The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site. The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. My Bibliography Citation manager Save citation to file Add to Collections Add to My Bibliography Your saved search Create a file for external citation management software Background: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. Methods: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539 , and EudraCT, 2020-000158-88, and is ongoing but not recruiting. Findings: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). Interpretation: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. Funding: HUTCHMED. Copyright © 2023 Elsevier Ltd. All rights reserved. PubMed Disclaimer Conflict of interest statement Declaration of interests AD reports support for the present manuscript from HUTCHMED; grants or contracts from HUTCHMED, Guardant Health, Natera, AAA/Novartis, Eisai, and Crinetics; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from HUTCHMED, Personalis, AAA/Novartis, Crinetics, and Voluntis. SL reports support for the present manuscript from HUTCHMED; grants or contracts from Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and Bristol Myers Squibb; consulting or advisory fees from Amgen, Merck Serono, Lilly, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Servier, and MSD; and speakers' bureau fees from Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen, and MSD. RG-C reports support for the present manuscript to their institution from HUTCHMED; grants for investigator-initiated clinical trials from Pfizer, Bristol Myers Squibb, and MSD; consulting fees from AAA/Novartis, Advanz Pharma, Amgen, Bayer, Bristol Myers Squibb, Boerhringer Ingelheim, Esteve, HUTCHMED, Ipsen, Merck, Midatech Pharma, MSD, Pierre Fabre, Roche, and Servier; and support for attending meetings or travel from AAA/Novartis, Esteve, Ipsen, Merck, MSD, and Roche. EE reports grants or contracts to their institution from Amgen, Array Biopharma, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX SAS, HUTCHMED, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, and Taiho Pharma USA; consulting fees and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, Bayer, Hoffmann-La Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, and Servier; support for attending meetings or travel from Amgen, Array BioPharma, Bristol Myers Squibb, Merck Serono, Roche, Sanofi, and Servier; participation on a data safety monitoring or advisory board for Amgen, Bayer, F Hoffmann-La Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, and Servier; and a paid or unpaid leadership or fiduciary role with the American Society of Clinical Oncology, European Society for Medical Oncology, and Sociedad Española de Oncología Médica. TY reports grants or contracts to their institution from Ono Pharmaceutical, Sanofi, Daiichi Sankyo, PAREXEL International, Pfizer Japan, Taiho Pharmaceutical, MSD, Amgen, Genomedia, Sysmex Corporation, Chugai Pharmaceutical, and Nippon Boehringer Ingelheim; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, and MSD. ASo reports consulting fees and attending meetings or travel support from HUTCHMED; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, Servier, MSD, Bristol Myers Squibb, Amgen, Merck, Bayer, Sanofi, and Pierre Fabre; and participation on a data safety monitoring or advisory board for Bristol Myers Squibb, Pierre Fabre, Amgen, HUTCHMED, MSD, and Servier. JY reports support for the present manuscript and consulting fees from HUTCHMED, Ipsen, Crinetics, Amgen, Chiasma, Advanced Accelerator Applications, and Novartis. PG-A reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events; and support for attending meetings or travel from and participation on a data safety monitoring or advisory board for Amgen, Merck, Roche, Sanofi, Servier, Lilly, and Pierre Fabre. AS-B reports lecture or educational event fees from Amgen, Bayer, Guardant Health, Merck, Sanofi, and Servier; and advisory board fees from Amgen, Bayer, Novartis, and Servier. TS reports grants or contracts from Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Daiichi Sankyo, Chugai Pharmaceutical, and Yakult Honsha; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, and Daiichi Sankyo. VR reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, Servier, and Pierre Fabre; and meetings or travel support from Merck, Bayer, Amgen, Vifor Pharma, and Accord Healthcare. JTo reports consulting fees and honoraria for lectures and presentations from Eisai, Roche, Merck, Servier, Amgen, Novartis, MSD, and Bristol Myers Squibb. GC reports consulting fees to their institution from and participation on a data safety monitoring or advisory board for Bristol Myers Squibb; support for attending meetings or travel from HUTCHMED; and research funding to their institution from HUTCHMED, Servier, Bayer, Isofol, Merck Serono, Bristol Myers Squibb, AstraZeneca, Pharmacyclics, Regeneron, Morphosys, and Incyte. ASP reports support for the present manuscript to the institution from HUTCHMED; grants or contracts for clinical trials to their institution from Ipsen, Bristol Myers Squibb, Exelixis, HUTCHMED, Taiho, Lilly, AstraZeneca, Incyte, Deciphers, G1 Therapeutics, Zentalkis, Tempus, Camurus, Relay Therapeutics, Nucana, Merck, Bayer, Sotio, and Innovations Cellular Therapeutics; educational event fees from Ideo Oncology, and MJH Life Sciences; travel support from Pfizer; participation on a data safety monitoring or advisory board for Amgen, Bristol Myers Squibb, Eisai, Ipsen, AAA, Exelixis, Pfizer, QED, Lilly, Mirati, HUTCHMED, Astellas, Incyte, AADi, Stromatis, EMD, and Serono; holding stock or stock options in Aptose, Actinium, and Alexion; and payment for medical writing services from Bayer, Ipsen, HUTCHMED, and Exelixis. TM reports grants or contracts to the institution from MSD, Daiichi Sankyo, Ono, Novartis, Amgen, Syneos Health Clinical, Boehringer Ingelheim, Pfizer, Cimic Shift Zero, and Eli Lilly; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Chugai, Merck Bio Pharma, Taiho, Bayer, Lilly Japan, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, and Bristol Myers Squibb. CC reports consulting fees from Merck, Pierre Fabre, Servier, Amgen, and Nordic Pharma; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Roche, Servier, MSD, Merck, and Pierre Fabre; payment for expert testimony from Bayer, Servier, Pierre Fabre, and Merck; support for attending meetings or travel from Amgen; and participation on a data safety monitoring or advisory board for Amgen and Mirati. FG reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events to their institution from AstraZeneca, Roche, and MSD; and support for attending meetings or travel from MSD. ASh reports grants or contracts to their institution from HUTCHMED, Merck, INHIBRx, Verastem Oncology, Turning Point Therapeutics, Gritstone, Bolt Therapeutics, Bristol Myers Squibb, Pfizer, Astellas, Oncologie, Macogenics, Seattle Genetics, Amgen, Daiichi Sankyo, Lilly, and Jacobio; advisory board fees from Regeneron/Sanofi, Pfizer, and Catalyst Pharmaceuticals; and speaker fees from OncLive, OSCO/ASCO Direct, ACPMP, Cholangiocarcinoma Summit, Cholangiocarcinoma Foundation, and ASCO Advantage. HSH reports consulting fees from Merck, Processa, and TRIGR; lecture fees from Natera; and participation on a data safety monitoring or advisory board for Genentech and Seattle Genetics. JKr reports support for the present manuscript to their institution from Syneos Health/HUTCHMED; grants or contracts to their institution from Genentech, Bristol Myers Squibb, Amgen, Isofol Medical, Novartis, Tempest Therapeutics, MedImmune/AstraZeneca, AbbVie, MedImmune, Icon, and Turning Point Therapeutics; and participation on a data safety monitoring board for Amgen (Codebreak 300 trial, NCT05198934). MD reports support for the present manuscript from HUTCHMED; research grants from Roche, Keocyt, and Bayer; advisory board consulting fees from Boehringer, Roche, Merck Serono, Daiichi Sankyo, Rafael, Bayer, Agenus, Terumo, Pierre Fabre, and Servier; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, Merck Serono, Bayer, Amgen, Pierre Fabre, Servier, Roche, Merck Serono, and MSD; support for attending meetings from Servier, Pierre Fabre, and Roche; participation on a data safety monitoring or advisory board for Roche and Pancan; and a personal conflict of interest with Sandoz. AE reports payments for advisory boards from Amgen, Merck, and Ewopharma; and lectures or educational events from Amgen, Merck, Ipsen, and Ewopharma. SK reports personal and institutional grants or contracts from Bristol Myers Squibb, Lilly, and Roche; consulting fees and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Amgen, Servier, Lilly, Merck Serono, Roche, MSD, and Pierre Fabre; consulting fees from Novartis and Incyte; support for attending meetings or travel from Pierre Fabre, Lilly, Amgen, Bristol Myers Squibb, Roche, and Merch Serono; and participation on a data safety monitoring board or advisory board for Novartis. EVC reports grants or contracts to their institution from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck, Novartis, Roche, and Servier; and consulting fees from AbbVie, ALX, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, and Zymeworks. DA reports support for the present manuscript from his institution; consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Roche, Sanofi, Servier, Sirtex, and Terumo; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Roche, Sanofi, Servier, Sirtex, Terumo, and CME providers Art Tempi, PriME Oncology, Medscape, and TRM Oncology; congress travel support from AstraZeneca; remunerated advisory board fees from Sanofi; non-remunerated advisory board fees from Oncolytics; and a paid or unpaid role with the European Society for Medical Oncology, European Organisation for Research in Treatment of Cancer, and Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society. SN, ZY, WRS, and MK report employment and holding stock or stock options with HUTCHMED. JTa reports consulting fees from Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, HUTCHMED, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; educational collaboration fees from Imedex/HMP, Medscape Education, MJH Life Sciences, and PeerView Institute for Medical Education and Physicians Education Resource; and holding stock or stock options in Oniria Therapeutics. CE reports support for the present manuscript from HUTCHMED; grants or contracts from Elevar, Merck, Pfizer, and Gritstone; and consulting fees from Bayer, GlaxoSmithKline, Halio Dx, and Boston Scientific. All other authors declare no competing interests. Angiogenesis inhibition in metastatic colorectal cancer continuum of care. Martinelli E, Ciardiello F. Martinelli E, et al. Lancet. 2023 Jul 1;402(10395):4-5. doi: 10.1016/S0140-6736(23)00867-X. Epub 2023 Jun 15. Lancet. 2023. PMID: 37331366 No abstract available. Angiogenesis inhibitors for metastatic colorectal cancer. Pfeiffer P, Liposits G, Taarpgaard LS. Pfeiffer P, et al. Transl Cancer Res. 2023 Dec 31;12(12):3241-3244. doi: 10.21037/tcr-23-1568. Epub 2023 Dec 26. Transl Cancer Res. 2023. PMID: 38192992 Free PMC article. No abstract available. 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