tended to have a greater reduction in stroke/systemic embolic event compared with patients without CAD (CAD: hazard ratio 0.65 (0.46-0.92) versus no CAD: hazard ratio 0.94 (0.79-1.12), p-INT 0.062) and also in myocardial infarction (CAD: hazard ratio 0.69 (0.49-0.98) versus no CAD: hazard ratio 1.24 (0.89-1.72), p-INT 0.017), while there was a similar reduction in bleeding irrespective of CAD status (hazard ratio 0.81 and 0.80, p-INT 0.97). Presence or absence of CAD did not modify the efficacy or safety profile of the lower-dose edoxaban regimen (versus warfarin). CONCLUSION The reduction in ischemic events with the higher-dose edoxaban regimen versus warfarin was greater in patients with CAD, while bleeding was significantly reduced with edoxaban regardless of CAD status. The efficacy and safety profile of the lower-dose edoxaban regimen relative to warfarin was unaffected by CAD status.
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Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial.
Vranckx, P, Valgimigli, M, Eckardt, L, Tijssen, J, Lewalter, T, Gargiulo, G, Batushkin, V, Campo, G, Lysak, Z, Vakaliuk, I, et al
Lancet (London, England). 2019;(10206):1335-1343
Abstract
BACKGROUND We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI). METHODS ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed. FINDINGS From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority). INTERPRETATION In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events. FUNDING Daiichi Sankyo.
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Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial.
Hohnloser, SH, Camm, J, Cappato, R, Diener, HC, Heidbüchel, H, Mont, L, Morillo, CA, Abozguia, K, Grimaldi, M, Rauer, H, et al
European heart journal. 2019;(36):3013-3021
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AIMS: Edoxaban is a direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF). Uninterrupted edoxaban therapy in patients undergoing AF ablation has not been tested. METHODS AND RESULTS The ELIMINATE-AF trial, a multinational, multicentre, randomized, open-label, parallel-group study, was conducted to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for dose reduction) vs. vitamin K antagonists (VKAs) in AF patients undergoing catheter ablation. Patients were randomized 2:1 to edoxaban vs. VKA. The primary endpoint (per-protocol population) was time to first occurrence of all-cause death, stroke, or International Society of Thrombosis and Haemostasis-defined major bleeding during the period from the end of the ablation procedure to end of treatment (90 days). Overall, 632 patients were enrolled, 614 randomized, and 553 received study drug and underwent ablation; 177 subjects underwent brain magnetic resonance imaging to assess silent cerebral infarcts. The primary endpoint (only major bleeds occurred) was observed in 0.3% (1 patient) on edoxaban and 2.0% (2 patients) on VKA [hazard ratio (95% confidence interval): 0.16 (0.02-1.73)]. In the ablation population (modified intent-to-treat population including patients with ablation), the primary endpoint was observed in 2.7% of edoxaban (N = 10) and 1.7% of VKA patients (N = 3) between start of ablation and end of treatment. There were one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Cerebral microemboli were detected in 13.8% (16) patients who received edoxaban and 9.6% (5) patients in the VKA group (nominal P = 0.62). CONCLUSION Uninterrupted edoxaban therapy represents an alternative to uninterrupted VKA treatment in patients undergoing AF ablation.
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A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of orally administered VT-1161 in the treatment of recurrent vulvovaginal candidiasis.
Brand, SR, Degenhardt, TP, Person, K, Sobel, JD, Nyirjesy, P, Schotzinger, RJ, Tavakkol, A
American journal of obstetrics and gynecology. 2018;(6):624.e1-624.e9
Abstract
BACKGROUND Lanosterol demethylase is an enzyme that is essential for fungal growth and catalyzes an early step in the biosynthetic pathway of ergosterol, which is a sterol that is required for fungal cell membrane formation and integrity. Lanosterol demethylase is the molecular target of the class of drugs referred to as "azole antifungals." VT-1161 is a novel, oral, selective inhibitor of fungal lanosterol demethylase and is being developed for the treatment of recurrent vulvovaginal candidiasis. OBJECTIVE We evaluated the efficacy and safety of 4 dosing regimens of oral VT-1161 compared with placebo in women with recurrent vulvovaginal candidiasis, which was defined as at least 3 symptomatic episodes of acute vulvovaginal candidiasis within a 12-month period. STUDY DESIGN Two hundred fifteen women with a documented history of recurrent vulvovaginal candidiasis and who, at screening, were experiencing an episode of acute vulvovaginal candidiasis (acute vulvovaginal candidiasis; composite vulvovaginal signs and symptoms score of ≥3 and a positive potassium hydroxide test for yeast) were enrolled. After treatment of the acute infection with fluconazole, subjects were assigned randomly to 1 of 5 treatment regimens: (1) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (2) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (3) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 23 weeks; (4) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 23 weeks; or (5) a matching placebo regimen for 24 weeks. The primary efficacy outcome was the proportion of subjects with ≥1 culture-verified acute vulvovaginal candidiasis episodes through week 48. RESULTS In the intent-to-treat population, the proportion of subjects with ≥1 acute vulvovaginal candidiasis episodes ranged from 0-7% across the 4 VT-1161 arms vs 52% in the placebo arm, with all arms achieving statistical significance vs placebo. VT-1161 was well-tolerated with a favorable safety profile, and the incidence of adverse events was lower in all VT-1161 arms compared with placebo. In addition, no patient in any VT-1161 arm discontinued the study early because of an adverse event or laboratory abnormality. There was also no evidence of an adverse effect of VT-1161 on liver function or electrocardiogram recordings. CONCLUSION In this study, VT-1161 was shown to be efficacious and safe in the treatment of patients with recurrent vulvovaginal candidiasis. These data strongly support further clinical investigation of VT-1161 for the treatment of recurrent vulvovaginal candidiasis.
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Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer.
Sanoff, HK, Goldberg, RM, Ivanova, A, O'Reilly, S, Kasbari, SS, Kim, RD, McDermott, R, Moore, DT, Zamboni, W, Grogan, W, et al
Cancer. 2018;(15):3118-3126
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Abstract
BACKGROUND Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double-blind, placebo-controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer. METHODS Patients with metastatic colorectal cancer who progressed on first-line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28-day cycle. Crossover was not allowed. The primary endpoint was progression-free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1-sided α value of .1. RESULTS One hundred eighty-one patients were randomized (120 to regorafenib-FOLFIRI and 61 to placebo-FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib-FOLFIRI than placebo-FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53-1.01; log-rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71-1.44). The response rate was higher with regorafenib-FOLFIRI (34%; 95% CI, 25%-44%) than placebo-FOLFIRI (21%; 95% CI, 11%-33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. CONCLUSIONS The addition of regorafenib to FOLFIRI as second-line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society.