levoleucovorin and regorafenib

Colorectal cancer is a lethal disease if not discovered early. Even though appropriate screening and preventive strategies are in place in many countries, a significant number of patients are still diagnosed at late stages of the disease. The management of metastatic colorectal cancer remains a significant clinical challenge to oncologists worldwide. While cytotoxic regimens constitute the main treatment of choice in this patient population, addition of the five biologics (bevacizumab, cetuximab, aflibercept, panitumumab and regorafenib) to these regimens has improved clinical outcomes. The most commonly used cytotoxic regimens include doublet combinations (FOLFOX/XELOX or FOLFIRI). Many clinical trials have been published and others are underway to compare the biologic agents with one another in order to prove the superiority of one regimen over another. Metastatic colorectal cancer patients have many treatment options; however, the optimal use and sequence of targeted agents remain to be determined. This review entails concise and updated clinical data on the management of metastatic colorectal cancer. The aim of the review is to determine where to fit the five biologic targets into the treatment algorithm of metastatic colorectal cancer patients and to derive treatment sequences that would achieve best clinical outcome based on the current available data.

Topics: Algorithms; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Clinical Trials as Topic; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Phenylurea Compounds; Pyridines; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

Significant advances have been made with respect to our understanding of the critical role of agents targeting angiogenic pathways in the treatment of metastatic colorectal cancer (mCRC). The approval of 3 agents that target angiogenic signaling, bevacizumab, ziv-aflibercept, and regorafenib, provides strong evidence that angiogenesis is an important process in mCRC. The addition of bevacizumab to combination chemotherapy in the first- and second-line treatment of mCRC has resulted in meaningful improvement in overall and progression-free survival. The standard of care for mCRC has evolved to incorporate cytotoxic chemotherapy as the backbone regimens (eg, FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin], FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]) with or without bevacizumab, and epidermal growth factor receptor-targeted therapies (eg, cetuximab, panitumumab) in the setting of wild-type KRAS. The development of ziv-aflibercept in combination with FOLFIRI has improved clinical efficacy in the second-line treatment of mCRC. Regorafenib, a small-molecule multikinase inhibitor, has recently been approved by the US Food and Drug Administration as single-agent therapy in the treatment of refractory and progressive mCRC. Each of these agents has been integrated into an evidence-based-albeit, still evolving-treatment continuum for initial treatment, treatment after first progression, and treatment after second progression. However, the most effective strategy for the use of these agents, and others in development remains unclear. This review provides an overview of the current clinical evidence for the use of antiangiogenic agents targeting in the treatment of mCRC.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaloacetates; Phenylurea Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyridines; Randomized Controlled Trials as Topic; ras Proteins; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retreatment; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Regorafenib is an oral multikinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor, and monoclonal antibodies targeting epidermal growth factor receptor. A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in a 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) regimen on the basis of an individual uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. The aim of this study is to address the efficacy and safety of a dose-adjusted combination of regorafenib and FOLFIRI for patients with mCRC.. A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose-escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival, and the secondary endpoints are overall survival, disease control rate, time to progression, and duration of treatment. Safety assessments will also be recorded.. Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidence regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC.. ClinicalTrials.gov, NCT03880877. Prospectively registered on 19 March 2019.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Genotyping Techniques; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Multicenter Studies as Topic; Phenylurea Compounds; Precision Medicine; Prodrugs; Progression-Free Survival; Pyridines; Randomized Controlled Trials as Topic; Time Factors; Young Adult

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.. 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.. 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.. 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.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Pyridines

The oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC.. In this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4-10 and 18-24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety.. Median overall treatment duration with any study drug was 9.9 months (range 0.6-19.6); median treatment duration with regorafenib was 7.7 months (range 0.1-19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications.. Regorafenib+mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Historically Controlled Study; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Phenylurea Compounds; Pyridines; Treatment Outcome

Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective).. Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) over 46 h, folinic acid 400 mg/m(2), and either oxaliplatin 85 mg/m(2) or irinotecan 180 mg/m(2). On days 4-10, patients received regorafenib 160 mg orally once daily.. The median duration of treatment was 108 (range 2-345 days). Treatment was stopped for adverse events or death (17 patients), disease progression (11 patients), and consent withdrawal or investigator decision (11 patients). Six patients remained on regorafenib at data cutoff (two without chemotherapy). Drug-related adverse events occurred in 44 patients [grade ≥ 3 in 32 patients: mostly neutropenia (17 patients) and leukopenia, hand-foot skin reaction, and hypophosphatemia (four patients each)]. Thirty-three patients achieved disease control (partial response or stable disease) for a median of 126 (range 42-281 days).. Regorafenib had acceptable tolerability in combination with chemotherapy, with increased exposure of irinotecan and SN-38 but no significant effect on 5-fluorouracil or oxaliplatin pharmacokinetics.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Phenylurea Compounds; Pyridines; Treatment Outcome; Young Adult

The patient was a 65-year-old man for whom a right hemicolectomy was performed for transverse colon cancer and multiple lymph node metastases. Peritoneal dissemination was observed throughout the abdominal cavity, and curative resection was not possible. Postoperative diagnosis: pT4bN2M1c(P3), Stage Ⅳc, and mutant RAS status. Therapy consisting of mFOLFOX6 plus bevacizumab was started 1 month after surgery, and up to 25 courses were completed. FOLFIRI plus bevacizumab therapy was performed up to 13 courses as the second-line therapy. Regorafenib 80 mg/day was started as the third-line therapy and the dose was gradually increased. It was performed up to 14 courses for about 13 months, without major adverse events, to keep the disease stable or slow its progression. Although up to 5 courses of FTD/TPI plus bevacizumab therapy were delivered as the fourth-line therapy, he died of disease progression. Regorafenib, which has been approved as a salvage line for metastatic colorectal cancer, features many adverse events, and there are few cases in which the approved dose can be administered. In our case, starting at a low dose resulted in fewer adverse events, adequate disease control, and long-term administration.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Phenylurea Compounds; Pyridines

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Mutation; Organoplatinum Compounds; Phenylurea Compounds; Proto-Oncogene Proteins p21(ras); Pyridines

Since the introduction of antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies (moAbs), the treatment of metastatic colorectal cancer (mCRC) has become crucially dependent on the mutation profile of the tumour over the last two decades. Recently, rechallenge strategy with cetuximab-based chemotherapy has demonstrated to be active in a subgroup of patients whose tumour maintained wild-type RAS and RAF status. In this setting, liquid biopsy may replace tissue sample for the identification of specific subgroups of pretreated patients that may benefit from the reintroduction of anti-EGFR moAbs. In November 2014, a 64-year-old man with IVB stage BRAF, KRAS and NRAS wild-type mCRC was admitted in our hospital. He received FOLFIRI cetuximab as first-line treatment with deep and long-lasting partial response (PR), followed by cetuximab maintenance therapy until January 2016. At the time of disease progression, FOLFIRI cetuximab regimen was reintroduced resulting in stabilization of disease and he continued with capecitabine cetuximab therapy until disease progression in October 2016. Then, the patient consecutively received FOLFOX bevacizumab, TAS-102, regorafenib and FOLFIRI followed by de Gramont maintenance treatment. Finally, he was retreated with FOLFIRI cetuximab with disease progression within 3 months and died in May 2019. During his clinical course, liquid biopsy detected two mutations: one in KRAS Cd.12 and one in NRAS Cd. 61. The longitudinal assessment of RAS status offers considerable advantages in order to avoid side effects and economic costs for ineffective treatment choices. Liquid biopsy could help better monitor the disease and provide molecularly guided treatments.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Colorectal Neoplasms; Disease Progression; DNA Mutational Analysis; Drug Combinations; Fluorouracil; Humans; Leucovorin; Liquid Biopsy; Male; Middle Aged; Mutation; Phenylurea Compounds; Pyridines; Pyrrolidines; ras Proteins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Thymine; Trifluridine

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Phenylurea Compounds; Pyridines

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Phenylurea Compounds; Pyridines

We present the case of a 59 year old patient with a rare mutation in BRAF codon 594, who progressed rapidly on all classical therapies but experienced a clear and long lasting response on treatment with Regorafenib.. Little is known about therapies that can be effective in the rare

Topics: Adenocarcinoma of Lung; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Carcinoembryonic Antigen; Cetuximab; Colonic Neoplasms; Exons; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Mutation; Organoplatinum Compounds; Phenylurea Compounds; Proto-Oncogene Proteins B-raf; Pyridines; Tomography, X-Ray Computed; Treatment Outcome

RAS- or BRAF-mutated metastatic colorectal cancers (mCRCs) progressing after first-line treatment have a poor prognosis.European and U.S. guidelines include the multikinase inhibitor regorafenib as a standard option for second-line therapy and beyond, based on the results of the randomized phase III CORRECT trial demonstrating improvement in survival.Although stopped prematurely for failing to accrue, the PREVIUM trial, the first prospective interventional study exploring regorafenib as second-line treatment for patients with mCRC bearing RAS or BRAF mutations, failed to demonstrate clinical activity in the population analyzed.. Patients with RAS- or BRAF-mutated (mut) metastatic colorectal cancer (mCRC) progressing on first-line bevacizumab plus 5-FU/irinotecan/oxaliplatin (FOLFOXIRI) have a poor prognosis. We aimed to assess the efficacy and safety of regorafenib in this population.. Regorafenib was administered daily for 3 weeks of each 4-week cycle until disease progression or other reason. The primary endpoint was 6-month progression-free survival (PFS).. KRAS, NRAS, or BRAF was mutated in mCRC samples in 60%, 20%, and 13% of patients, respectively. Median time from initial diagnosis of metastases to the start of regorafenib and treatment duration was 13.8 months and 7 weeks, respectively. Reasons for discontinuation included disease progression (80%), investigator decision (13%), and adverse events (AEs; 7%). Seven patients (47%) required dose reduction, mostly for asthenia (43%). The most common regorafenib-related grade 3 AEs were asthenia (33%), dysphonia (13%), and hypertension (13%) (Table 1). There were no grade 4 toxicities. No patient was progression-free at 6 months. Median PFS, time to progression (TTP), and overall survival (OS) were 2.2, 2.0, and 3.3 months, respectively.. Although stopped prematurely for failing to accrue, in the population analyzed, regorafenib failed to demonstrate clinical activity in KRAS- or BRAF-mutated mCRC with progression following first-line with FOLFOXIRI plus bevacizumab, although tolerability was acceptable. Our trial suggests that exploring regorafenib efficacy in an earlier line of therapy should not be undertaken without better population refinement.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Phenylurea Compounds; Proto-Oncogene Proteins B-raf; Pyridines; ras Proteins

We analyzed the results of previously treated patients with metastatic colorectal cancer (mCRC) who received regorafenib plus FOLFIRI with the irinotecan dose escalation on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping. Thirteen patients with previously treated mCRC were subjected to UGT1A1 genotyping between October 2013 and June 2015 and were administered regorafenib plus FOLFIRI with irinotecan dose escalation. Patients with UGT1A1*1/*1 and *1/*28 genotypes were administered 180 mg/m2 of irinotecan, whereas those with the UGT1A1*28/*28 genotype were administered 120 mg/m2 of irinotecan. For all patients, the irinotecan dose was increased by 30 mg/m2 every two cycles until grade ≥3 adverse events or severe adverse events developed, following which the dose was reverted to and maintained at the previously tolerated level. The oral regorafenib dose was adjusted to 120 mg/day daily. The median follow-up period was 10.0 months (1.0-21.0 months). The disease control rate was 69.2%, whereas the median progression-free survival and overall survival were 9.5 and 13.0 months, respectively. Our findings indicate that regorafenib plus FOLFIRI with irinotecan dose escalation based on UGT1A1 genotyping in previously treated patients with mCRC and with UGT1A1*1/*1 and UGT1A1*1/*28 genotypes is clinically effective and yields improved oncological outcomes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Phenylurea Compounds; Pyridines; Retreatment; Treatment Outcome

The past decade has seen unprecedented advancements in our ability to treat patients with metastatic colorectal cancer. When applying these advances--hepatic resection and multi-agent chemotherapy--to the care of older patients, it is essential to first perform some assessment of function beyond performance status and to elicit feedback from the patient about how he/she values quality versus quantity of life. For robust older patients with potentially surgically resectable oligometastatic cancer, we recommend a standard approach of surgery with perioperative chemotherapy. However, operative risk increases with age, and careful discussion about prognosis is warranted. For patients with unresectable cancer, first-line chemotherapy with either 5-fluoruracil/leucovorin alone, or with a 20% dose reduced FOLFOX or FOLFIRI regimen, is well tolerated by older patients. Either dose escalation or addition of a second drug can typically be undertaken after 1-2 cycles. First-line bevacizumab with chemotherapy is warranted in those with low risk for atherothrombotic complications. EGFR inhibitors with combination chemotherapy for KRAS wild type cancers offer the best response rates, but toxicity can be difficult and may be best reserved for second-line in all but the fittest elderly. In second-line, we routinely offer continued chemotherapy with the agents that the patient has not yet received. The role of aflibercept and regorafenib has not been well studied in the elderly, but they are both reasonable options for patients with good function and no contraindication. With this cautious approach older patients can be expected to maintain a good quality of life during treatment for metastatic colorectal cancer.

Topics: Age Factors; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; ErbB Receptors; Fluorouracil; Humans; Leucovorin; Phenylurea Compounds; Prognosis; Pyridines; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Risk Factors; Vitamin B Complex