Fruquintinib

Fruquintinib has not been sufficiently studied in patients with moderate hepatic impairment (total bilirubin greater than 1.5 times and less than 3 times ULN and any AST).

Fruquintinib is not recommended for use in patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST).

Initiation of fruquintinib in patients with a recent history of thromboembolic events should be carefully considered.

Risk Summary

Based on findings in animal studies and its mechanism of action, fruquintinib can cause fetal harm when administered to a pregnant woman. In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during the period of organogenesis resulted in teratogenicity and embryo lethality at exposures below the clinical exposure (see Data). There are no data on the use of fruquintinib in pregnant women. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In an embryo-fetal developmental study in pregnant rats, daily oral administration of fruquintinib at doses ≥0.1 mg/kg [approximately 0.2 times the recommended clinical dose of 5 mg based on body surface area (BSA)] during the period of organogenesis resulted in fetal external (edema and head and tail abnormalities), visceral, and skeletal malformations. At doses of 0.25 mg/kg (approximately 0.5 times the recommended clinical dose of 5 mg based on BSA), an increase in postimplantation loss and reduction in live fetuses was observed.

There are no data regarding the presence of fruquintinib or its metabolites in human milk or its effects on a breastfed child or on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with fruquintinib and for 2 weeks after the last dose.

Carcinogenicity studies have not been conducted with fruquintinib.

Fruquintinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro Chinese hamster ovary chromosome aberration assay. Fruquintinib was not genotoxic in the in vivo rat micronucleus or alkaline comet assays.

• Hypertension
• Hemorrhagic Events
• Infections
• Gastrointestinal Perforation
• Hepatotoxicity
• Proteinuria
• Palmar-Plantar Erythrodysesthesia (PPE)
• Posterior Reversible Encephalopathy Syndrome (PRES)

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS and below reflects exposure to fruquintinib as a single agent in 911 patients with mCRC who were enrolled in three randomized, placebo-controlled studies (FRESCO-2, FRESCO and 2012-013-00CH1) (N=781); three open-label studies (2009-013-00CH1, 2012-013-00CH3 and 2015-013-00US1) (N=124); and an open-label lead-in cohort of FRESCO-2 (N=6). Among the 911 patients who received fruquintinib, 23% were exposed for 6 months or longer and 3.5% were exposed for greater than one year. These patients received at least one dose of fruquintinib at the recommended dosage of 5 mg daily for the first 21 days of each 28-day cycle. The median age was 60 years (range: 23 to 82) and 34% were 65 years of age or older. The most common adverse reactions (incidence ≥20%) that occurred in pooled monotherapy studies were hypertension, PPE, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia.

Metastatic Colorectal Cancer

FRESCO-2 Study

The safety of fruquintinib was evaluated in FRESCO-2, a randomized, double-blind, placebo-controlled study. Patients received either fruquintinib 5 mg daily for the first 21 days of each 28-day cycle plus best supportive care (BSC) (n=456) or matching placebo plus BSC (n=230).

The median duration of therapy with fruquintinib was 3 months (range: 0.3 to 19.1 months).

Serious adverse reactions occurred in 38% of patients treated with fruquintinib. Serious adverse reactions in ≥2% of patients treated with fruquintinib included hemorrhage (2.2%) and gastrointestinal perforation (2.0%). Fatal adverse reaction(s) occurred in 14 (3.1%) patients who received fruquintinib. Fatal adverse reactions occurring in ≥2 patients include pneumonia (n=3), sepsis/septic shock (n=2), and hepatic failure/encephalopathy (n=2).

Adverse reactions leading to treatment discontinuation occurred in 20% of patients treated with fruquintinib. Adverse reactions leading to treatment discontinuations of fruquintinib in ≥1% of patients were asthenia and gastrointestinal perforation.

Dose interruptions of fruquintinib due to an adverse reaction occurred in 47% of patients. Adverse reactions leading to dose interruptions of fruquintinib in ≥2% of patients were PPE, proteinuria, asthenia, abdominal pain, hypertension, vomiting, and diarrhea.

Dose reductions of fruquintinib due to an adverse reaction occurred in 24% of patients. Adverse reactions leading to dose reductions of fruquintinib in ≥2% of patients were PPE, hypertension and asthenia.

Table 1 summarizes the adverse reactions in FRESCO-2.

Table 1. Adverse Reactions (≥10%) in Patients who Received fruquintinib and with a Difference Between Arms of ≥5% Compared to Placebo in FRESCO-2 (All Grades):

^* Represents a composite of multiple related terms.

Other important adverse reactions (all grades) that occurred in <10% of patients treated with fruquintinib included urinary tract infection (4.6%), epistaxis (3.9%), proctalgia (3.5%), pneumonia (2.4%), gastrointestinal hemorrhage (1.5%), gastrointestinal perforation (1.3%), thrombotic microangiopathy (0.2%), and posterior reversible encephalopathy syndrome (0.2%).

Table 2 provides laboratory abnormalities observed in FRESCO-2.

Table 2. Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients in FRESCO-2:

^* Graded according to NCI CTCAE version 5.0.
^† Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: fruquintinib (range: 409-444) and placebo (range: 195-216).

FRESCO Study

The safety of fruquintinib was evaluated in FRESCO, a randomized, double-blind, placebo-controlled study. Patients received either fruquintinib 5 mg daily for the first 21 days of each 28-day cycle plus BSC (n=278) or matching placebo plus BSC (n=137).

The median duration of therapy with fruquintinib was 3.68 months (range: 0.3 to 22.1 months).

Serious adverse reactions occurred in 15% of patients treated with fruquintinib. Serious adverse reactions in ≥2% of patients included intestinal obstruction (2.9%) and hemorrhage (2.2%). Fatal adverse reaction(s) occurred in 7 (2.5%) patients who received fruquintinib including cerebral infarction (n=1), gastrointestinal hemorrhage (n=1), hemoptysis (n=1), bacterial infection (n=1), lung/lower respiratory infection (n=2), and multiple organ dysfunction (n=1).

Adverse reactions leading to treatment discontinuation occurred in 15% of patients who received fruquintinib. Adverse reactions leading to treatment discontinuations of fruquintinib in ≥1% were intestinal obstruction, proteinuria and hepatic function abnormalities.

Dose interruptions of fruquintinib due to an adverse reaction occurred in 35% of patients. Adverse reactions leading to dose interruptions of fruquintinib in ≥2% of patients were PPE, proteinuria, platelet count decreased, ALT increased, hypertension, and diarrhea.

Dose reductions of fruquintinib due to an adverse reaction occurred in 24% of patients. Adverse reactions leading to dose reduction of fruquintinib in ≥2% of patients were PPE, proteinuria, and hypertension.

Table 3 summarizes the adverse reactions in FRESCO.

Table 3. Adverse Reactions (≥10%) in Patients who Received Fruquintinib and with a Difference Between Arms of ≥5% Compared to Placebo in FRESCO (All Grades):

^* Represents a composite of multiple related terms.

Other clinically important adverse reactions (all grades) that occurred in <10% of patients treated with fruquintinib included urinary tract infection (9%), rash (9%), upper respiratory tract infection (4.7%), proctalgia (3.6%), pneumonia (2.9%), and gastrointestinal perforation or fistula (2.2%).

Table 4 provides laboratory abnormalities observed in FRESCO.

Table 4. Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients in FRESCO:

^* Graded according to NCI CTCAE version 4.03.
^† Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: fruquintinib (range: 257-277) and placebo (range: 126-134).