Summary Basis of Decision for Stivarga

 

Clinical Pharmacology

Regorafenib, the active ingredient in Stivarga, is a multikinase inhibitor that blocks several enzymes involved in tumour angiogenesis, oncogenesis, and the tumour microenvironment.

The data from the submitted clinical pharmacokinetic studies are considered sufficient and there are no major concerns to prevent the approval of Stivarga for the specified indication. Extensive labelling changes were proposed for the clinical pharmacokinetic parts of the Stivarga Product Monograph and the sponsor accepted all of the proposed changes. Appropriate warnings and precautions are in place in the approved Stivarga Product Monograph to address the identified safety concerns.

For further details, please refer to the Stivarga Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy and safety of Stivarga were evaluated in an international, multicentre, randomized, double-blind, placebo-controlled Phase III study (Study 14387) in patients with metastatic colorectal cancer (CRC) who had progressed after failure of standard therapy [including fluoropyrimidine-based chemotherapy, an anti-vascular endothelial growth factor (anti-VEGF) therapy, and, if KRAS wild type, an anti-epidermal growth factor receptor (anti-EGFR) therapy].

In total, 760 patients were randomized 2:1 to receive 160 mg regorafenib (4 tablets Stivarga, each containing 40 mg regorafenib) orally once daily plus best supportive care (BSC; n = 505) or matching placebo plus BSC (n = 255), for 3 weeks on therapy followed by 1 week off therapy. Patients continued therapy until disease progression or unacceptable toxicity were identified.

Demographics and baseline disease characteristics were comparable between the Stivarga and placebo groups with regard to age, gender, and Eastern Cooperative Oncology Group (ECOG) performance status. The primary site of disease was colon (64% vs. 67.5%), rectum (29.9% vs. 27.1%) or colon and rectum (5.9% vs. 5.5%). KRAS mutation was reported in 54.1% of the patients in the Stivarga group vs. 61.6% in the placebo group. All patients received prior treatment with fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab. Of the patients with a KRAS wild type tumour, 99.5% in the Stivarga group and 100% in the placebo group had received prior treatment with cetuximab and/or panitumumab.

The primary efficacy endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR).

The median duration of treatment phase was 7 weeks (approximately 2 cycles). The addition of Stivarga to BSC resulted in a statistically significant improvement in survival compared to placebo plus BSC.

The results of this pivotal Phase III study demonstrated a statistically significant reduction in the risk of death in patients treated with Stivarga compared to placebo [hazard ratio (HR) 0.77 (95% Confidence Interval (CI): 0.64, 0.94); p = 0.010356]. The median survival time (OS) was 6.4 months (95% CI: 5.8, 7.3) in the Stivarga-treated patients compared to 5.0 months (95% CI: 4.4, 5.8) in placebo-treated patients. Although there was a statistically significant reduction in the estimated risk of progression [HR 0.49 (95% CI: 0.42, 0.58); p <0.000001], a 7-day improvement in the median PFS (59 days vs. 52 days) with Stivarga over placebo is not considered to be clinically meaningful.

There were no complete tumour responses according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Five (1%) Stivarga-treated patients and 1 (0.4%) placebo-treated patient achieved a partial response with no difference in ORR (p = 0.19). Disease control rate (DCR) was assessed after 6-8 weeks post randomization and was comprised of stable disease, non-complete response or non-progressive disease. The median duration of stable disease was 60 days in the Stivarga group and 52 days in the placebo group. Given a high rate of missing/out of schedule assessment and lack of independent review, the DCR data could be biased. Stable disease was reported in 43% vs. 14% of patients in the Stivarga group compared to the placebo group.

Exploratory subgroup analyses were conducted for subgroups such as age, gender, number of prior therapies and various disease characteristics in 25 pre-specified sub-group analyses across OS and PFS. All subgroup analyses were descriptive in nature where a HR of less than 1 suggested a beneficial trend in efficacy in favour of Stivarga and a HR of greater than 1 suggested a trend in favor of placebo. A HR of approximately 1 represented no trend in favour of either treatment. All tests were one-sided. The results showed a beneficial trend towards improvement in OS in 24/25 subgroups analysed, including 11 subgroups with statistically significant prolongation in OS (p<0.05). A HR <1 was maintained in all but one subgroup (metastatic CRC of both colon and rectum) of patients. The results of PFS analysis strongly supported the OS results showing HR <1 in all 25 subgroups tested. The effect of Stivarga over placebo was more pronounced in a subgroup of patients with KRAS wild type (n = 299) based on the HR = 0.653 (95% CI: 0.476, 0.895) corresponding to 35% reduction in the risk of death. In contrast, Stivarga-treated patients with KRAS mutations (n = 430) demonstrated a statistically insignificant reduction in the risk of death by 13% based on the HR = 0.867 (95% CI: 0.670, 1.123). The Stivarga Product Monograph contains information to highlight this difference in survival benefit based on historical KRAS mutational status.

Health Related Quality of Life (HRQoL) data showed deterioration in patients' quality of life of similar magnitude in both treatment arms, with a trend to worsening the HRQoL with Stivarga compared to placebo. However, a higher attrition rate in the placebo arm compared to the Stivarga arm and a short observation time (median 8 weeks) preclude any meaningful conclusion regarding the patient reported outcome.

The results of several ad hocsensitivity analyses of OS and PFS demonstrated consistency with the primary analyses results, thus confirming prolongation of survival time with Stivarga over placebo. These results are considered to be supportive for a definite survival benefit of the Stivarga treatment.

In conclusion, the efficacy results from the pivotal Phase III study are considered positive with regard to clinical and statistical relevance as well as internal consistency. The credibility of the results in this pivotal study is confirmed by the primary endpoint, which demonstrates a statistically significant benefit of Stivarga in OS. Moreover, all the sensitivity analyses confirmed the primary analyses, indicating that the data are robust.

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

Clinical Safety

The clinical safety evaluation was based on results from the pivotal Phase III, randomized, double-blind, placebo-controlled Study 14387 (described in Clinical Efficacy), in which 500 patients received Stivarga at a dose of 160 mg daily plus BSC, and 253 patients received placebo plus BSC, for 3 weeks of each 4-week treatment cycle, until disease progression or unacceptable toxicity were identified. The median duration of treatment was 7 weeks and safety observation was <3 months (median time) in both treatment groups.

A dose modification occurred in 67% and 22% of patients in the Stivarga and placebo group, respectively. Due to adverse reactions, 61% of the Stivarga-treated patients required a dose interruption and 38% of the patients had their dose reduced. Treatment cessations occurred with similar incidence (18% vs. 13%) indicating that most adverse events in the Stivarga-treated patients could be managed by dose modifications. There appears to be a narrow safety margin between therapeutic and toxic doses of Stivarga. Dose-limiting toxicities included hepatotoxicity, hemorrhage, gastrointestinal (GI), and dermatological toxicities.

The most frequently observed treatment-emergent adverse events (≥30%) in the Stivarga group were fatigue (64%), decreased appetite (47%), hand foot skin reaction (HFSR, 47%), diarrhea (43%), decreased weight (32%), hypertension (30%), and dysphonia (32%). The most common Grade 3 events in the Stivarga group were HFSR (17%), fatigue (15%), diarrhea (8%), hypertension (8%) infection (7%) and hyperbilirubinemia (6%).

The important identified risks are severe drug-induced liver injury (DILI), hemorrhage, myocardial ischemia and infarction, arterial hypertension and hypertensive crisis, palmar-plantar erythrodysesthesia syndrome/HFSR, GI perforation and fistula, reversible posterior leukoencephalopathy syndrome (RPLS), and Stevens-Johnson syndrome (SJS). These identified risks are due to the known class effects and clinical safety data suggesting a causal link to regorafenib, the medicinal ingredient of Stivarga. Severe DILI, hemorrhage, myocardial infarction/ischemia, SJS and RPLS are considered important because of their potential to result in severe or fatal outcomes. Hypertension and HFSR are important in that they are very common and may adverselyimpact effective therapy delivery and quality of life. The Stivarga Product Monograph has a Serious Warnings and Precautions box containing warnings regarding hepatotoxicity, hemorrhage involving the respiratory and gastrointestinal tracts, RPLS, GI perforation and fistula, arterial hypertension, and HFSR. All of the important identified risks are appropriately labelled to raise the physicians' and patients' awareness, and statements including advice on clinical management are provided in the corresponding sections of the finalized Product Monograph for Stivarga.

The cardiovascular section of the Stivarga Product Monograph contains explicit warnings regarding the increased incidence of cardiac adverse events (8.4 vs. 5.5%) including cardiac arrhythmia (3% vs. 0.8%), cardiac ischemia and infarction (1.2% vs. 0.4%) and severe (Grade 3/4) congestive heart failure (1.2% vs. 0.4%) in Stivarga-treated patients compared to placebo-treated patients. Arterial hypertension was the most common vascular disorder, reported in 30% of Stivarga-treated patients. Adequate monitoring, conventional management, and dose interruption/reduction are recommended for patients with persisting hypertension. In the event of a hypertensive crisis, Stivarga should be discontinued. Based on the cardiosafety review, Stivarga may decrease heart rate. Caution should be observed in patients with a low heart rate at baseline, a history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular (AV) block, ischemic heart disease, or congestive heart failure. Concomitant medications that result in a decrease in heart rate should be avoided to the extent possible during treatment with Stivarga.

Stivarga increased the incidence of hypothyroidism (4.2% vs. 0.4%) and incidence of fistula (0.8% vs. 0.4%), compared to placebo. A precautionary statement recommends the discontinuation of Stivarga in patients who develop GI perforation or fistula.

Stivarga increased the incidence of hemorrhage (21% vs. 8%) compared to placebo. Fatal hemorrhage involving the respiratory, genitourinary and GI tracts was reported in 4 (0.8%) Stivarga-treated patients. No placebo-treated patients had a fatal bleeding event. Treatment with Stivarga should be stopped in patients with severe and life-threatening hemorrhage. Close monitoring of the International Normalized Ratio (INR) in patients receiving warfarin is advised.

Data from a regorafenib safety database indicated that severe DILI with fatal outcomes was reported in 3 of 1,100 patients treated with regorafenib. All cases occurred within the first 2 months of therapy and exhibited hepatocellular necrosis and clinical manifestations of hepatic failure including ascites, neurological deterioration, and abnormal coagulation.

In Study 14387, the incidence of hepatobiliary disorders was higher in Stivarga-treated patients (20% vs. 12%) compared to placebo-treated patients. Fatal events of hepatic dysfunction were reported in 10/500 (2%) Stivarga-treated patients compared to 4 (1.6%) placebo-treated patients. Adverse events of hepatic dysfunction led to the treatment cessation in 7 (1.4%) Stivarga-treated patients and 3 (1.2%) placebo-treated patients. Hepatic injury/failure adverse events (fibrosis, cirrhosis and other liver damage-related conditions) were reported in 37/500 (7.4%) Stivarga-treated patients compared to 13/253 (5.1%) placebo-treated patients. Dose modifications should be carried out in cases of liver dysfunction. Early discontinuation is the most important risk mitigation in cases of DILI.

The incidence of skin and subcutaneous disorders was higher in the Stivarga-treated patients (72%) as compared to the placebo-treated patients (24%). There was one event of Grade 4 SJS in a patient treated with Stivarga (0.2%). The overall incidence of HFSR/palmar-plantar erythrodysesthesia syndrome (47% vs. 8%) and Grade 3 HFSR (17% vs. 0%) was increased in Stivarga-treated patients. The overall incidence of rash (29% vs. 5%) and Grade 3 rash (6% vs. 0%) was higher in Stivarga-treated patients as compared to patients in the placebo group. Measures for the prevention and treatment of skin adverse reactions include topical treatments, dose reduction/interruption, or in severe or persistent cases, permanent discontinuation of Stivarga.

In cases of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, treatment should be discontinued until further pulmonary investigation excludes interstitial lung disease or pneumonitis. In addition to the important risks mentioned above, metabolic and biochemical abnormalities have been frequently reported, but are generally mild and not associated with clinical complications.

Most of the Stivarga-related adverse drug reactions resolve after drug interruption or discontinuation, however, rare cases with fatal outcomes have been reported. Close monitoring of identified targets of Stivarga toxicity is advised, especially in the first 2 months of treatment. Dose modifications and early discontinuations are the most important risk mitigation in case of severe adverse drug reactions. Corresponding risk minimization measures are included in the Stivarga Product Monograph.

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