Takeda Pharmaceutical Company Limited: Takeda Receives Approval from European Commission for FRUZAQLA in Previously Treated Metastatic Colorectal Cancer

Approval Based on Results from Positive, Global, Phase 3 FRESCO-2 Trial

FRUZAQLA (fruquintinib) is the First Novel Targeted Therapy in the EU for Metastatic Colorectal Cancer (mCRC) Regardless of Biomarker Status in Over a Decade

Takeda (TSE:4502/NYSE:TAK) today announced that the European Commission (EC) approved FRUZAQLA (fruquintinib) as a monotherapy indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents, and who have progressed on or are intolerant to treatment with either trifluridine-tipiracil or regorafenib. The decision follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on April 25, 2024, and approval by the U.S. Food and Drug Administration (FDA) for adults with mCRC who have been previously treated with oxaliplatin- and irinotecan-based regimens on November 8, 2023.^1,2

"People living with metastatic colorectal cancer face numerous difficulties, stemming both from their illness and the adverse effects of therapies. Given the complex nature of the disease, introducing innovative treatments such as fruquintinib an oral, chemotherapy-free targeted agent is essential. I am looking forward to having a new choice for appropriate patients," said Josep Tabernero, MD, PhD, director of Vall d'Hebron Institute of Oncology (VHIO).

The approval is based on results from the Phase 3 multi-regional FRESCO-2 trial. The trial investigated FRUZAQLA plus best supportive care (BSC) versus placebo plus BSC in patients with previously treated mCRC. FRESCO-2 met all its primary and key secondary efficacy endpoints and showed consistent benefit among patients treated with FRUZAQLA, regardless of the prior types of therapies they received. FRUZAQLA demonstrated a manageable safety profile in FRESCO-2. Adverse reactions leading to treatment discontinuation occurred in 20% of patients treated with FRUZAQLA plus BSC versus 21% of those treated with placebo plus BSC. Data from FRESCO-2 were published in The Lancet in June 2023.³

"Today's approval marks an important moment for the colorectal cancer community in the EU. For the first time in over a decade, patients with previously treated metastatic colorectal cancer have a new targeted treatment option that can be used irrespective of whether their tumors harbor actionable mutations," said Teresa Bitetti, president of the Global Oncology Business Unit at Takeda. "We look forward to offering patients a novel treatment option that has a manageable safety profile and can be effective regardless of the prior types of therapies they have received."

About FRUZAQLA (fruquintinib)

FRUZAQLAis a selective oral inhibitor of all three VEGF receptors (-1, -2 and -3). VEGFR inhibitors play a pivotal role in blocking tumor angiogenesis. FRUZAQLAwas designed to have enhanced selectivity that limits off-target kinase activity, allowing for high drug exposure, sustained target inhibition, and flexibility for potential use as part of combination therapy.

Takeda has the exclusive worldwide license to further develop, commercialize, and manufacture fruquintinib outside of mainland China, Hong Kong and Macau. FRUZAQLA was approved by the U.S. Food and Drug Administration (FDA) in November 2023. A submission to the Japan Pharmaceuticals and Medical Devices Agency (PMDA) took place in September 2023. Fruquintinib is developed and marketed in China by HUTCHMED. Fruquintinib was approved for marketing by the China National Medical Products Administration (NMPA) in September 2018 and commercially launched in China in November 2018 under the brand name ELUNATE

EUROPEAN UNION IMPORTANT SAFETY INFORMATION

Please consult the FRUZAQLA (fruquintinib) Summary of Product Characteristics (SmPC) before prescribing.

Guidance for use: FRUZAQLA should be initiated by a physician experienced in the administration of anticancer therapy. Patients should be given the package leaflet.

CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients.

SPECIAL POPULATIONS: Renal impairment: No dose adjustment is required for patients with mild, moderate, or severe renal impairment; Hepatic impairment: No dose adjustment is required for patients with mild or moderate hepatic impairment. FRUZAQLA is not recommended for use in patients with severe hepatic impairment as FRUZAQLA has not been studied in this population; Elderly: No dose adjustment is required in patients aged 65 years or above; Paediatric population: There is no relevant use of FRUZAQLA in the paediatric population for the indication of metastatic colorectal cancer; Women of childbearing potential/Contraception in females: Women of childbearing potential should be advised to use highly effective contraception during treatment and for at least 2 weeks following the last dose of FRUZAQLA; Pregnancy: There are no clinical data available on the use of FRUZAQLA in pregnant women. Based on its mechanism of action, FRUZAQLA has the potential to cause foetal harm. Animal studies have shown reproductive toxicity, including foetal malformations. FRUZAQLA should not be used during pregnancy unless the clinical condition of the woman requires treatment with FRUZAQLA. If FRUZAQLA is used during pregnancy or if the patient becomes pregnant while on treatment, the patient must be informed of the potential hazard to the foetus; Breast-feeding: The safe use of FRUZAQLA during breast-feeding has not been established. It is not known whether FRUZAQLA or its metabolites are excreted in human milk. There are no animal data on the excretion of FRUZAQLA in animal milk. A risk to the breastfeeding newborns/infants cannot be excluded. Breastfeeding should be discontinued during treatment and for 2 weeks after the last dose; Fertility: There are no data on the effects of FRUZAQLA on human fertility. Results from animal studies indicate that FRUZAQLA may impair male and female fertility.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

• Hypertension: Hypertension, including hypertensive crisis, has been reported in patients treated with FRUZAQLA. Pre-existing hypertension should be monitored and adequately controlled in accordance with standard medical practices before starting FRUZAQLA treatment.
  
  Hypertension should be medically managed with antihypertensive medicinal products and adjustment of the FRUZAQLA dose, if necessary. FRUZAQLA should be permanently discontinued for hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis.

• Haemorrhagic events: Haemorrhagic events have been reported in patients treated with FRUZAQLA, including gastrointestinal (GI) tract events. Serious and sometimes fatal bleeding events have been reported in patients after treatment with FRUZAQLA.
  
  Haematologic and coagulation profiles should be monitored in accordance with standard medical practices in patients at risk for bleeding, including those treated with anticoagulants or other concomitant medicinal products that increase the risk of bleeding. In the event of severe bleeding requiring immediate medical intervention, FRUZAQLA should be permanently discontinued.

• Gastrointestinal perforation: GI perforation events, including fatal events, have been reported in patients treated with FRUZAQLA.
  
  Symptoms of GI perforation should be periodically monitored during treatment with FRUZAQLA.
  
  FRUZAQLA should be permanently discontinued in patients developing GI perforation.

• Proteinuria: Proteinuria events have occurred in patients treated with FRUZAQLA.
  
  Proteinuria should be monitored before initiation and during treatment with FRUZAQLA in accordance with standard medical practices. If urine dipstick proteinuria 2 g 24 hours is detected, dose interruptions, adjustments, or discontinuation may be necessary. FRUZAQLA should be permanently discontinued in patients developing nephrotic syndrome.

• Palmar-plantar erythrodysaesthesia syndrome (PPES): PPES is the most frequently reported dermatological adverse reaction.
  
  If Grade 2 skin reactions are detected, dose interruptions, adjustments, or discontinuation may be necessary.

• Posterior reversible encephalopathy syndrome (PRES): PRES has been reported in 1 patient (0.1%) treated with FRUZAQLA in clinical studies. PRES is a rare neurologic disorder that can present with headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, discontinuation of FRUZAQLA, along with control of hypertension and supportive medical management of other symptoms, are recommended.

• Impaired wound healing: Impaired wound healing has been reported in 1 patient (0.1%) treated with FRUZAQLA in clinical studies.
  
  Patients are recommended to withhold FRUZAQLA for at least 2 weeks prior to surgery. FRUZAQLA should not be resumed for at least 2 weeks after surgery, as clinically indicated when there is evidence of adequate wound healing.

• Arterial and venous thromboembolic events: It is recommended to avoid starting treatment with FRUZAQLA in patients with a history of thromboembolic events (including deep vein thrombosis and pulmonary embolism) within the past 6 months or if they have a history of stroke and/or transient ischemic attack within the last 12 months. If arterial thrombosis is suspected, FRUZAQLA should be discontinued immediately.

INTERACTIONS

Effects of other medicinal products on the pharmacokinetics of FRUZAQLA

CYP3A inducers

Co-administration of FRUZAQLA with rifampicin (a strong CYP3A inducer) 600 mg once daily decreased FRUZAQLA AUCinf by 65% and decreased Cmax by 12%. The concomitant use of FRUZAQLA with strong and moderate CYP3A inducers should be avoided.

CYP3A inhibitors

Co-administration of FRUZAQLA with itraconazole (a strong CYP3A inhibitor) 200 mg twice daily did not result in clinically meaningful changes in the area under the concentration-time curve (AUC) and Cmax of FRUZAQLA. No dose adjustment of FRUZAQLA is needed during concomitant use with CYP3A inhibitors.

Gastric acid lowering agents

Co-administration of FRUZAQLA with rabeprazole (a proton pump inhibitor) 40 mg once daily did not result in clinically meaningful changes in the AUC of FRUZAQLA. No dose adjustment of FRUZAQLA is needed during concomitant use with gastric acid lowering agents.

Effect of FRUZAQLA on the pharmacokinetics of other medicinal products

Medicinal products that are substrates of P-glycoprotein (P-gp)

Co-administration of a single dose of dabigatran etexilate 150 mg (a P-gp substrate) with a single dose of FRUZAQLA 5 mg decreased AUC of dabigatran by 9%. No dose adjustment is recommended for P-gp substrates during concomitant use with FRUZAQLA.

Medicinal products that are substrates of breast cancer resistance protein (BCRP)

Co-administration of a single 10 mg dose of rosuvastatin (a BCRP substrate) with a single 5 mg dose of FRUZAQLA decreased AUC of rosuvastatin by 19%. No dose adjustment is recommended for BCRP substrates during concomitant use with FRUZAQLA.

UNDESIRABLE EFFECTS: The most commonly reported adverse reactions with FRUZAQLA are:

Very common (frequency =1/10)	Thrombocytopenia, hypothyroidism, anorexia, hypertension, dysphonia, diarrhoea, stomatitis, aspartate aminotransferase increased, total bilirubin increased, alanine aminotransferase increased, palmar-plantar erythrodysaesthesia syndrome, musculoskeletal discomfort, arthralgia, proteinuria, asthenia, and fatigue
Common (=1/100 to <1/10)	Pneumonia, upper respiratory tract infection, bacterial infections, leukopenia, neutropenia, hypokalemia, epistaxis, throat pain, gastrointestinal haemorrhage, gastrointestinal perforation, pancreatic enzymes increased, oral pain, rash, and mucosal inflammation

About CRC

CRC is a cancer that starts in either the colon or rectum. According to the International Agency for Research on Cancer, CRC is the third most prevalent cancer worldwide and was associated with more than 1.9 million new cases and 900,000 deaths in 2022. In Europe, CRC was the second most common cancer in 2022, with approximately 538,000 new cases and 248,000 deaths.⁴ In the U.S., it is estimated that 153,000 patients will be diagnosed with CRC and 53,000 deaths from the disease will occur in 2024.⁵ In Japan, CRC was the most common cancer in 2022, with more than 145,000 new cases and 60,000 deaths.⁴ Although early-stage CRC can be surgically resected, metastatic CRC remains an area of high unmet need with poor outcomes and limited treatment options. Some patients with metastatic CRC may benefit from personalized therapeutic strategies based on molecular characteristics; however, most patients have tumors that do not harbor actionable mutations.^6,7,8,9,10

About the Phase 3 FRESCO-2 Trial

The FRESCO-2 study is a multi-regional clinical trial conducted in the U.S., Europe, Japan and Australia investigating FRUZAQLA plus BSC vs placebo plus BSC in patients with previously treated mCRC (NCT04322539). The study met all of its primary and key secondary endpoints, demonstrating that treatment with FRUZAQLA resulted in statistically significant and clinically meaningful improvement in OS and PFS. The safety profile of FRUZAQLA in FRESCO-2 was consistent with previously reported fruquintinib monotherapy studies. Results from the study were presented at ESMO in September 2022 and subsequently published in The Lancet in June 2023.^11,3

About Takeda

Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit www.takeda.com.

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References:

1. Takeda Pharmaceuticals. (2024 April 26). Takeda Receives Positive CHMP Opinion for Fruquintinib in Previously Treated Metastatic Colorectal Cancer [Press Release]. Available here.
2. Takeda Pharmaceuticals. (2023 November 8). Takeda Receives U.S. FDA Approval of FRUZAQLA (fruquintinib) for Previously Treated Metastatic Colorectal Cancer [Press Release]. Available here.
3. 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. Lancet. 2023;402(10395):41-53. doi:10.1016/S0140-6736(23)00772-9.
4. Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 [online ahead of print]. doi: 10.3322/caac.21834
5. American Cancer Society. Cancer Facts Figures 2024. Atlanta, American Cancer Society; 2024.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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): S808-S869. Doi:10.1016/annonc/annonc1089.

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