Summary Basis of Decision for Fruzaqla

Clinical Pharmacology

Fruquintinib, the medicinal ingredient in Fruzaqla, is a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 with half maximal inhibitory concentration (IC50) values of 33, 35, and 0.5 nM, respectively. The inhibition of these receptors restricts tumour growth and progression by limiting angiogenesis, the formation of blood vessels that supply the tumour.

The pharmacokinetics of Fruzaqla was well characterized in healthy subjects and the intended cancer patient population. Based on the population pharmacokinetic analyses and a dedicated pharmacokinetic study, no restriction for use in patients with renal impairment is required. No clinically meaningful differences in the pharmacokinetics of Fruzaqla were observed between patients with normal hepatic function and patients with mild hepatic impairment. As such, no dosage adjustment was required in these patients. As indicated in the Fruzaqla Product Monograph, too few patients were studied to permit a valid evaluation of safety in patients with moderate hepatic impairment based on the National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG) criteria. Fruzaqla has not been studied in the patients with severe hepatic impairment and is not recommended for this population.

Study results showed that food does not have an effect on fruquintinib exposure; therefore, Fruzaqla is proposed to be taken with or without food. The administration of Fruzaqla without regard to food is also in agreement with dosing instructions in the protocol of the pivotal Phase III FRESCO-2 study that was provided in support of the safety and efficacy of Fruzaqla (discussed in the Clinical Efficacy section below). The extent and rate of fruquintinib absorption were not affected by co-administration with an acid-reducing agent.

Fruzaqla has a low potential for interaction effects on other drugs but is subject to clinically relevant effects of cytochrome P450 (CYP)3A inducers, which limits concomitant use.

No prolongation of heart rate-corrected QT (QTc) interval (>10 milliseconds) was observed at the recommended dosage of Fruzaqla. A concentration-QT analysis showed no evidence of association between fruquintinib plasma concentrations and changes in QTc interval from baseline.

Overall, the clinical pharmacology data support the use of Fruzaqla for the recommended indication. Key clinical pharmacology findings and relevant management strategies are properly addressed in the Fruzaqla Product Monograph. For further details, please refer to the Fruzaqla Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Fruzaqla was supported by data from the pivotal Phase III FRESCO-2 Study, a global, randomized, double-blind, placebo-controlled, multicentre study. This study was designed to assess the efficacy and safety of Fruzaqla in combination with best supportive care (BSC) as compared to placebo in combination with BSC in patients with metastatic colorectal cancer (mCRC) who had progressed on, or were intolerant to, chemotherapy, biologics, and trifluridine/tipiracil (TAS-102) and/or regorafenib. In addition, patients with mCRC were evaluated in the key supportive Phase III FRESCO study, a randomized, placebo-controlled study conducted in China.

The primary endpoint in both studies was overall survival (OS) in the intent-to-treat (ITT) population. The key secondary endpoint was progression-free survival (PFS) as assessed by the investigator using Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1). Other evaluated endpoints included objective response rates (proportion of patients with a best overall response of confirmed complete response or partial response) and quality of life.

For both studies, patients were excluded if they had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2 or higher, a left ventricular fraction of 50% or less, systolic blood pressure higher than 140 mmHg or diastolic blood pressure higher than 90 mmHg, urine protein 1 g/24 h or higher, or body weight less than 40 kg.

FRESCO-2 Study

The pivotal FRESCO-2 Study included 691 patients who were randomized in a 2:1 ratio to treatment with Fruzaqla plus BSC or placebo plus BSC. The median age of the randomized patients was 64 years (range: 25 to 86 years), with 47% of patients being 65 years of age or older and 55.7% of patients being male. In addition, 80.9% of patients were White, 8.8% were Asian, and 2.9% were Black or African American. A total of 43.1% of patients had an ECOG PS of 0, while the remaining 56.9% had an ECOG PS of 1. RAS wild-type tumour was reported in 36.9% of patients at study entry. The median duration of metastatic disease was 39 months (range: 6 months to 16.1 years). The median number of prior lines of therapy for metastatic disease was 4 (range: 2 to 16).

Randomization was stratified by prior therapy (trifluridine/tipiracil versus [vs.] regorafenib vs. both trifluridine/tipiracil and regorafenib), RAS status (wild-type vs. mutant), and duration of metastatic disease (18 months or less vs. more than 18 months). Patients were treated in 28-day cycles of once-daily oral doses of Fruzaqla 5 mg plus BSC or placebo plus BSC for 21 days (on therapy) followed by 7 days off therapy.

The FRESCO-2 study met its primary endpoint demonstrating a statistically significant improvement in OS among patients in the Fruzaqla arm compared with the placebo arm (hazard ratio [HR]: 0.662; 95% confidence interval [CI]: 0.549, 0.800; stratified log-rank test p <0.001) with a median OS of 7.4 months vs. 4.8 months. This represents a 34% decrease in the risk of death. Although this benefit was considered of moderate magnitude, it can be regarded as clinically meaningful in this highly pretreated population with no other treatment options.

The FRESCO-2 study also met its key secondary endpoint, with a statistically significant improvement in PFS (HR: 0.321; 95% CI: 0.267, 0.386; p <0.001) for patients treated with Fruzaqla. The median PFS in the Fruzaqla arm was 3.7 months (95% CI: 3.5, 3.8) compared with 1.8 months (95% CI: 1.8, 1.9) in the placebo arm. Sensitivity analyses of PFS were consistent to the results of the ITT population. The investigator assessed confirmed objective response rate was 1.5% (total number [n] = 7) in the Fruzaqla arm and 0% in the placebo arm. All of the responders had a partial response, and no complete responses were observed. The median duration of response was 10.7 months (95% CI: 3.9, not estimable) in the Fruzaqla arm and was not estimable for the placebo arm.

FRESCO Study

The FRESCO Study was conducted in China and included 416 patients who were randomized in a 2:1 ratio to treatment with Fruzaqla plus BSC or placebo plus BSC. Among these patients, the median age was 56 years (range: 23 to 75 years), with 19% of patients being 65 years of age or older and 61.3% of patients being male. All patients were Asian and had an ECOG PS of 0 (27%) or 1 (73%). The median number of prior lines of therapy for metastatic disease was 2 (range: 2 to 3). The presence of a tumour KRAS mutation was reported in 44% of patients at study entry.

Randomization was stratified by prior use of a VEGF inhibitor (yes vs. no) and KRAS gene status (wild-type vs. mutant). Patients were treated in 28-day cycles of once-daily oral doses of Fruzaqla 5 mg plus BSC or placebo plus BSC for 21 days (on therapy) followed by 7 days off therapy.

Results from the FRESCO study supported the findings of FRESCO-2 with a median OS of 9.3 months in the Fruzaqla arm compared to 6.6 months in the placebo arm and an HR of 0.65 (95% CI: 0.51, 0.83; p <0.001). The median PFS in the Fruzaqla arm was 3.7 months (95% CI: 3.7, 4.6) compared with 1.8 months (95% CI: 1.8, 1.8) in the placebo arm.

Overall Analysis of Efficacy

The efficacy results of the pivotal and supportive study support the clinical relevance of angiogenesis inhibition, even in the later line setting, and in patients with previous exposure to antiangiogenic agents. Consequently, Fruzaqla is considered a beneficial and clinically meaningful treatment option for the heavily pretreated mCRC population.

Indication

The New Drug Submission for Fruzaqla was filed by the sponsor with the following proposed indication:

Fruzaqla (fruquintinib capsules) is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with or are not considered candidates for available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy.

Health Canada approved the following indication:

Fruzaqla (fruquintinib capsules) is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with or are not considered candidates for available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, an anti-EGFR agent (if RAS wild-type), and either trifluridine-tipiracil or regorafenib.

For more information, refer to the Fruzaqla Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Fruzaqla was evaluated using pooled data from 911 patients with mCRC who were enrolled in the following studies:

• 781 patients who took part in three randomized, placebo-controlled studies (FRESCO-2, FRESCO, and Study 2012-013-00CH1);

• 124 patients who took part in three open-label studies (Study 2009-013-00CH1, Study 2012-013-00CH3, and Study 2015-013-00US1); and

• 6 patients who took part in an open-label lead-in cohort of the FRESCO-2 Study.

All patients were exposed to at least one dose of Fruzaqla (5 mg once daily for 21 days [on therapy] followed by 7 days off therapy) for a median of 3.68 months. In this patient population, the most common adverse reactions of any grade (with an incidence of 20% or more) were hypertension (49.3%), anorexia (35.6%), proteinuria (35.5%), palmar-plantar erythrodysaesthesia syndrome (PPES; 34.6%), hypothyroidism (32.4%), dysphonia (28.6%), diarrhoea (26.3%), and asthenia (24.5%). The majority of these reactions were Grade 1 or 2 in severity. The most common Grade 3/4 adverse reactions (with an incidence of 5% or more) were hypertension (19.1%) and PPES (8.3%). This is consistent with the safety profile identified in the pivotal study (FRESCO-2) and for drugs of the same class.

The most common serious adverse reactions (with an incidence of 1% or more) were gastrointestinal haemorrhage (1.5%), pneumonia (1.5%), hypertension (1.5%), and gastrointestinal perforation (1.3%). This is consistent with the serious adverse reactions identified in the pivotal study (FRESCO-2) and for drugs of the same class.

Of the 911 mCRC patients treated with Fruzaqla, 8.0% discontinued. The most common adverse reactions leading to treatment discontinuation were proteinuria (1.6%), and gastrointestinal perforation (1%). Adverse reactions leading to dose reduction occurred in 20.5% of patients. Deaths due to adverse reactions occurred in approximately 1% of patients. The most common adverse reactions leading to death were pneumonia (0.4%) and gastrointestinal hemorrhage (0.2%).

Notable safety risks observed in the pooled dataset for Fruzaqla-treated mCRC patients included cardiovascular (hypertension), gastrointestinal (gastrointestinal perforation), hepatic (elevated transaminases and bilirubin), infections, neurologic (posterior reversible encephalopathy syndrome [PRES]), impaired wound healing, renal (proteinuria), reproductive (teratogenic and fertility impairment), skin (PPES), and vascular toxicity (arterial thromboembolic events, hemorrhage, aneurysms, and artery dissection).

In summary, the safety profile from the pooled dataset of 911 patients was consistent with that identified in the pivotal study (FRESCO-2), and that for drugs of the same class (i.e. VEGF inhibitors). Moreover, no new safety signals were identified in Fruzaqla-treated patients as compared to other drugs in the class. Appropriate warnings and precautions as well as mitigation strategies are in place in the approved Fruzaqla Product Monograph to address the identified safety concerns. As such, the safety risks are considered manageable and acceptable.

For more information, refer to the Fruzaqla Product Monograph, approved by Health Canada and available through the Drug Product Database.

Fruquintinib is a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3, with half maximal inhibitory concentration (IC50) values of 33, 35, and 0.5 nM, respectively. In vitro studies showed fruquintinib inhibited vascular endothelial growth factor (VEGF)-mediated endothelial cell proliferation and tubular formation. In vitro and in vivo studies showed fruquintinib inhibited VEGF-induced VEGFR-2 phosphorylation. In vivo studies showed fruquintinib inhibited tumor growth in a tumor xenograft mouse model of colon cancer.

Repeat dose studies in animals identified that treatment with fruquintinib led to toxicity in the gastrointestinal tract, hepatobiliary system, immune system, skeletal system, kidneys, hematopoietic system, pancreas, and adrenal glands. Additionally, reproductive studies identified embryolethal, teratogenic effects and potential fertility impairment in males and females. These toxicities have the potential to cause serious harm in humans at clinically relevant exposures and have therefore been adequately labelled in the Fruzaqla Product Monograph.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Fruzaqla Product Monograph. In view of the intended use of Fruzaqla, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Fruzaqla Product Monograph, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Fruzaqla has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 30 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC) in the original container to protect from moisture. The bottle should be tightly closed and the desiccant must remain in the bottle.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

One excipient in the capsule shell, gelatin, is of animal origin. Compliance statements and a certificate of suitability granted by the European Directorate for the Quality of Medicines were provided. The gelatin used in the manufacture is also compliant with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3).