FRESCO-2 STUDY DESIGN

FRESCO-2 was a global, randomized, double-blind, multicenter phase 3 study^1,3

FRESCO-2 clinical trial design: FRUZAQLA® + BSC vs placebo + BSC.

Inclusion criteria^1,3

ECOG PS 0‑1
Progression during or after prior treatment with fluoropyrimidine‑, oxaliplatin‑, or irinotecan‑based chemotherapy, an anti‑VEGF biological therapy, and, if RAS wild type, an anti‑EGFR biological therapy
Progression during or after prior treatment with trifluridine‑tipiracil, regorafenib, or both

Stratification³

Prior therapy (trifluridine‑tipiracil vs regorafenib vs trifluridine‑tipiracil and regorafenib)^†
RAS mutational status (wild type vs mutant)
Duration of metastatic disease (≤18 months vs >18 months)

^*Best supportive care was determined by local clinical practice.³
^†To prevent unintentional enrichment, the number of patients previously treated with regorafenib was limited to 50% of the total randomly assigned patients.³

BSC=best supportive care; mCRC=metastatic colorectal cancer.

FRUZAQLA was studied in a robust clinical trial that included a heterogeneous patient population^1,3,4

FRESCO-2 patient characteristics^1,3

FRESCO-2 patient characteristics for FRUZAQLA + BSC group (n=461) to the Placebo + BSC group (n=230). Key data for the FRUZAQLA versus Placebo groups include: a median age of 64 years for both; a majority of male patients (53% vs. 61%); and a high percentage of patients with liver metastases (74% vs. 68%). Nearly all patients in both groups had received prior VEGF inhibitor therapy (97% vs. 96%), and the distribution of patients by region, primary tumor site, and RAS status was also highly similar between

^aLower quartile/25th percentile–upper quartile/75th percentile.⁴
^bECOG PS scores range from 0 to 5, with 0 indicating fully active and higher scores indicating greater disability.³
^cDuration of metastatic disease=(date of randomization – date of diagnosis of metastatic disease)/30.4375.³

FRESCO-2 OVERALL SURVIVAL

Meaningful Time: In a study of FRUZAQLA+ BSC placebo+ BSC in patients with previously treated mCRC, FRUZAQLA demonstrated a significant nearly 3-month improvement in median OS.¹

OS in patients with previously treated mCRC

FRESCO-2: Overall survival (OS) in adult patients with previously treated metastatic colorectal cancer taking FRUZAQLA® + BSC vs placebo + BSC.FRUZAQLA + BSC improved overall survival compared to Placebo + BSC. Median OS was 7.4 months for the FRUZAQLA group (n=461) versus 4.8 months for the placebo group (n=230), representing a 2.6-month difference.

Early and rapid separation of OS curve evident at Month 1¹

CI=confidence interval; HR=hazard ratio.

34% reduction in risk of death with FRUZAQLA® + BSC vs placebo + BSC.

OS benefit was consistent across most prespecified subgroups³

Results seen regardless of duration of metastatic disease, RAS status, prior types of therapy, and presence of liver metastases³

FRESCO-2: Overall survival (OS) comparing FRUZAQLA® + BSC vs placebo + BSC across prespecified subgroups. FRESCO-2 results showed a median OS of 7.4 months for FRUZAQLA versus 4.8 months for placebo, with a HR of 0.66, including patients with liver metastases (Median OS 6.4 vs. 3.7 months; HR 0.58) and those with wild-type RAS status (Median OS 7.7 vs. 4.4 months; HR 0.67).

The FRESCO-2 study was not powered to show significance in OS across these specified groups.

FRESCO-2 DISEASE CONTROL

FRUZAQLA demonstrated improved anti-tumor activity vs placebo^1,3,5

**Disease control rate was stable for more than half of patients treated with FRUZAQLA + BSC*^1,3**

FRESCO-2: 56% disease control rate with FRUZAQLA® + BSC vs 16% with placebo + BSC.

This study was not powered to show significance in disease control rate.

^*Disease control was defined as the proportion of patients with a best overall response of confirmed complete response, partial response, or stable disease for ≥7 weeks.³
^†Includes patients who received study drug and had ≥1 post baseline scan.⁵

FRESCO-2 PROGRESSION-FREE SURVIVAL

In a study of FRUZAQLA + BSC vs placebo + BSC in patients with previously treated mCRC

FRUZAQLA more than doubled median progression-free survival^1,3

PFS in patients with previously treated mCRC^1,3

FRESCO-2: Progression free survival (PFS) in adult patients with previously treated metastatic colorectal cancer taking FRUZAQLA® + BSC vs placebo + BSC. The chart highlights a median PFS of 3.7 months for the FRUZAQLA group (n=461) versus 1.8 months for the placebo group (n=230). This benefit corresponds to a 68% reduction in the risk of disease progression or death, with a Hazard Ratio (HR) of 0.32 and a pvalue of less than 0.001.

Early and rapid separation of PFS curve evident at Month 1^1,3

In a study of FRUZAQLA + BSC vs placebo + BSC in patients with previously treated mCRC

PFS benefit was consistent across most prespecified subgroups³

FRESCO-2: Progression free-survival (PFS) comparing FRUZAQLA® + BSC vs placebo + BSC across prespecified subgroups. FRESCO-2 had a median PFS of 3.7 months for FRUZAQLA versus 1.8 months for placebo, with a HR of 0.32. This occurred across most subgroups, including patients with liver metastases (Median PFS 3.6 vs. 1.8 months; HR 0.29) and those with mutant RAS status (Median PFS 3.6 vs. 1.8 months; HR 0.32).

The FRESCO-2 study was not powered to show significance in PFS across these specified groups.

BSC=best supportive care; CI=confidence interval; DCR=disease control rate; DoR=duration of response; ECOG PS=Eastern Cooperative Oncology Group performance status; EGFR=epidermal growth factor receptor; HR=hazard ratio; ORR=objective response rate; OS=overall survival; PFS=progression-free survival. RAS=rat sarcoma; VEGF=vascular endothelial growth factor.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hypertension occurred in 49% of 911 patients with mCRC treated with FRUZAQLA, including Grade 3-4 events in 19%, and hypertensive crisis in three patients (0.3%). Do not initiate FRUZAQLA unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first month and at least monthly thereafter as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue FRUZAQLA based on severity of hypertension.

Hemorrhagic Events including serious, fatal events can occur with FRUZAQLA. In 911 patients with mCRC treated with FRUZAQLA, 6% of patients experienced gastrointestinal hemorrhage, including 1% with a Grade ≥3 event and 2 patients with fatal hemorrhages. Permanently discontinue FRUZAQLA in patients with severe or life-threatening hemorrhage. Monitor the International Normalized Ratio (INR) levels in patients receiving anticoagulants.

Infections. FRUZAQLA can increase the risk of infections, including fatal infections. In 911 patients with mCRC treated with FRUZAQLA, the most common infections were urinary tract infections (6.8%), upper respiratory tract infections (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%). Withhold FRUZAQLA for Grade 3 or 4 infections, or worsening infection of any grade. Resume FRUZAQLA at the same dose when the infection has resolved.

Gastrointestinal Perforation occurred in patients treated with FRUZAQLA. In 911 patients with mCRC treated with FRUZAQLA, 1.3% experienced a Grade ≥3 gastrointestinal perforation, including one fatal event. Permanently discontinue FRUZAQLA in patients who develop gastrointestinal perforation or fistula.

Hepatotoxicity. FRUZAQLA can cause liver injury. In 911 patients with mCRC treated with FRUZAQLA, 48% experienced increased ALT or AST, including Grade ≥3 events in 5%, and fatal events in 0.2% of patients. Monitor liver function tests (ALT, AST, and bilirubin) before initiation and periodically throughout treatment with FRUZAQLA. Temporarily hold and then reduce or permanently discontinue FRUZAQLA depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests.

Proteinuria. FRUZAQLA can cause proteinuria. In 911 patients with mCRC treated with FRUZAQLA, 36% experienced proteinuria and 2.5% of patients experienced Grade ≥3 events. Monitor for proteinuria before initiation and periodically throughout treatment with FRUZAQLA. For proteinuria ≥2g/24 hours, withhold FRUZAQLA until improvement to ≤Grade 1 proteinuria and resume FRUZAQLA at a reduced dose. Discontinue FRUZAQLA in patients who develop nephrotic syndrome.

Palmar-Plantar Erythrodysesthesia (PPE) occurred in 35% of 911 patients treated with FRUZAQLA, including 8% with Grade 3 events. Based on severity of PPE, withhold FRUZAQLA and then resume at the same or reduced dose.

Posterior Reversible Encephalopathy Syndrome (PRES), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 911 patients treated with FRUZAQLA. Perform an evaluation for PRES in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue FRUZAQLA in patients who develop PRES.

Impaired Wound Healing. In 911 patients with mCRC treated with FRUZAQLA, 1 patient experienced a Grade 2 event of wound dehiscence. Do not administer FRUZAQLA for at least 2 weeks prior to major surgery. Do not administer FRUZAQLA for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of FRUZAQLA after resolution of wound healing complications has not been established.

Arterial Thromboembolic Events. In 911 patients with mCRC treated with FRUZAQLA, 0.8% of patients experienced an arterial thromboembolic event. Initiation of FRUZAQLA in patients with a recent history of thromboembolic events should be carefully considered. In patients who develop arterial thromboembolism, discontinue FRUZAQLA.

Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6 (Sunset Yellow FCF). FRUZAQLA 1 mg capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. FRUZAQLA 1 mg contains FD&C Yellow No. 6 (sunset yellow FCF), which may cause allergic reactions.

Embryo-Fetal Toxicity. Based on findings in animal studies and its mechanism of action, FRUZAQLA can cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥20%) following treatment with FRUZAQLA included hypertension, palmar-plantar erythrodysesthesia (hand-foot skin reactions), proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia.

DRUG INTERACTIONS

Avoid concomitant administration of FRUZAQLA with strong or moderate CYP3A inducers.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during treatment with FRUZAQLA and for 2 weeks after the last dose.

Females and Males of Reproductive Potential

Pregnancy Testing: Verify pregnancy status of females of reproductive potential prior to initiating FRUZAQLA.
Contraception: Females of childbearing potential and males with female partners of childbearing potential should use effective contraception during treatment and for 2 weeks after the last dose of FRUZAQLA.
Infertility: Advise females of reproductive potential that FRUZAQLA may cause post-implantation loss.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-662-8532 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see FRUZAQLA (fruquintinib) full Prescribing Information.

FRESCO-2 STUDY DESIGN

FRESCO-2 was a global, randomized, double-blind, multicenter phase 3 study^1,3

FRUZAQLA was studied in a robust clinical trial that included a heterogeneous patient population^1,3,4

FRESCO-2 patient characteristics^1,3

FRESCO-2 OVERALL SURVIVAL

Meaningful Time: In a study of FRUZAQLA+ BSC placebo+ BSC in patients with previously treated mCRC, FRUZAQLA demonstrated a significant nearly 3-month improvement in median OS.¹

OS in patients with previously treated mCRC

OS benefit was consistent across most prespecified subgroups³

Results seen regardless of duration of metastatic disease, RAS status, prior types of therapy, and presence of liver metastases³

FRESCO-2 DISEASE CONTROL

FRUZAQLA demonstrated improved anti-tumor activity vs placebo^1,3,5

**Disease control rate was stable for more than half of patients treated with FRUZAQLA + BSC*^1,3**

FRESCO-2 PROGRESSION-FREE SURVIVAL

FRUZAQLA more than doubled median progression-free survival^1,3

PFS in patients with previously treated mCRC^1,3

PFS benefit was consistent across most prespecified subgroups³

IMPORTANT SAFETY INFORMATION AND INDICATION

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

INDICATION

FRESCO-2 STUDY DESIGN

FRESCO-2 was a global, randomized, double-blind, multicenter phase 3 study1,3

FRUZAQLA was studied in a robust clinical trial that included a heterogeneous patient population1,3,4

FRESCO-2 patient characteristics1,3

FRESCO-2 OVERALL SURVIVAL

Meaningful Time: In a study of FRUZAQLA+ BSC placebo+ BSC in patients with previously treated mCRC, FRUZAQLA demonstrated a significant nearly 3-month improvement in median OS.1

OS in patients with previously treated mCRC

OS benefit was consistent across most prespecified subgroups3

Results seen regardless of duration of metastatic disease, RAS status, prior types of therapy, and presence of liver metastases3

FRESCO-2 DISEASE CONTROL

FRUZAQLA demonstrated improved anti-tumor activity vs placebo1,3,5

Disease control rate was stable for more than half of patients treated with FRUZAQLA + BSC*1,3

FRESCO-2 PROGRESSION-FREE SURVIVAL

FRUZAQLA more than doubled median progression-free survival1,3

PFS in patients with previously treated mCRC1,3

PFS benefit was consistent across most prespecified subgroups3

IMPORTANT SAFETY INFORMATION AND INDICATION

FRESCO-2 was a global, randomized, double-blind, multicenter phase 3 study^1,3

FRUZAQLA was studied in a robust clinical trial that included a heterogeneous patient population^1,3,4

FRESCO-2 patient characteristics^1,3

Meaningful Time: In a study of FRUZAQLA+ BSC placebo+ BSC in patients with previously treated mCRC, FRUZAQLA demonstrated a significant nearly 3-month improvement in median OS.¹

OS benefit was consistent across most prespecified subgroups³

Results seen regardless of duration of metastatic disease, RAS status, prior types of therapy, and presence of liver metastases³

FRUZAQLA demonstrated improved anti-tumor activity vs placebo^1,3,5

**Disease control rate was stable for more than half of patients treated with FRUZAQLA + BSC*^1,3**

FRUZAQLA more than doubled median progression-free survival^1,3

PFS in patients with previously treated mCRC^1,3

PFS benefit was consistent across most prespecified subgroups³