HUTCHMED Announces Takeda Receives FDA Approval of FRUZAQLA™ (Fruquintinib) for Previously Treated Metastatic Colorectal Cancer
HUTCHMED
Biopharmaceutical Manufacturer
Takeda
Biopharmaceutical Manufacturer
Source:HUTCHMED
Hong Kong, China, Shanghai, and the United StatesZeXizhou:Thursday, November 9, 2023:HUTCHMED (CHINA) LIMITED (referred to as "HUTCHMED") (Nasdaq/LSE: HCM; HKEX: 13) Today announced that its partner Takeda has achievedFRUZAQLA™ (Fruquintinib) FDA ApprovalThis is an oral targeted therapy for the treatment of adult patients with metastatic colorectal cancer who have previously received chemotherapy based on fluorouracil, oxaliplatin, and irinotecan, anti-vascular endothelial growth factor (VEGF) therapy, and anti-epidermal growth factor receptor (EGFR) therapy (if RAS wild-type and medically applicable).FRUZAQLA is the first and only highly selective inhibitor targeting all three VEGF receptor kinases approved in the U.S. for the treatment of previously treated metastatic colorectal cancer, regardless of the patient's biomarker status.[1,2] This approval was granted through the Priority Review process, more than 20 days ahead of the original Prescription Drug User Fee Act (PDUFA) target review date of November 30, 2023.
For American patients with metastatic colorectal cancer, this is a landmark moment as they are about to receive a much-needed new treatment option that improves their survival rates without negatively impacting their quality of life. Over the past five years, we have improved treatment outcomes for patients in China through our innovative oncology drugs, and now we are witnessing our first market approval outside of China, which marks another landmark moment for HUTCHMED. At the end of 2022, we launched a partner strategy to help advance our innovative drug candidates globally, and we are pleased to see initial success from this new strategy just one year later. This early achievement is credited to our partner Takeda, who recognized the value of fruquintinib. Sharing the same vision, we are working together to bring it to the global stage and secure U.S. approval. We look forward to further collaboration with Takeda to bring FRUZAQLA to patients worldwide.
CEO of HUTCHMED
& Chief Scientific Officer
Dr. Su Wei-Guo
Takeda holds the global exclusive license to advance the development, commercialization, and production of fruquintinib for all indications outside of China. According to the terms of the agreement between HUTCHMED and Takeda,FRUZAQLA's FDA Approval Triggers $35 Million Milestone PaymentHUTCHMED is eligible to receive additional potential payments for regulatory, development and commercial sales milestones, plus royalties based on net sales.Fruquintinib was approved in China in September 2018. It was co-developed by HUTCHMED and Eli Lilly and Company, and marketed under the brand name ELUNATE™.
Colorectal cancer is one of the leading causes of cancer deaths in the United States, and over the past decade, there have been few innovations for patients with metastatic colorectal cancer. We are proud that our collaboration with HUTCHMED has enabled us to bring a new option to this patient population, and we look forward to continuing to serve these underserved cancer patients.
The approval of FRUZAQLA was based on data from two large Phase III clinical trials, including:International multicenter clinical trial FRESCO-2 study, its data has also been published in The LancetPublished in The Lancet; and inThe FRESCO study conducted in China has also been published in the Journal of the American Medical Association (JAMA) 》Published on。The above research explored FRUZAQLA in combination with best supportive care versus placebo in combination with best supportive care for the treatment of pretreated patients with metastatic colorectal cancer. Both the FRESCO and FRESCO-2 studies met their primary and key secondary endpoints, demonstrating consistent benefits across a total of 734 patients treated with FRUZAQLA. The safety profiles of each study were also consistent.
(Vanderbilt University Medical Center)
Cathy MD, FACP
In the United States, an estimated 153,000 new cases of colorectal cancer are expected to be diagnosed in 2023., accounting for 7.8% of all new cancer cases。[3],[4]About 70% of patients with colorectal cancer will experience metastasis at the time of diagnosis or after treatment. Metastasis remains the leading cause of death related to colorectal cancer.。[5],[6]
The data from the FRESCO and FRESCO-2 studies also supported the submission of the marketing authorization application for fruquintinib to the European Medicines Agency ("EMA"), which was confirmed and accepted in June 2023. Additionally, an application was submitted to the Pharmaceuticals and Medical Devices Agency ("PMDA") in September 2023.
About FRUZAQLA
(Fruquintinib)
FRUZAQLA (Fruquintinib) is a selective oral inhibitor of VEGFR-1, -2, and -3. VEGFR inhibitors play a crucial role in inhibiting tumor angiogenesis. FRUZAQLA is designed to have higher kinase selectivity, aiming to reduce off-target kinase activity, thereby enabling higher drug exposure, sustained target coverage, and greater flexibility when potentially used as part of combination therapy. To date, FRUZAQLA has demonstrated a manageable safety profile, and studies on its use in combination with other anti-cancer therapies are ongoing.
About Colorectal Cancer
Colorectal cancer is a type of cancer that starts in the colon or rectum. According to the International Agency for Research on Cancer (IARC), colorectal cancer is the third most common cancer worldwide, with an estimated 935,000 deaths in 2020.。[7] In the United States, it is estimated that there will be 153,000 new cases of colorectal cancer and 53,000 deaths in 2023.。[3]In Europe, colorectal cancer is the second most common cancer, with approximately 520,000 new cases and 245,000 deaths in 2020. In Japan, colorectal cancer is the most common cancer, with an estimated 148,000 new cases and 60,000 deaths in 2020.。[7] Although early-stage colorectal cancer can be treated with surgical resection, the outcomes for metastatic colorectal cancer remain poor with limited treatment options, and there is still a significant unmet medical need. While some patients with metastatic colorectal cancer may benefit from personalized treatment strategies based on molecular characteristics, the majority of patients do not carry mutations that can serve as therapeutic targets.。[8-12]
About the FRESCO-2 Phase III Study
FRESCO-2 is an international, multicenter clinical trial conducted in the United States, Europe, Japan, and Australia, designed to investigate FRUZAQLA (fruquintinib) combined with best supportive care versus placebo combined with best supportive care for the treatment of patients with previously treated metastatic colorectal cancer (NCT04322539). The study met its primary endpoint and key secondary endpoints, demonstrating that FRUZAQLA treatment achieved statistically significant and clinically meaningful improvements in both overall survival (OS) and progression-free survival (PFS). The safety profile of FRUZAQLA in the FRESCO-2 study was consistent with the known profile reported in previous FRUZAQLA clinical trials. The results of this study were presented at the European Society for Medical Oncology (ESMO) Congress in September 2022 and subsequently published in *The Lancet*.。[13],[14]
Warnings and PrecautionsItem
Among the 911 patients with metastatic colorectal cancer treated with FRUZAQLA, 49% experiencedHypertension, of which 19% experienced Grade 3-4 events, and 3 patients (0.3%) developed hypertensive crisis. Do not initiate FRUZAQLA unless blood pressure is adequately controlled. Monitor blood pressure once weekly during the first month, and at least monthly thereafter as clinically indicated. Initiate or adjust antihypertensive therapy as appropriate. Based on the severity of hypertension, withhold, reduce the dose, or permanently discontinue FRUZAQLA.
Bleeding EventMay occur during FRUZAQLA treatment, including serious or fatal events. Among 911 patients with metastatic colorectal cancer treated with FRUZAQLA, 6% experienced gastrointestinal bleeding, with 1% experiencing Grade ≥3 events and two patients experiencing fatal bleeding. Permanently discontinue FRUZAQLA in patients with severe or life-threatening bleeding. Monitor International Normalized Ratio (INR) levels in patients receiving anticoagulant therapy.
Infection。FRUZAQLA may increase the risk of infections, including fatal infections. Among 911 patients with metastatic colorectal cancer treated with FRUZAQLA, the most common infections were urinary tract infection (6.8%), upper respiratory tract infection (3.2%), and pneumonia (2.5%); fatal infections included pneumonia (0.4%), sepsis (0.2%), bacterial infection (0.1%), lower respiratory tract infection (0.1%), and septic shock (0.1%). If Grade 3 or 4 infection occurs, or if any grade of infection worsens, FRUZAQLA should be suspended. After the infection is controlled, resume FRUZAQLA at the original dose.
Gastrointestinal PerforationMay occur in patients receiving FRUZAQLA treatment. Among 911 patients with metastatic colorectal cancer treated with FRUZAQLA, 1.3% experienced ≥Grade 3 gastrointestinal perforation, including one fatal event. FRUZAQLA should be permanently discontinued in patients who develop gastrointestinal perforation or fistula.
Hepatotoxicity。FRUZAQLA can cause hepatotoxicity. Among 911 patients with metastatic colorectal cancer treated with FRUZAQLA, 48% experienced elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST), including 5% with Grade ≥3 events and 0.2% with fatal events. Monitor liver function tests (ALT, AST, and bilirubin) before initiating FRUZAQLA and periodically throughout treatment. Withhold, reduce the dose, or permanently discontinue FRUZAQLA based on the severity and persistence of hepatotoxicity indicated by elevated liver function tests.
Proteinuria。FRUZAQLA may cause proteinuria. Among 911 patients with metastatic colorectal cancer treated with FRUZAQLA, 36% developed proteinuria and 2.5% experienced Grade ≥3 events. Proteinuria should be monitored regularly before initiating FRUZAQLA and throughout the treatment course. If 24-hour urine protein quantification is ≥2g, FRUZAQLA should be suspended until improvement to Grade ≤1 proteinuria, then resumed at a reduced dose. FRUZAQLA should be discontinued in patients who develop nephrotic syndrome.
Among 911 patients treated with FRUZAQLA, 35% experiencedPalmar-Plantar Erythrodysesthesia (PPE), of which 8% experienced Grade 3 events. Based on the severity of PPE, suspend FRUZAQLA treatment and then resume at the original dose or a reduced dose.
Posterior Reversible Encephalopathy Syndrome (PRES)Among the 911 patients treated with FRUZAQLA, one case has been reported. This is a subcortical vasogenic edema syndrome diagnosed through characteristic MRI findings. Any patient presenting with seizures, headache, visual disturbances, confusion, or changes in mental function should be evaluated for PRES. FRUZAQLA should be discontinued in patients who develop PRES.
Delayed Wound Healing。Among 911 patients with metastatic colorectal cancer treated with FRUZAQLA, one patient experienced a Grade 2 wound dehiscence event. Do not take FRUZAQLA at least 2 weeks prior to major surgery. Do not use FRUZAQLA for at least 2 weeks after major surgery or until the wound is fully healed. The safety of resuming FRUZAQLA treatment after resolution of wound healing complications has not been established.
Arterial Thromboembolic Events。Among 911 patients with metastatic colorectal cancer treated with FRUZAQLA, 0.8% experienced arterial thromboembolic events. FRUZAQLA should be used with caution in patients with a recent history of thromboembolic events. FRUZAQLA should be discontinued in patients who develop arterial thromboembolic events.
Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6 (Sunset Yellow FCF)。FRUZAQLA 1mg capsules contain FD&C Yellow No. 5 (Tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. FRUZAQLA 1mg contains FD&C Yellow No. 6 (Sunset Yellow FCF), which may cause allergic reactions.
Embryo-fetal Toxicity。Based on findings from animal studies and its mechanism of action, FRUZAQLA may cause fetal harm when administered to pregnant women. Pregnant women should be informed of the potential risk to the fetus. It is recommended that females of reproductive potential and males with female partners of reproductive potential use effective contraception during treatment with FRUZAQLA and for 2 weeks after the last dose.
Adverse Reactions
The most common (incidence ≥20%) adverse reactions after FRUZAQLA treatment include hypertension, palmar-plantar erythrodysesthesia (hand-foot skin reaction), proteinuria, dysphonia, abdominal pain, diarrhea, and fatigue.
MedicineDrug Interactions:Avoid concomitant administration of FRUZAQLA with strong or moderate CYP3A inducers.
Use in Specific Populations
Breastfeeding: It is recommended that women do not breastfeed during FRUZAQLA treatment and within 2 weeks after the last dose.
To report a suspected adverse reaction, please call 1-844-662-8532 to contact Takeda Pharmaceuticals or call 1-800-FDA-1088 or visit www.fda.gov/medwatch to contact the FDA.
References:
[1] Xu X, et al. Efficacy and safety of regorafenib and fruquintinib as third-line treatment for colorectal cancer: a narrative review. Transl Cancer Res 2022;11(1):276-287. doi: 10.21037/tcr-20-3539.
[2] Sun Q, et al. (2014) 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 15:12, 1635-1645. doi: 10.4161/15384047.2014.964087.
[3] Siegel RL, et al. Colorectal cancer statistics, 2023 [published online ahead of print, 2023 Mar 1]. CA Cancer J Clin. 2023; 73(3):233-254. doi:10.3322/caac.21772.
[4] National Cancer Institute. Available at: https://seer.cancer.gov/statfacts/html/colorect.html (accessed May 2023).
[5] Atreya CE, Yaeger R, Chu E. Systemic therapy for metastatic colorectal cancer: from current standards to future molecular targeted approaches. Am Soc Clin Oncol Educ Book. 2017;37:246-256. doi:10.1200/EDBK_175679.
[6] Vatandoust S, et al. Colorectal cancer: Metastases to a single organ. World J Gastroenterol. 2015;21(41):11767-76. doi:10.3748/wjg.v21.i41.11767.
[7] Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660.
[8] Bando H, et al. Therapeutic landscape and future direction of metastatic colorectal cancer. Nat Rev Gastroenterol Hepatol 2023; 20(5)306-322. doi:10.1038/s41575-022-00736-1.
[9] D'Haene N, et al. Clinical application of targeted next-generation sequencing for colorectal cancer patients: a multicentric Belgian experience. Oncotarget. 2018;9(29):20761-20768. Published 2018 Apr 17. doi:10.18632/oncotarget.25099.
[10] Venderbosch, et al. Mismatch repair status and braf mutation status in metastatic colorectal cancer patients: A pooled analysis of the Cairo, Cairo2, coin, and Focus Studies. Clinical Cancer Res.,2014; 20(20):5322–5330. doi:10.1158/1078-0432.ccr-14-0332.
[11] Koopman, M., et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 209;100(2), 266–273. doi:10.1038/sj.bjc.6604867.
[12] Ahcene Djaballah S, et al. HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target. Am Soc Clin Oncol Educ Book. 2022;42:1-14. doi:10.1200/EDBK_351354.
[13] Dasari NA, et al. LBA25 – FRESCO-2: A global phase 3 multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Ann Oncol. 2022 Sep;33(suppl_7): S1391-S1392. doi:10.1016/j.annonc.2022.08.021.
[14] Dasari NA, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study [published online ahead of print, 2023 Jun 15]. Lancet. 2023. doi: 10.1016/S0140-6736(23)00772-9.
Forward-Looking Statements
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