BACKGROUND: Fruquintinib is a highly selective, oral inhibitor of all 3 VEGF receptors. The global, randomized, double-blind phase 3 FRESCO-2 trial (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival in patients with refractory metastatic colorectal cancer (mCRC) who received fruquintinib plus best supportive care (BSC) versus placebo plus BSC. Here we report detailed safety data from FRESCO-2 including an analysis of treatment-related adverse events of special interest (AESIs). PATIENTS AND METHODS: Patients with mCRC eligible for FRESCO-2 had received all standard chemotherapies and prior anti-VEGF and anti-EGFR therapies if indicated, and displayed progression on, or intolerance to, TAS-102 and/or regorafenib. Prespecified AESIs based on VEGFR tyrosine kinase inhibitor drug classes were evaluated. RESULTS: Incidences of treatment-related AESIs were 64.9% with fruquintinib + BSC versus 23.0% with placebo + BSC. The most frequent all-grade treatment-related AESIs for fruquintinib were hypertension (28.9%; grade ≥3 10.7%), palmar-plantar erythrodysesthesia syndrome/hand-foot skin reaction (PPE 18.6%; grade ≥3 6.1%), and hypothyroidism (15.6%; grade ≥3 0.4%). Dose reductions due to treatment-related AESIs were reported in 10.3% of patients who received fruquintinib + BSC versus 0.4% with placebo + BSC. The most common treatment-related AESIs resulting in dose reduction for fruquintinib were PPE syndrome (5.0%), hypertension (2.9%), and proteinuria (1.3%). Overall, 5.9% versus 0.9% had treatment-related AESIs resulting in study drug discontinuation. CONCLUSION: Fruquintinib + BSC demonstrated a predictable and manageable safety profile in pretreated patients with mCRC and is a novel oral treatment option that prolongs survival and enriches the continuum of care in this population.

Department of Complex Oncology Care Masaryk Memorial Cancer Institute Brno 60200 Czech Republic

Department of Gastroenterological Surgery Graduate School of Medicine Osaka University Suita 565 0871 Japan

Department of Gastroenterology and Gastrointestinal Oncology National Cancer Center Hospital East Kashiwa Chiba 277 8577 Japan

Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 United States

Department of Medical Oncology Azienda Ospedaliera San Martino Genoa 16132 Italy

Department of Medicine Division of Hematology and Oncology Vanderbilt Ingram Cancer Center Nashville TN 37232 United States

Department of Oncology and Hemato Oncology Università degli Studi di Milano Milan 20122 Italy

Department of Oncoradiology Bács Kiskun Megyei Oktatókórház Kecskemét 6000 Hungary

Hepato Gastroenterology Department CHU de Poitiers F 86000 Poitiers France

HUTCHMED International Corporation Florham Park NJ 07932 United States

Medical Oncology HM Universitario Sanchinarro Centro Integral Oncológico Clara Campal Madrid 28050 Spain

Medical Oncology Hospital Universitario Gregorio Marañón Madrid 28007 Spain

Medical Oncology Unit 1 Veneto Institute of Oncology IOV IRCCS Padua Padua 35128 Italy

Olivia Newton John Cancer and Wellness Centre Austin Hospital Heidelberg VIC 3084 Australia

Oncology Department Hospital Universitario 12 de Octubre Facultad de Medicina Universidad Complutense de Madrid Madrid 28041 Spain

Vall d'Hebron Barcelona Hospital Campus Vall d'Hebron Institute of Oncology Barcelona 08035 Spain

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Bray F, Laversanne M, Sung H, et al.Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229-263. https://doi.org/10.3322/caac.21834 PubMed DOI

Siegel RL, Miller KD, Wagle NS, Jemal A.. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17-48. https://doi.org/10.3322/caac.21763 PubMed DOI

Cervantes A, Adam R, Roselló S, et al.; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:10-32. https://doi.org/10.1016/j.annonc.2022.10.003 PubMed DOI

American Cancer Society. Survival rates for colorectal cancer 2023. Accessed September 2024. https://www.cancer.org/cancer/types/colon-rectal-cancer/detection-diagnosis-staging/survival-rates.html

Grothey A, Prager G, Yoshino T.. The mechanism of action of regorafenib in colorectal cancer: a guide for the community physician. Clin Adv Hematol Oncol. 2019;12(17 Suppl):1-19. PubMed

Arora SP, Mahalingam D.. Immunotherapy in colorectal cancer: for the select few or all? J Gastrointest Oncol. 2018;9:170-179. https://doi.org/10.21037/jgo.2017.06.10 PubMed DOI PMC

Xie YH, Chen YX, Fang JY.. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020;5:22. https://doi.org/10.1038/s41392-020-0116-z PubMed DOI PMC

Papadimitriou K, Rolfo C, Dewaele E, et al.Incorporating anti-VEGF pathway therapy as a continuum of care in metastatic colorectal cancer. Curr Treat Options Oncol. 2015;16:18. https://doi.org/10.1007/s11864-015-0333-9 PubMed DOI

Strickler JH, Cercek A, Siena S, et al.; MOUNTAINEER investigators. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 2023;24:496-508. https://doi.org/10.1016/S1470-2045(23)00150-X PubMed DOI

Buchler T. Microsatellite instability and metastatic colorectal cancer—a clinical perspective. Front Oncol. 2022;12:888181. https://doi.org/10.3389/fonc.2022.888181 PubMed DOI PMC

Giordano G, Parcesepe P, Bruno G, et al.Evidence-based second-line treatment in RAS wild-type/mutated metastatic colorectal cancer in the precision medicine era. Int J Mol Sci. 2021;22:7717. https://doi.org/10.3390/ijms22147717 PubMed DOI PMC

Tabernero J, Ros J, Élez E.. The evolving treatment landscape in BRAF-V600E-mutated metastatic colorectal cancer. Am Soc Clin Oncol Educ Book. 2022;42:1-10. https://doi.org/10.1200/EDBK_349561 PubMed DOI

Grothey A, Van Cutsem E, Sobrero A, et al.; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303-312. https://doi.org/10.1016/S0140-6736(12)61900-X PubMed DOI

Mayer RJ, Van Cutsem E, Falcone A, et al.; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372:1909-1919. https://doi.org/10.1056/NEJMoa1414325 PubMed DOI

Prager GW, Taieb J, Fakih M, et al.; SUNLIGHT Investigators. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388:1657-1667. https://doi.org/10.1056/NEJMoa2214963 PubMed DOI

LONSURF (trifluridine and tipiracil) Prescribing Information, Taiho Pharmaceutical, Inc., revised August 2023. Accessed September 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/207981s012lbl.pdf

LONSURF (trifluridine and tipiracil) EU Summary of Product Characteristics, Taiho Pharmaceutical, Inc. Accessed September 2024. https://www.ema.europa.eu/en/documents/product-information/lonsurf-epar-product-information_en.pdf

STIVARGA (regorafenib) Prescribing Information, Bayer, Inc., revised Apr 2017. Accessed September 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf

STIVARGA (regorafenib) EU Summary of Product Characteristics, Bayer Inc. Accessed September 2024. https://www.ema.europa.eu/en/documents/product-information/stivarga-epar-product-information_en.pdf

Dasari A, Sobrero A, Yao J, et al.FRESCO-2: a global phase III study investigating the efficacy and safety of fruquintinib in metastatic colorectal cancer. Future Oncol. 2021;17:3151-3162. https://doi.org/10.2217/fon-2021-0202 PubMed DOI

Sun Q, Zhou J, Zhang Z, et al.Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther. 2014;15:1635-1645. https://doi.org/10.4161/15384047.2014.964087 PubMed DOI PMC

Cao J, Zhang J, Peng W, et al.A phase I study of safety and pharmacokinetics of fruquintinib, a novel selective inhibitor of vascular endothelial growth factor receptor-1, -2, and -3 tyrosine kinases in Chinese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016;78:259-269. https://doi.org/10.1007/s00280-016-3069-8 PubMed DOI

Zhang Y, Zou JY, Wang Z, Wang Y.. Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer. Cancer Manag Res. 2019;11:7787-7803. https://doi.org/10.2147/CMAR.S215533 PubMed DOI PMC

Li J, Qin S, Xu RH, et al.Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319:2486-2496. https://doi.org/10.1001/jama.2018.7855 PubMed DOI PMC

Dasari A, Lonardi S, Garcia-Carbonero R, et al.; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402:41-53. https://doi.org/10.1016/S0140-6736(23)00772-9 PubMed DOI

Sobrero AF, Dasari A, Lonardi S, et al.Health-related quality of life (HRQoL) associated with fruquintinib in the global phase 3, placebo-controlled, double-blind FRESCO-2 study. J Clin Oncol. 2023;41:67-67. https://doi.org/10.1200/jco.2023.41.4_suppl.67 DOI

FRUZAQLA™ (fruquintinib) prescribing information. Takeda Pharmaceuticals America, Inc; 2023. Accessed November 09, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217564s000lbl.pdf

Whelton PK, Carey RM, Aronow WS, et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Hypertension. 2018;71:1269-1324. https://doi.org/10.1161/HYP.0000000000000066 PubMed DOI

Li J, Guo W, Bai Y, et al.Safety profile and adverse events of special interest for fruquintinib in Chinese patients with previously treated metastatic colorectal cancer: analysis of the phase 3 FRESCO trial. Adv Ther. 2020;37:4585-4598. https://doi.org/10.1007/s12325-020-01477-w PubMed DOI

FRUZAQLA™ (fruquintinib) summary of product characteristics. EMA. Accessed September 2024. https://www.ema.europa.eu/en/documents/product-information/fruzaqla-epar-product-information_en.pdf

Kamba T, McDonald DM.. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96:1788-1795. https://doi.org/10.1038/sj.bjc.6603813 PubMed DOI PMC

Pandey AK, Singhi EK, Arroyo JP, et al.Mechanisms of VEGF (vascular endothelial growth factor) inhibitor-associated hypertension and vascular disease. Hypertension. 2018;71:e1-e8. https://doi.org/10.1161/HYPERTENSIONAHA.117.10271 PubMed DOI PMC

Schmidinger M. Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors. EJC Suppl. 2013;11:172-191. https://doi.org/10.1016/j.ejcsup.2013.07.016 PubMed DOI PMC

Zhu Y, Zhang X, Lou X, et al.Vascular endothelial growth factor (VEGF) antibody significantly increases the risk of hand-foot skin reaction to multikinase inhibitors (MKIs): A systematic literature review and meta-analysis. Clin Exp Pharmacol Physiol. 2018;45:659-667. https://doi.org/10.1111/1440-1681.12935 PubMed DOI PMC

Wilhelm SM, Dumas J, Adnane L, et al.Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129:245-255. https://doi.org/10.1002/ijc.25864 PubMed DOI

Zhao B, Zhao H.. Incidence and risk of regorafenib-induced hepatotoxicity. Oncotarget. 2017;8:84102-84111. https://doi.org/10.18632/oncotarget.21106 PubMed DOI PMC

Van Cutsem E, Martinelli E, Cascinu S, et al.Regorafenib for patients with metastatic colorectal cancer who progressed after standard therapy: results of the large, single-arm, open-label phase IIIb CONSIGN study. Oncologist. 2019;24:185-192. https://doi.org/10.1634/theoncologist.2018-0072 PubMed DOI PMC