Regorafenib in metastatic colorectal cancer: more data for clinical decisions

Regorafenib is a multiple kinase inhibitor. It influences/blocks angiogenesis (VEGFR1-3, TIE2), proliferation (KIT, RET, RAF-1, BRAF), metastatic activity (VEGFR2-3, PDGFR), tumor immunogenicity (CSF1R), tumor microenvironment (PDGFR-, PDGFR-, FGFR1-2). Regorafenib has several indications including metastatic colorectal cancer. Efficacy and safety of regorafenib data from clinical trials (CORRECT, CONCUR, CONSIGN) and observational trials from real world (REBECCA, CORRELATE, RECORA, PMS, REGOTAS) are summarized and presented in this issue. State of the matter of molecular-biologic predictors (KRAS, PIK3CA ANG-2, VEGF-A, LDH, CCL5/CCR5, CA 19-9) and radiological predictors (RadioCORRECT and other trials) is highlighted. Regimens with dose modification and its influence on effectiveness and tolerability of regorafenib are described according to the data from ReDOS, RESET, REARRANGE trials. The results from retrospective trials comparing regorafenib and another approved for refractory metastatic colorectal cancer drug trifluridine/tipiracil are presented.

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Exceptional responses in patients with metastatic colorectal cancer enrolled in first-in-man studies from 2002 through 2012.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.687 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 687-687

Author(s):

Shiven B. Patel ◽

Danielle Tometich ◽

Zachary L Reese ◽

Sunil Sharma ◽

Ignacio Garrido-Laguna

Keyword(s):

Colorectal Cancer ◽

Clinical Trials ◽

Metastatic Colorectal Cancer ◽

Kinase Inhibitor ◽

Phase 1 ◽

Complete Response ◽

Response To Therapy ◽

Search Term ◽

Tumor Type ◽

Gamma Secretase

687 Background: Understanding exceptional responses to therapy at the molecular level may open new venues for the treatment of patients with metastatic colorectal cancer (mCRC). Responses in first-in-man (FIM) studies with targeted therapies are rare and may indicate that actionable genetic aberrations are present in these patients. Methods: We utilized Scopus using the search term “phase 1 and solid tumors” to collect all FIM studies published between 2002 and 2012. We identified patients with mCRC who attained an exceptional response to therapy defined as a complete response (CR) or a partial response (PR) lasting > 6 months (m). Results: We identified 118 FIM studies enrolling 5,369 patients with advanced malignancies. mCRC was the most common tumor type, totaling 1,055 (19.6%) patients. Of these, two patients enrolled in protocols with MDX-1106 (anti PD-1) and RG7180 (mAb EGFR) attained a complete response (CR). Five patients had PR lasting > 6 m. These patients were treated with RG7180 (time on study 7.8 m), Apatinib, a VEGFR tyrosine kinase inhibitor (8.5 and 7.1 m), PV701, a replication-competent oncolytic virus (10 m) and RO4929097, a gamma-secretase inhibitor (7 m). In addition two patients had PR lasting < 6 m with regorafenib (5.3 m) and RG7180 (5.6 m). This database of exceptional responders to therapy will be publicly available at Huntsman Cancer Institute website. Currently, regorafenib and EGFR mAbs (cetuximab and panitumumab) are approved for use in mCRC. EGFR mAbs have shown improvement in survival in RAS wild-type mCRC. Clinical trials are underway evaluating apatinib. Anti-PD1s have shown limited activity as single agents in mCRC and are currently undergoing testing in combination with chemotherapy. Conclusions: We identified exceptional responses among patients with mCRC enrolled in FIM in the last decade. Ongoing efforts are directed to conduct next generation sequencing (NGS) in archived tissue from these patients. Ultimately, this initiative may facilitate the identification of biomarkers of response to be tested in clinical trials with these or novel drugs sharing similar mechanisms of action.

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The efficacy and safety of apatinib in patients with metastatic colorectal cancer refractory to standard therapies.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15003 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15003-e15003 ◽

Cited By ~ 1

Author(s):

Wangxia Lv ◽

Meiqin Yuan ◽

Yunshan Yang ◽

Zhong Shi ◽

Haijun Zhong

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Kinase Inhibitor ◽

Phase Iii ◽

Tolerability Profile ◽

Efficacy And Safety ◽

Once Daily ◽

Phase Iii Trial ◽

Hand Foot Syndrome ◽

Clinically Significant

e15003 Background: Colorectal cancer is the third most frequent cancer and the fourth most frequent cause of cancer-related death worldwide.25% of patients with colorectal cancer have metastatic disease which leads a clinically significant detrimental effect on prognosis. After failure of standard treatments, regorafinib will be recommended to patients, but it has not been approved in China now. Apatinib is a novel, small-molecule tyrosine kinase inhibitor of VEGFR-2 which has shown a survival benefit in gastric cancer in a Phase III trial. This study is an initial clinical experience about the efficacy and safety of apatinib in patients with metastatic colorectal cancer refractory to standard therapies. Methods: Patients with refractory metastatic colorectal cancer received apatinib 500mg once daily. A treatment cycle was defined as 28 days (4 weeks). Response was assessed using RECIST 1.1 criteria. Toxicity was recorded using CTCAE version 4.0. Results: Between August 2015 to October 2016, seventeen patients were enrolled. One patient had PR (5.9%),twelve patients had SD (70.6%), and four had PD (23.6%). The ORR was 5.9% and DCR was 76.5%. The median PFS was 125 days (4.0months, 95%,CI = 1.1-6.9). The grade3/4 adverse events were hypertension (2/17;11.8%), proteinuria (2/17;11.8%), Hand-foot syndrome (2/17;11.8%), leukopenia(1/17;5.9%), neutropenia(1/17;5.9%), hyperbilirubinemia(1/17;5.9%), and diarrhea(1/17;5.9%),respectively.There were no treatment-related deaths. Conclusions:Apatinib is active for the treatment of refractory metastatic colorectal cancer with a manageable tolerability profile. Further investigations of apatinib in mCRC are needed.

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FRESCO-2: a global Phase III study investigating the efficacy and safety of fruquintinib in metastatic colorectal cancer

Future Oncology ◽

10.2217/fon-2021-0202 ◽

2021 ◽

Author(s):

Arvind Dasari ◽

Alberto Sobrero ◽

James Yao ◽

Takayuki Yoshino ◽

William Schelman ◽

...

Keyword(s):

Colorectal Cancer ◽

Supportive Care ◽

Metastatic Colorectal Cancer ◽

Kinase Inhibitor ◽

Progression Free Survival ◽

Best Supportive Care ◽

Phase Iii ◽

Efficacy And Safety ◽

Double Blind ◽

Phase Iii Study

Fruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy. Approximately 687 patients will be randomized 2:1 to fruquintinib plus best supportive care or placebo plus best supportive care. Primary and key secondary end points are overall survival and progression-free survival, respectively. FRESCO-2 is enrolling in the USA, Europe, Australia and Japan.

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A Critical Review of Second-generation anti-EGFR Monoclonal Antibodies in Metastatic Colorectal Cancer

Current Drug Targets ◽

10.2174/1389450121666200727121011 ◽

2020 ◽

Vol 21 ◽

Author(s):

Daniel Sur ◽

Andrei Havasi ◽

Alecsandra Gorzo ◽

Claudia Burz

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Clinical Trials ◽

Monoclonal Antibodies ◽

Metastatic Colorectal Cancer ◽

Second Generation ◽

Current Data ◽

Braf Mutations ◽

Durable Response ◽

Ongoing Research

Background: Anti-EGFR monoclonal antibodies (mAbs) have become a relevant solution for the treatment of patients with metastatic colorectal cancer. Current anti-EGFR monoclonal antibodies face a series of problems, including resistance and non-durable response, and RAS and BRAF mutations serve as exclusion criteria for treatment with anti-EGFR mAbs. Advances in molecular tumor profiling and information on subsequent pathways responsible for disease progression and drug resistance helped develop a new generation of anti-EGFR mAbs. These second-generation mAbs have been developed to overcome existing resistance mechanisms and to limit common side effects. For the moment, existing literature suggests that these novel anti-EGFR mAbs are far from finding their way to clinical practice soon. Objective: In this review, we summarize and evaluate current data regarding ongoing research and completed clinical trials for different second-generation anti-EGFR monoclonal antibodies. Conclusion: Anti-EGFR mAbs exhibit efficacy in advanced colorectal cancer, but second-generation mAbs failed to prove their benefit in the treatment of metastatic colorectal cancer. Understanding the biological basis of primary and acquired drug resistance could allow scientists to design better clinical trials and develop improved second-generation mAbs.

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4CPS-294 Efficacy and safety profile of trifluridine–tipiracil and regorafenib in the treatment of metastatic colorectal cancer

10.1136/ejhpharm-2021-eahpconf.126 ◽

2021 ◽

Author(s):

L Cantarelli ◽

JA Morales Barrios ◽

F Gutierrez Nicolas ◽

S Garcia Gil ◽

B Del Rosario Garcia ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Safety Profile ◽

Efficacy And Safety

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Radioembolization for Rare Metastatic Disease

Digestive Disease Interventions ◽

10.1055/s-0041-1729875 ◽

2021 ◽

Author(s):

Andrew S. Niekamp ◽

Govindarajan Narayanan ◽

Brian J. Schiro ◽

Constantino Pena ◽

Alex Powell ◽

...

Keyword(s):

Colorectal Cancer ◽

Hepatocellular Carcinoma ◽

Metastatic Colorectal Cancer ◽

Treatment Modality ◽

Treatment Options ◽

Efficacy And Safety ◽

Multiple Tumor ◽

Tumor Types ◽

Hepatic Malignancies ◽

Yttrium 90

AbstractRadioembolization has become a widespread treatment modality for both primary and metastatic hepatic malignancies. Although the majority of data and indication for yttrium-90 radioembolization have been for hepatocellular carcinoma and metastatic colorectal cancer, radioembolization with yttrium-90 has rapidly expanded into the treatment options for multiple tumor types with metastases to the liver. This article reviews the clinical data and expanding utilization of radioembolization for rare metastatic diseases with an emphasis on efficacy and safety.

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Cetuximab Plus Irinotecan in Heavily Pretreated Metastatic Colorectal Cancer Progressing on Irinotecan: MABEL Study

Journal of Clinical Oncology ◽

10.1200/jco.2008.16.3758 ◽

2008 ◽

Vol 26 (33) ◽

pp. 5335-5343 ◽

Cited By ~ 69

Author(s):

Hansjochen Wilke ◽

Robert Glynne-Jones ◽

Josef Thaler ◽

Antoine Adenis ◽

Peter Preusser ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Progression Free Survival ◽

Primary Objective ◽

Practice Setting ◽

Community Practice ◽

Efficacy And Safety ◽

Intention To Treat ◽

Heavily Pretreated ◽

N 93

Purpose This large, multinational study aimed to confirm in a community practice setting the efficacy and safety of cetuximab plus irinotecan in patients with epidermal growth factor–expressing metastatic colorectal cancer (mCRC) who had recently failed an irinotecan-containing regimen. Patients and Methods The primary objective was to determine the progression-free survival (PFS) rate at 12 weeks. The initial cetuximab dose was 400 mg/m2 and was followed weekly by 250 mg/m2; irinotecan (according to prestudy regimen) was given weekly (125 mg/m2 weekly for 4 of 6 weeks), every 2 weeks (180 mg/m2 each), or every 3 weeks (350 mg/m2 each). Results The intention-to-treat/safety population comprised 1,147 treated patients who received irinotecan weekly (n = 93); every 2 weeks (n = 670); every 3 weeks (n = 356); or another dose (n = 28). The PFS rate at 12 weeks was 61%, and the median survival was 9.2 months. Treatment was generally well tolerated. The most common treatment-related grades 3 to 4 adverse events were diarrhea (19%), neutropenia (10%), rash (7%), and asthenia (6%). The rate of grades 3 to 4 infusion-related reactions (IRRs; composite adverse event category) was 1% for patients who received both antihistamine and corticosteroid premedication. Conclusion Tolerability (except IRR incidence), PFS rate, and overall survival rate were in line with previous results. At 1%, the rate of IRRs in patients who received prophylactic premedication with both antihistamine and corticosteroid is lower than previously reported. MABEL clearly confirms in a community practice setting the efficacy and safety of cetuximab plus irinotecan in the treatment of mCRC.

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