Bintrafusp Alfa: A Bifunctional Fusion Protein Targeting PD-L1 and TGF-ß, in Patients with Pretreated Colorectal Cancer: Results from a Phase I Trial.

Colorectal cancer (CRC) is a heterogeneous and complex disease with limited treatment options. Targeting transforming growth factor ß (TGF-ß) and programmed death ligand 1 pathways may enhance antitumor efficacy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-ß receptor II (a TGF-ß "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death ligand 1. We report results from an expansion cohort of a phase I study (NCT02517398) in patients with heavily pretreated advanced CRC treated with bintrafusp alfa. As of May 15, 2020, 32 patients with advanced CRC had received bintrafusp alfa for a median duration of 7.1 weeks. The objective response rate was 3.1% and the disease control rate was 6.3% (1 partial response, 1 stable disease); 2 patients were not evaluable. The safety profile was consistent with previously reported data.

Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies.

This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored. No dose-limiting toxicities were identified, and maximum tolerated dose was not reached. Most common nonhematologic treatment-emergent adverse events (TEAEs) were diarrhea/colitis (36%), nausea (36%), fatigue (31%), and rash (31%). Grade 3/4 neutropenia occurred in 19% of patients. Serious TEAEs (>2 patients) were diarrhea/colitis (n = 9), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3). Aspartate and alanine transaminase elevations occurring before treatment discontinuation were grade 1, except 1 grade 3 event each, secondary to sepsis. Two patients experienced 3 fatal parsaclisib-unrelated TEAEs (respiratory failure; respiratory failure and sepsis). In non-Hodgkin lymphoma (NHL), objective response rates to monotherapy were 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma; 93% of responses occurred at first assessment (∼9 weeks). Parsaclisib has demonstrated antitumor activity in relapsed or refractory B-cell NHL with the potential for improved long-term patient outcomes. Phase 2 studies in relapsed or refractory B-cell NHL subtypes are ongoing. This trial was registered at www.clinicaltrials.gov as #NCT02018861.

Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer.

PURPOSE: Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor (EGFR) -targeted drugs in patients with non-small-cell lung cancer (NSCLC). We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC. PATIENTS AND METHODS: Patients with recurrent NSCLC were randomly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib; crossover was allowed at progression. Tumor tissue was required to assess MET status by immunohistochemistry (IHC). Coprimary end points were progression-free survival (PFS) in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included overall survival (OS), objective response rate, and safety. RESULTS: There was no improvement in PFS or OS in the ITT population (n = 137; PFS hazard ratio [HR], 1.09; P = .69; OS HR, 0.80; P = .34). MET-positive patients (n = 66) treated with erlotinib plus onartuzumab showed improvement in both PFS (HR, .53; P = .04) and OS (HR, .37; P = .002). Conversely, clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib (n = 62; PFS HR, 1.82; P = .05; OS HR, 1.78; P = .16). MET-positive control patients had worse outcomes versus MET-negative control patients (n = 62; PFS HR, 1.71; P = .06; OS HR, 2.61; P = .004). Incidence of peripheral edema was increased in onartuzumab-treated patients. CONCLUSION: Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.

Safety and immunogenicity of heat-treated zoster vaccine (ZVHT) in immunocompromised adults.

BACKGROUND: Safety and immunogenicity of heat-treated zoster vaccine (ZVHT) were assessed in immunocompromised adults. METHODS: In a randomized, double-blind, placebo-controlled, multicenter study, 4 doses ZVHT or placebo were administered approximately 30 days apart to adults with either solid tumor malignancy (STM); hematologic malignancy (HM); human immunodeficiency virus (HIV) with CD4(+) ≤200; autologous hematopoietic stem-cell transplant (HCT) or allogeneic-HCT recipients. Varicella-zoster virus (VZV) T-cell responses by interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT) and VZV antibody concentrations by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were measured at baseline and approximately 28 days after each dose. RESULTS: No safety signals were found in any group. IFN-γ ELISPOT geometric mean fold rises (GMFR) after dose 4 in STM, HM, HIV, and autologous-HCT patients were 3.00 (P < .0001), 2.23 (P = .004), 1.76 (P = .026), and 9.01 (P = NA), respectively. Similarly, antibody GMFR were 2.35 (P < .0001), 1.28 (P = .003), 1.37 (P = .017), and 0.90 (P = NA), respectively. T-cell and antibody responses were poor after 4 doses of ZVHT in allogeneic-HCT patients. CONCLUSION: ZVHT was generally safe and immunogenic through 28 days post-dose 4 in adults with STM, HM, and HIV. Autologous-HCT but not allogeneic-HCT patients had a rise in T-cell response; antibody responses were not increased in either HCT population. Study identification. V212-002 Clinical Trials Registration. NCT00535236.

Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer.

PURPOSE: XL647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (EGFR), vascular endothelial growth factor receptor 2, HER2 and Ephrin type-B receptor 4 (EphB4). We undertook an open-label, multi-institutional Phase II study to investigate the efficacy and safety of XL647 in treatment-naive non-small-cell lung cancer patients clinically enriched for the presence of EGFR mutations. METHODS: Eligibility included patients with advanced-stage treatment-naive lung adenocarcinoma with a known sensitizing mutation of EGFR or patients with at least one of the following criteria: being Asian, female, or having minimal or no smoking history. Two dosing schedules were evaluated; in the "intermittent 5 & 9 dosing" cohort, XL647 350 mg for 5 days every 14 days was given; and in the "daily dosing" cohort, XL647 300 mg daily for 28 days was administered. Tumor EGFR mutation status was determined on available tissue. The primary end point was confirmed objective response rate. RESULTS: Forty-one patients were treated on the intermittent 5 & 9 dosing- and 14 on the daily-dosing schedule. The majority of patients were eligible on the basis of smoking history. The response rate and progression-free survival for the two schedules combined were 20% and 5.3 months (90% confidence interval, 3.7-6.7), respectively. Thirty-eight patients (69%) had material available for mutation testing and 14 EGFR-sensitizing mutations were detected. The response rate and progression-free survival for EGFR-mutation-positive patients were 57% (8/14) and 9.3 months (90% confidence interval, 5.5-11.7). The toxicities were comparable between the two schedules; the most common adverse effects being diarrhea, nausea, and fatigue. CONCLUSIONS: XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. The adverse-event profile was similar for the two dosing schedules.

Phase 2 trial of Linifanib (ABT-869) in patients with advanced non-small cell lung cancer.

INTRODUCTION: This study assessed activity and safety of linifanib (ABT-869), a selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, in patients with locally advanced or metastatic non-small cell lung cancer. METHODS: In this open-label trial (NCT00517790), patients who received one to two prior lines of systemic therapy were randomized to oral linifanib 0.10 mg/kg (low dose) or 0.25 mg/kg (high dose) once daily. Tumor responses were assessed by independent central imaging review every 8 weeks. The primary end point was progression-free rate at 16 weeks. Secondary end points included objective response rate, time to progression, progression-free survival, and overall survival. Safety was also assessed. RESULTS: Between August 2007 and October 2008, 139 patients were enrolled; 60% had two or more prior regimens, and 88% had nonsquamous cell carcinoma. The objective response rate (low dose and high dose) was 5.0% (3.1 and 6.8%), progression-free rate at 16 weeks was 33.1% (32.3 and 33.8%), median time to progression was 3.6 months (3.6 and 3.7 months), median progression-free survival was 3.6 months (3.5 and 3.6 months), and median overall survival was 9.0 months (10.0 and 8.3 months). The most common linifanib-related adverse events were fatigue (42%), decreased appetite (38%), hypertension (37%), diarrhea (32%), nausea (27%), palmar-plantar erythrodysesthesia (24%), and proteinuria (22%). These events were more common in the high-dose group. The most common linifanib-related grade 3 or 4 adverse event was hypertension (14%). CONCLUSIONS: Linifanib is active in advanced non-small cell lung cancer as second- or third-line therapy. Increased adverse event rates were observed at the high dose of linifanib.

Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non-small-cell lung cancer.

PURPOSE: ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: One hundred seventy-one patients received intravenous pemetrexed 500 mg/m(2) day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed. RESULTS: The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS. CONCLUSION: Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.

Analysis of the diurnal intraocular pressure profile pre and post trabeculectomy using 24-hour monitoring of intraocular pressure.

PURPOSE: To compare the diurnal intraocular pressure (IOP) profile pre and post trabeculectomy with a control group of medically controlled patients. We compared the change in mean, peak, and diurnal IOP fluctuation. METHODS: This was an observational study of patients at the Bristol Eye Hospital, United Kingdom. All patients underwent initial and subsequent phasing, with surgery between for cases. The unpaired Student t test compared the changes (initial-subsequent) in mean, peak, and fluctuation between cases and controls. RESULTS: Fifteen eyes underwent trabeculectomy surgery while the control group contained 17 eyes controlled on topical medical treatment. There was a statistically significant reduction in both mean IOP of 3.7 mmHg (p=0.002) and peak IOP of 4.4 mmHg (p=0.025) in the surgical group compared to the medical group. There was no statistically significant change in the IOP fluctuation between the 2 study groups (p=0.296). CONCLUSIONS: There is a significant reduction in mean IOP and peak IOP following trabeculectomy. We showed no statistically significant change in the diurnal fluctuation of IOP following trabeculectomy.

The clinical time-course of experimental autoimmune uveoretinitis using topical endoscopic fundal imaging with histologic and cellular infiltrate correlation.

PURPOSE: EAU is an established preclinical model for assessment of immunotherapeutic efficacy toward translation of therapy for posterior uveitis. Reliable screening of clinical features that correlate with underlying retinal changes and damage has not been possible to date. This study was undertaken to describe, validate, and correlate topical endoscopic fundus imaging (TEFI) with histologic features of murine experimental autoimmune uveoretinitis (EAU), with the intent of generating a rapid noninvasive panretinal assessment of ocular inflammation. METHODS: EAU was induced in B10.RIII mice by immunization with the peptide RBP-3(161-180). The clinical disease course (days 0-63) was monitored and documented using TEFI. Disease severity and pathology were confirmed at various time points by histologic assessment. The composition of the cell infiltrate was also examined and enumerated by flow cytometry. RESULTS: TEFI demonstrated the hallmark features of EAU, paralleling many of the clinical features of human uveitis, and closely aligned with underlying histologic changes, the severity of which correlated significantly with the number of infiltrating retinal leukocytes. Leukocytic infiltration occurred before manifestation of clinical disease and clinically fulminant disease, as well as cell infiltrate, resolved faster than histologic scores. During the resolution phase, neither the clinical appearance nor number of infiltrating retinal leukocytes returned to predisease levels. CONCLUSIONS: In EAU, there is a strong correlation between histologic severity and the number of infiltrating leukocytes into the retina. TEFI enhances the monitoring of clinical disease in a rapid and noninvasive fashion. Full assessment of preclinical immunotherapeutic efficacy requires the use of all three parameters: TEFI, histologic assessment, and flow cytometric analysis of retinal infiltrate.

Ocular presentation of pediatric Miller-Fisher syndrome.

The authors describe a case of Miller-Fisher syndrome in a child who presented to the ophthalmology department with bilateral abducens nerve palsies. Miller-Fisher syndrome is an important differential diagnosis in any case of bilateral sixth nerve palsies but should only be definitively diagnosed once tumors, infections, and other neurological diseases have been conclusively ruled out.

Electrolysis-needle cauterization of corneal vessels in patients with lipid keratopathy.

PURPOSE: To describe a technique of corneal vessel occlusion by using electrolysis-needle cautery. METHODS: A prospective case series of three patients. RESULTS: Corneal vessels were successfully occluded in all patients. Vessels remained occluded during the first 8 months post-cautery follow up. Two patients needed repeat cautery at 9 and 10 months respectively. Patients found the procedure comfortable. There was no post-operative induced astigmatism. CONCLUSION: The technique of ENC is simple, effective and controlled. This technique compares favorably and may prove to be more versatile than Fine Needle Diathermy in the occlusion of corneal vessels that lead to lipid keratopathy.

Non-invasive detection of multinucleated giant cells in the conjunctiva of patients with sarcoidosis by in-vivo confocal microscopy.

AIM: To explore the use of in-vivo confocal microscopy (IVCM) as a potential non-invasive adjunctive tool for diagnosing sarcoidosis. METHODS: Conjunctivae were imaged using confocal microscopy in 10 patients with sarcoidosis and 27 control subjects. We utilized the ASL-1000 Scanning Confocal Microscope (Advanced Scanning Ltd., New Orleans, LA) and the Confoscan 3 (Nidek Co. Ltd., Gamagori, Japan). Two masked observers reviewed the in-vivo confocal images of the conjunctivae in these subjects. One masked observer was experienced in reviewing confocal images. The most striking and obvious feature seen in granulomatous inflammation on confocal microscopy is the presence of multinucleated giant cells (MGCs). RESULTS: Unmasked observation of the scans revealed MGCs in six of the 10 sarcoid patients and no MGCs in the controls. One experienced masked observer found MGCs in five of the 10 patients with sarcoidosis and had no false-positive results (Fisher's exact test, p = 0.001; specificity = 1; sensitivity = 50% for the diagnosis of sarcoidosis and 83% compared to the unmasked observer). The second less-experienced masked observer detected MGCs in three of the 10 patients and three of the 27 controls (11.1% of the controls) (p = 0.186; specificity = 0.89; sensitivity = 30% of all patients with sarcoidosis and 50% compared to the unmasked observer). CONCLUSIONS: The utilization of IVCM to visualize the basic histology and pathology in sarcoidosis of the conjunctiva is novel. Initial results indicate that trained observers can detect MGCs in granulomatous inflammation. The ASL-1000 microscope tends to have better resolution and deeper penetration of the conjunctiva compared with the Confoscan 3.

Long-term follow-up of patients with birdshot retinochoroidopathy treated with systemic immunosuppression.

PURPOSE: Birdshot retinochoroidopathy (BRC) is a rare uveitis syndrome of presumed autoimmune etiology. Therapy with systemic and periocular corticosteroids is of inconsistent efficacy, attendant with numerous potential long-term side effects. Corticosteroid-sparing strategies with agents such as cyclosporine A or azathioprine have been suggested for this disease. METHODS: We retrospectively reviewed the medical charts of patients with BRC who were evaluated consecutively at a tertiary-care, referral-based North American uveitis clinic over a 15-year period. RESULTS: Eleven Caucasian patients (22 eyes) were diagnosed with BRC, representing approximately 1% of all cases seen at the uveitis clinic. HLA-A29 was positive in all 11 patients. We elected to treat five patients with azathioprine, methotrexate, cyclosporine A, mycophenolate mofetil, and/or IvIg, as well as systemic or periocular corticosteroid injections. The median period of follow-up for the five treated patients was six years (range: 8 months-13 years). Inflammation was reduced or stabilized in five of five patients. CONCLUSION: Although the definitive strategy for the management of BRC is unknown, control of intraocular inflammation and preservation of vision is possible with corticosteroid-sparing immunosuppressive agents.

A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes.

OBJECTIVE: Infliximab, a monoclonal antibody against tumor necrosis factor alpha, is approved by the US Food and Drug Administration for treatment of numerous autoimmune disorders. We conducted a prospective, open-label phase 2 clinical trial to assess the effectiveness of infliximab in treating refractory autoimmune uveitis. METHODS: We prospectively enrolled 23 patients from the uveitis clinic of the Casey Eye Institute, Portland, Ore, into this trial. All patients meeting eligibility criteria received 3 infliximab infusions at weeks 0, 2, and 6. Clinical success was ascertained at week 10. Patients meeting initial criteria for success received an infusion at week 14 and every 8 weeks thereafter, with dose escalation permitted for breakthrough inflammation, and underwent outcome measurements at week 50. RESULTS: All patients underwent outcome assessment at week 10. Eighteen (78%) of these subjects met criteria for clinical success at this time. Success was judged by the composite clinical end point of visual acuity, control of intraocular inflammation, ability to taper concomitant medication therapy, and improvement in inflammatory signs on fluorescein angiography and/or ocular coherence tomography. Successful grading required improvement in at least 1 of 4 subcomponents and worsening in none. Seven of 14 patients enrolled for 1 year continued infliximab therapy and maintained their successful grading. Five did not complete 1 year of treatment because of significant adverse events, and 2 terminated treatment early for reasons unrelated to the study. Serious adverse events that were potentially related to infliximab included pulmonary embolus, congestive heart failure, lupus-like reaction in 2, and vitreous hemorrhage in 2 patients. Antinuclear antibodies developed in 15 of 20 enrolled patients receiving 3 or more infusions. CONCLUSIONS: Infliximab was an effective short-term immunosuppressive agent in most of the patients, with 18 of 23 meeting criteria for clinical success at week 10. Infliximab was effective in the long term in all patients able to complete 50 weeks of therapy. Although some patients achieved clear benefit, the rate of serious toxic effects was unexpectedly high. Further long-term studies are warranted to determine the safety and efficacy of infliximab in treating intraocular inflammation.

Bilateral uveitis manifesting as a complication of chronic graft-versus-host disease after allogeneic bone marrow transplantation.

PURPOSE: To document the rare occurrence of uveitis presumed secondary to chronic graft-versus-host disease (cGVHD). METHODS: Observational case report. RESULTS: A 52-year-old Filipino male who had undergone allogeneic BMT 10 years earlier presented with bilateral uveitis and biopsy-proven cutaneous cGVHD. There was no evidence of infection or other immune-related causes and the inflammation had a temporal correlation with his dermatological GVHD. The patient responded to treatment with oral cyclosporin A. CONCLUSION: The coexistence of uveitis and cGVHD is rare. The ophthalmologist should be aware of such an association and work together with the oncologist to treat these patients appropriately.

In vivo confocal microscopy of keratic precipitates.

OBJECTIVE: To evaluate the heterogeneity of keratic precipitates (KP) in varying subtypes of uveitis by in vivo confocal microscopy (IVCM). METHODS: The KP were viewed with a scanning confocal microscope in patients (n = 33) who sought care at a tertiary referral uveitis service for immune-mediated and infectious forms of uveitis, including HLA-B27-associated uveitis, sarcoidosis, Vogt-Koyanagi-Harada syndrome, juvenile chronic arthritis, Fuchs heterochromic iridocyclitis, cytomegalovirus retinitis, herpes zoster ophthalmicus, ocular toxoplasmosis, and idiopathic uveitis. Images were captured and digitalized in real time. RESULTS: Forty-two eyes of 33 patients were examined in this study. Patient age ranged from 22 to 84 years, with a mean age of 49.4 years. Seventeen (52%) of the patients were women, and 16 patients (48%) were men. The KP ranged in diameter from 10 to 350 mum. We observed the following absolute and speculative outcomes: KP are markedly heterogeneous and variable as documented by IVCM; KP in individual patients are consistent throughout the cornea; the morphologic features of KP change across time; infectious vs noninfectious causes of uveitis seem to be readily distinguishable by using IVCM; and KP may have consistency for specific disease states and therefore may have diagnostic importance. CONCLUSIONS: To our knowledge, this is the first time that IVCM has been used to describe the architecture and heterogeneity of KP in uveitis. Such observations reveal a heterogeneity that could not be appreciated by conventional slitlamp microscopy and may have diagnostic relevance.

Randomized multicenter phase II trial of bolus plus infusional fluorouracil/leucovorin compared with fluorouracil/leucovorin plus oxaliplatin as third-line treatment of patients with advanced colorectal cancer.

PURPOSE: The addition of oxaliplatin to fluorouracil (FU) and leucovorin (LV) improves the outcome of patients with colorectal cancer (CRC). This multicenter study evaluated FU/LV with or without oxaliplatin in patients with metastatic CRC after disease progression on sequential fluoropyrimidine and irinotecan. PATIENTS AND METHODS: Two hundred fourteen patients were randomly assigned to receive LV 200 mg/m2 intravenously (IV) and FU 400 mg/m2 IV bolus, followed by FU 600 mg/m2 IV over 22 hours on days 1 and 2, every 2 weeks (LV5FU2); or LV and FU as described, plus oxaliplatin 85 mg/m2 IV over 2 hours on day 1 of the schedule (FOLFOX4). The primary end point was overall response. RESULTS: Baseline characteristics were similar in the two treatment arms. Objective response (complete + partial) rates for LV5FU2 versus FOLFOX4 were 2% v 13% (P = .0027), respectively. Median time to disease progression was 2.4 v 4.8 months (P < .0001), and median survival was 11.4 v 9.9 months (P = .20) for LV5FU2 and FOLFOX4, respectively. Among the 72 patients who crossed over from LV5FU2 to FOLFOX4, 6% responded. Symptomatic improvement was significantly better for patients in the FOLFOX4 arm (32% v 18% for LV5FU2, P = .05). Grade 3/4 toxicities for LV5FU2 and FOLFOX4 were neutropenia (13% and 42%, respectively), diarrhea (6% and 16%, respectively), and overall neuropathy (0% and 6%, respectively). CONCLUSION: In patients with metastatic CRC, the FOLFOX4 regimen was superior to LV5FU2 with a higher response rate and time to disease progression. FOLFOX4 is an effective regimen even after disease progression on two previous chemotherapy regimens with fluoropyrimidines and irinotecan.