Regorafenib

Regorafenib is indicated as monotherapy for the treatment of adult patients with

- metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy

- unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib

- hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Regorafenib should be prescribed by physicians experienced in the administration of anticancer therapy.

Posology

The recommended dose of regorafenib is 160 mg (4 tablets of 40 mg) taken once daily for 3 weeks followed by 1 week off therapy. This 4-week period is considered a treatment cycle.

If a dose is missed, then it should be taken on the same day as soon as the patient remembers. The patient should not take two doses on the same day to make up for a missed dose. In case of vomiting after regorafenib administration, the patient should not take additional tablets.

Treatment should continue as long as benefit is observed or until unacceptable toxicity occurs.

Patients with performance status (PS) 2 or higher were excluded from clinical studies. There is limited data in patients with PS >2.

Posology adjustments

Dose interruptions and/or dose reductions may be required based on individual safety and tolerability. Dose modifications are to be applied in 40 mg (one tablet) steps. The lowest recommended daily dose is 80 mg. The maximum daily dose is 160 mg.

For recommended dose modifications and measures in case of hand-foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia syndrome see Table 1.

Table 1: Recommended dose modifications and measures for HFSR

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Table 2: Recommended measures and dose modifications in case of drug-related liver function test abnormalities

Hepatic impairment

Regorafenib is eliminated mainly via the hepatic route.

In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients with mild hepatic impairment (Child-Pugh A) and normal hepatic function. No dose adjustment is required in patients with mild hepatic impairment. Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B), no dose recommendation can be provided. Close monitoring of overall safety is recommended in these patients.

Regorafenib is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Regorafenib has not been studied in this population.

Renal impairment

Available clinical data indicate similar exposure of regorafenib and its metabolites M-2 and M-5 in patients with mild, moderate or severe renal impairment compared to patients with normal renal function.).

Elderly population

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Gender

In clinical studies, no relevant differences in exposure, safety or efficacy were observed between male and female patients.).

Ethnic differences

In clinical studies, no relevant differences in exposure or efficacy were observed between patients of different ethnic groups. A higher incidence of hand foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia syndrome, severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Regorafenib compared with Caucasians. The Asian patients treated with Regorafenib in clinical studies were primarily from East Asia (~90%). There is limited data on regorafenib in the black patient population.

No dose adjustment is necessary based on ethnicity.

Paediatric population

There is no relevant use of Regorafenib in the paediatric population in the indication of metastatic colorectal cancer.

The safety and efficacy of regorafenib in patients below 18 years of age in the indication gastrointestinal stromal tumours (GIST) have not been established. No data are available.

There is no relevant use of Regorafenib in the paediatric population in the indication of hepatocellular carcinoma.

Method of administration

Regorafenib is for oral use.

Regorafenib should be taken at the same time each day. The tablets should be swallowed whole with water after a light meal that contains less than 30% fat. An example of a light (low-fat) meal would include 1 portion of cereal (about 30 g), 1 glass of skimmed milk, 1 slice of toast with jam, 1 glass of apple juice, and 1 cup of coffee or tea (520 calories, 2 g fat).

Hepatic effects

Abnormalities of liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with Regorafenib. Severe liver function test abnormalities (Grade 3 to 4) and hepatic dysfunction with clinical manifestations (including fatal outcomes) have been reported in a small proportion of patients.

In clinical trials, a higher incidence of severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Regorafenib, compared with Caucasians.

It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of treatment with Regorafenib and monitor closely (at least every two weeks) during the first 2 months of treatment. Thereafter, periodic monitoring should be continued at least monthly and as clinically indicated.

Regorafenib is a uridine diphosphate glucuronosyl transferase (UGT) 1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert's syndrome.

For patients with observed worsening of liver function tests considered related to treatment with Regorafenib (i.e. where no alternative cause is evident, such as post-hepatic cholestasis or disease progression), the dose modification and monitoring advice in Table 2 should be followed.

Regorafenib is eliminated mainly via the hepatic route.

2). Regorafenib is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Regorafenib has not been studied in this population and exposure might be increased in these patients.

Infections

Regorafenib has been associated with an increased incidence of infection events, some of which were fatal.

In cases of worsening infection events, interruption of Regorafenib treatment should be considered.

Haemorrhage

Regorafenib has been associated with an increased incidence of haemorrhagic events, some of which were fatal. Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants (e.g. warfarin and phenprocoumon) or other concomitant medicinal products that increase the risk of bleeding. Screening for and subsequent treatment of oesophageal varices in patients with liver cirrhosis should be performed as per standard of care before starting treatment with Regorafenib. In the event of severe bleeding necessitating urgent medical intervention, permanent discontinuation of Regorafenib should be considered.

Gastrointestinal perforation and fistula

Gastrointestinal perforation (including fatal outcome) and fistulae have been reported in patients treated with Regorafenib. These events are also known to be common disease-related complications in patients with intra-abdominal malignancies. Discontinuation of Regorafenib is recommended in patients developing gastrointestinal perforation or fistula.

Cardiac ischaemia and infarction

Regorafenib has been associated with an increased incidence of myocardial ischaemia and infarction. Patients with unstable angina or new onset angina (within 3 months of starting Regorafenib therapy), recent myocardial infarction (within 6 months of starting Regorafenib therapy) and those with cardiac failure New York Heart Association (NYHA) Classification 2 or higher were excluded from the clinical studies.

Patients with a history of ischaemic heart disease should be monitored for clinical signs and symptoms of myocardial ischaemia. In patients who develop cardiac ischaemia and/or infarction, interruption of Regorafenib is recommended until resolution. The decision to re-start Regorafenib therapy should be based on careful consideration of the potential benefits and risks of the individual patient. Regorafenib should be permanently discontinued if there is no resolution.

Posterior reversible encephalopathy syndrome (PRES)

PRES has been reported in association with Regorafenib treatment. Signs and symptoms of PRES include seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging. In patients developing PRES, discontinuation of Regorafenib, along with control of hypertension and supportive medical management of other symptoms is recommended.

Arterial hypertension

Regorafenib has been associated with an increased incidence of arterial hypertension. Blood pressure should be controlled prior to initiation of treatment with Regorafenib. It is recommended to monitor blood pressure and to treat hypertension in accordance with standard medical practice. In cases of severe or persistent hypertension despite adequate medical management, treatment should be temporarily interrupted and/or the dose reduced at the discretion of the physician. In case of hypertensive crisis, Regorafenib should be discontinued.

Wound healing complications

As medicinal products with anti-angiogenic properties may suppress or interfere with wound healing, temporary interruption of Regorafenib is recommended for precautionary reasons in patients undergoing major surgical procedures. The decision to resume treatment with Regorafenib following major surgical intervention should be based on clinical judgment of adequate wound healing.

Dermatological toxicity

Hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia syndrome and rash represent the most frequently observed dermatological adverse reactions with Regorafenib. In clinical trials, a higher incidence of HFSR was observed in Asian (in particular Japanese) patients treated with Regorafenib, compared with Caucasians. Measures for the prevention of HFSR include control of calluses and use of shoe cushions and gloves to prevent pressure stress to soles and palms. Management of HFSR may include the use of keratolytic creams (e.g. urea-, salicylic acid-, or alpha hydroxyl acid-based creams applied sparingly only on affected areas) and moisturizing creams (applied liberally) for symptomatic relief. Dose reduction and/or temporary interruption of Regorafenib, or in severe or persistent cases, permanent discontinuation of Regorafenib should be considered.

Biochemical and metabolic laboratory test abnormalities

Regorafenib has been associated with an increased incidence of electrolyte abnormalities (including hypophosphatemia, hypocalcaemia, hyponatraemia and hypokalaemia) and metabolic abnormalities (including increases in thyroid stimulating hormone, lipase and amylase). The abnormalities are generally of mild to moderate severity, not associated with clinical manifestations, and do not usually require dose interruptions or reductions. It is recommended to monitor biochemical and metabolic parameters during Regorafenib treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Dose interruption or reduction, or permanent discontinuation of Regorafenib should be considered in case of persistent or recurrent significant abnormalities.

Important information about some of the ingredients

Each daily dose of 160 mg contains 2.427 mmol (or 55.8 mg) of sodium. To be taken into consideration by patients on a controlled sodium diet. Each daily dose of 160 mg contains 1.68 mg of lecithin (derived from soya).

Disease-specific precautions - Hepatocellular carcinoma (HCC)

In the pivotal placebo-controlled phase III study, patients received prior therapy with sorafenib.

There is insufficient data on patients who discontinued sorafenib therapy due to sorafenib-related toxicity or only tolerated a low dose (< 400 mg daily) of sorafenib. The tolerability of Regorafenib in these patients has not been established.

No studies on the effects of Regorafenib on the ability to drive or use machines have been performed. If patients experience symptoms affecting their ability to concentrate and react during treatment with Regorafenib, it is recommended that they do not drive or use machines until the effect subsides.

Summary of the safety profile

The overall safety profile of Regorafenib is based on data from more than 4,800 treated patients in clinical trials including placebo-controlled phase III data for 636 patients with metastatic colorectal cancer (CRC), 132 patients with gastrointestinal stromal tumours (GIST) and 374 patients with hepatocellular carcinoma (HCC).

The safety profile of regorafenib in these studies was consistent with the safety results of a phase III B study conducted in 2872 patients with metastatic colorectal cancer whose disease had progressed after treatment with standard therapies.

The most serious adverse drug reactions in patients receiving Regorafenib are severe liver injury, haemorrhage, gastrointestinal perforation and infection.

The most frequently observed adverse drug reactions (>30%) in patients receiving Regorafenib are pain, hand foot skin reaction, asthenia/fatigue, diarrhoea, decreased appetite and food intake, hypertension and infection.

Tabulated list of adverse reactions

The adverse drug reactions reported in clinical trials in patients treated with Regorafenib are shown in Table 3. They are classified according to System Organ Class and the most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); and rare (>1/10,000 to <1/1,000).

Within each frequency group, undesirable effects are presented in order of decreasing seriousness.

Table 3: Adverse drug reactions (ADRs) reported in clinical trials in patients treated with Regorafenib

* fatal cases have been reported

** palmar-plantar erythrodysesthesia syndrome in MedDRA terminology

^# according to drug-induced liver injury (DILI) criteria of the international DILI expert working group

Description of selected adverse reactions

In most cases of severe liver injury, liver dysfunction had an onset within the first 2 months of therapy, and was characterized by a hepatocellular pattern of injury with transaminase elevations >20xULN, followed by bilirubin increase. In clinical trials, a higher incidence of severe liver injury with fatal outcome was observed in Japanese patients (~1.5%) treated with Regorafenib, compared with non-Japanese patients (<0.1%).

In the placebo-controlled phase III trials, the overall incidence of haemorrhage was 18.2% in patients treated with Regorafenib and 9.5% in patients receiving placebo. Most cases of bleeding events in patients treated with Regorafenib were mild to moderate in severity (Grades 1 and 2: 15.2%), most notably epistaxis (6.1%). Fatal outcome in patients treated with Regorafenib was uncommon (0.7%), and included cerebral, respiratory, gastrointestinal and genitourinary events.

In the placebo-controlled phase III trials, infections were more often observed in patients treated with Regorafenib, compared to patients receiving placebo (all grades: 31.6% vs. 17.2%). Most infections in patients treated with Regorafenib were mild to moderate in severity (Grades 1 and 2: 23.0%), and included urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) as well as pneumonia (2.6%). Fatal outcomes associated with infection were observed more often in patients treated with Regorafenib (1.0%), compared to patients receiving placebo (0.3%), and were mainly respiratory events.

In the placebo-controlled phase III trials, the overall incidence of hand-foot skin reaction was higher in patients treated with Regorafenib, compared to patients receiving placebo (all grades: 51.4% vs. 6.5% CRC, 66.7% vs. 15.2% GIST and 51.6% vs.7.3% HCC). Most cases of hand-foot skin reaction in patients treated with Regorafenib appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 34.3%%, CRC, 44.7%, GIST and 39.3%, HCC). The incidence of Grade 3 hand-foot skin reaction was 17.1% (CRC), 22.0% (GIST) and 12.3% (HCC). The overall incidence of hand-foot skin reaction (74.8%, CRC, 88.2%, GIST and 67.1%, HCC) was higher in Regorafenib-treated Asian patients, compared to other ethnicities. The incidence of Grade 3 hand-foot skin reaction in Asians was 20.5% (CRC), 23.5% (GIST) and 13.5% (HCC).

In the placebo-controlled phase III trials, the overall incidence of hypertension was higher in patients treated with Regorafenib, compared to patients receiving placebo (29.6% vs. 7.5% CRC, 60.6% vs. 25.8% GIST and 31.0% vs. 6.2% HCC). Most cases of hypertension in patients treated with Regorafenib appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 20.9%, CRC, 31.1%, GIST and 15.8% HCC). The incidence of Grade 3 hypertension was 8.7% (CRC), 27.3% (GIST) and 15.2% (HCC). One case of Grade 4 hypertension was reported in the GIST trial.

In the placebo-controlled phase III trials, the overall incidence of treatment emergent proteinuria was 9.1% in patients treated with Regorafenib, compared to 1.9% in patients receiving placebo. Of these events, 35.6% in the Regorafenib arm and 54.5% in the placebo arm have been reported as not recovered/not resolved.

Across all clinical trials, cardiac disorder events (all grades) have been more often (13.7% vs. 6.5%) reported in Regorafenib-treated patients aged 75 years or older (N=410), compared to Regorafenib-treated patients below 75 years (N=4108).

Laboratory test abnormalities

Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase ).

Table 4: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trials in patients with metastatic CRC (CORRECT), GIST (GRID) and HCC (RESORCE)

^a Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0

^b Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

* International normalized ratio

BSC = Best Supportive Care

Compared to the global phase III CRC trial (CORRECT) with predominantly (~80%) Caucasian patients enrolled, a higher incidence of liver enzyme increases was observed in Regorafenib-treated patients in the Asian phase III CRC trial (CONCUR) with predominantly (> 90%) East Asian patients enrolled.

Table 4a: Treatment emergent liver enzyme test abnormalities reported in placebo-controlled phase III trial in Asian patients with metastatic CRC (CONCUR)

^§ Best Supportive Care

* Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

In the placebo-controlled phase III trials, tests on thyroid stimulating hormone (TSH) showed post baseline >ULN in 34.6% of patients treated with Regorafenib and in 17.2% of patients receiving placebo. TSH post baseline >4 times ULN was reported in 6.5% of patients treated with Regorafenib and in 1.3% of patients receiving placebo. Concentration of free triiodothyronine (FT3) post baseline below lower limit of normal (<LLN) was reported in 29.2% of patients treated with Regorafenib and in 20.4% of patients receiving placebo. Concentration of free thyroxin (FT4) post baseline <LLN was reported in 8.1% of patients treated with Regorafenib and 5.6% of patients receiving placebo. Overall approximately 4.6% of patients treated with Regorafenib developed hypothyroidism requiring hormonal replacement treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

The highest dose of Regorafenib studied clinically was 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhoea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue.

There is no specific antidote for Regorafenib overdose. In the event of suspected overdose, Regorafenib should be discontinued immediately, with best supportive care initiated by a medical professional, and the patient should be observed until clinical stabilisation.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor;

ATC Code: L01XE21

Mechanism of action and pharmacodynamic effects

Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAF^V600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R). In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumours, and thereby blocks tumour cell proliferation. In preclinical studies regorafenib has demonstrated potent antitumour activity in a broad spectrum of tumour models including colorectal, gastrointestinal stromal and hepatocellular tumour models which is likely mediated by its anti-angiogenic and anti-proliferative effects. In addition, regorafenib reduced the levels of tumour associated macrophages and has shown anti-metastatic effects in vivo. Major human metabolites (M-2 and M-5) exhibited similar efficacies, compared to regorafenib in in vitro and in vivo models.

Clinical efficacy and safety

Metastatic colorectal cancer (CRC)

The clinical efficacy and safety of Regorafenib have been evaluated in an international, multi-centre, randomised, double-blind, placebo-controlled phase III study (CORRECT) in patients with metastatic colorectal cancer who have progressed after failure of standard therapy.

The primary efficacy endpoint was Overall Survival (OS). Secondary endpoints were Progression-Free Survival (PFS), objective tumour response rate and disease control rate.

In total, 760 patients were randomised 2:1 to receive 160 mg regorafenib (4 tablets Regorafenib each containing 40 mg regorafenib) orally once daily (N=505) plus Best Supportive Care (BSC) or matching placebo (N=255) plus BSC for 3 weeks on therapy followed by 1 week off therapy. The mean daily regorafenib dose received was 147 mg.

Patients continued therapy until disease progression or unacceptable toxicity. A pre-planned interim analysis for efficacy was performed when 432 deaths had occurred. The study was un-blinded after this planned interim analysis of OS had crossed the pre-specified efficacy boundary.

Of the 760 randomised patients, the median age was 61 years, 61% were male, 78% were Caucasian, and all patients had baseline ECOG Performance Status (PS) of 0 or 1. PS >2 was reported during Regorafenib treatment in 11.4% of patients. The median treatment duration and daily dose, as well as the rate of dose modification and dose reduction were similar to those observed in patients with a reported PS > 2 receiving placebo (8.3%). The majority of patients with PS >2 discontinued treatment for progressive disease. The primary site of disease was colon (65%), rectum (29%), or both (6%). A KRAS mutation was reported in 57% of patients at study entry.

Most patients (52%) received 3 or fewer previous lines of treatment for metastatic disease. Therapies included treatment with fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if the patient was KRAS wild type, an anti-EGFR therapy.

The addition of Regorafenib to BSC resulted in significantly longer survival, compared to placebo plus BSC with a p value of 0.005178 from stratified log rank test, a hazard ratio of 0.774 [95% CI 0.636, 0.942] ) and a median OS of 6.4 months vs. 5.0 months (see Table 5 and Figure 1). PFS was significantly longer in patients receiving Regorafenib plus BSC (hazard ratio: 0.494, p<0.000001, see Table 5). The response rate (complete response or partial response) was 1% and 0.4% for Regorafenib and placebo treated patients, respectively (p=0.188432, 1-sided). The disease control rate (complete response or partial response or stable disease) was significantly higher in patients treated with Regorafenib (41.0% vs. 14.9%, p<0.000001, 1 sided).

Table 5: Efficacy results from the CORRECT study

^§ Best Supportive Care

* Hazard ratio < 1 favours Regorafenib

** based on investigator's assessment of tumour response

Figure 1: Kaplan-Meier curve of overall survival

Subgroup analyses for overall survival and progression free survival according to age (<65; >65), gender, ECOG PS, primary site of disease, time from first diagnosis of metastatic disease, prior anticancer treatment, prior treatment lines for metastatic disease, and KRAS mutation status showed a treatment effect favouring the regorafenib regimen over the placebo regimen.

Subgroup analysis results by historical KRAS mutational status showed a treatment effect for OS in favour of regorafenib over placebo for patients with KRAS wild-type tumours whereas a numerically lower effect was reported in patients with KRAS mutant tumours; the treatment effect for PFS favouring regorafenib was observed regardless of KRAS mutational status. The hazard ratio (95% CI) of overall survival was 0.653 (0.476 to 0.895) for patients with KRAS wild-type tumours and 0.867 (0.670 to 1.123) for patients with KRAS mutant tumours, with no evidence of heterogeneity in treatment effect (non-significant interaction test). The hazard ratio (95% CI) of progression free survival was 0.475 (0.362 to 0.623) for patients with KRAS wild-type tumours and 0.525 (0.425 to 0.649) for patients with KRAS mutant tumours.

A second phase III, international, multi-centre, randomised, double blind, placebo-controlled study (CONCUR) evaluated the efficacy and safety of Regorafenib in 204 pre-treated Asian patients (> 90% East Asian) with metastatic colorectal cancer who have progressed after failure of fluoropyrimidine-based chemotherapy. Only 59.5 % of patients enrolled in the CONCUR study were also previously treated with VEGF- or EGFR-targeted agents. The primary efficacy endpoint was OS. The addition of Regorafenib to BSC resulted in a significantly longer survival, compared to placebo plus BSC with a hazard ratio of 0.550 (p = 0.000159 stratified log rank test) and a median OS of 8.8 months vs. 6.3 months [95% CI 0.395, 0.765]. PFS was also significantly longer in patients receiving Regorafenib plus BSC (hazard ratio: 0.311, p<0.000001), median PFS 3.2 months with Regorafenib vs. 1.7 months with placebo. The safety profile of Regorafenib plus BSC in the CONCUR study was consistent with the safety profile observed in the CORRECT study.

Gastrointestinal stromal tumours (GIST)

The clinical efficacy and safety of Regorafenib have been evaluated in an international, multi-centre, randomised, double-blind, placebo-controlled phase III study (GRID) in patients with gastrointestinal stromal tumours (GIST) previously treated with 2 tyrosine kinase inhibitors (imatinib and sunitinib).

The analysis of the primary efficacy endpoint Progression-Free Survival (PFS) was conducted after 144 PFS events (central blinded assessment). Secondary endpoints including Time To Progression (TTP) and Overall Survival (OS) (interim analysis) were also assessed.

In total, 199 patients with GIST were randomised 2:1 to receive either 160 mg regorafenib plus Best Supportive Care (BSC; N=133) orally once daily or matching placebo plus BSC (N=66) for 3 weeks on therapy followed by 1 week off therapy. The mean daily regorafenib dose received was 140 mg.

Patients continued therapy until disease progression or unacceptable toxicity. Patients receiving placebo who experienced disease progression were offered open-label regorafenib (cross-over option). Patients receiving regorafenib who experienced disease progression and for whom in the investigator's opinion, treatment with regorafenib was providing clinical benefit, were offered the opportunity to continue open-label regorafenib.

Of the 199 randomised patients, the mean age was 58 years, 64% were male, 68% were Caucasian, and all patients had baseline ECOG Performance Status (PS) of 0 or 1. The overall median time since most recent progression or relapse to randomisation was 6 weeks.

Regorafenib plus BSC resulted in significantly longer PFS, compared to placebo plus BSC with a hazard ratio of 0.268 [95% CI 0.185, 0.388] and a median PFS of 4.8 months vs. 0.9 months (p < 0.000001). The relative risk of disease progression or death was reduced by approximately 73.2% in regorafenib-treated patients, compared to placebo treated patients (see Table 6, Figure 2).The increase in PFS was consistent independent of age, sex, geographic region, prior lines of treatment, ECOG PS.

TTP was significantly longer in patients receiving regorafenib plus BSC than in patients receiving placebo plus BSC with a hazard ratio of 0.248 [95% CI 0.170, 0.364], and median TTP of 5.4 months vs. 0.9 months (p<0.000001) (see Table 6).

The HR for OS was 0.772 (95% CI, 0.423, 1.408; p = 0.199; median OS not reached in either arm); 85% of patients initially randomised to the placebo arm received post-progression treatment with regorafenib (see Table 6, Figure 3).

Table 6: Efficacy Results from the GRID study

^§ Best Supportive Care

* Hazard ratio < 1 favours Regorafenib

** NR: not reached

Figure 2: Kaplan-Meier curves of Progression-Free Survival

Figure 3: Kaplan-Meier curves of Overall Survival

In addition, 56 placebo plus BSC patients received open-label Regorafenib after cross-over following disease progression and a total of 41 Regorafenib plus BSC patients continued Regorafenib treatment after disease progression. The median secondary PFS (as measured by the investigator's assessment) were 5.0 and 4.5 months, respectively.

Hepatocellular carcinoma (HCC)

The clinical efficacy and safety of Regorafenib have been evaluated in an international, multi-centre, randomised, double-blind, placebo-controlled phase III study (RESORCE) in patients with hepatocellular carcinoma who have been previously treated with sorafenib.

The primary efficacy endpoint was Overall Survival (OS). Secondary endpoints were Progression-Free Survival (PFS), Time To Progression (TTP), Objective Tumour Response Rate (ORR) and Disease Control Rate (DCR).

In total, 573 patients with HCC were randomised 2:1 to receive either 160 mg regorafenib orally once daily (n=379) plus Best Supportive Care (BSC) or matching placebo (n=194) plus BSC for 3 weeks on therapy followed by 1 week off therapy. The mean daily regorafenib dose received was 144 mg. Patients were eligible to participate in the study if they experienced radiological disease progression during treatment with sorafenib and if they had a liver function status of Child-Pugh class A. Patients who permanently discontinued sorafenib therapy due to sorafenib-related toxicity or who tolerated less than 400 mg sorafenib once daily prior to withdrawal were excluded from the study. Randomisation was performed within 10 weeks after the last treatment with sorafenib. Patients continued therapy with Regorafenib until clinical or radiological disease progression or unacceptable toxicity. However, patients could continue Regorafenib therapy past progression at the discretion of the investigator.

Demographics and baseline disease characteristics were comparable between the Regorafenib- and placebo-treated groups and are shown below for all 573 randomised patients:

- Median age: 63 years

- Male: 88%

- Caucasian: 36%, Asian: 41%

- ECOG Performance Status of 0: 66% or ECOG Performance Status of 1: 34%

- Child-Pugh A: 98%, Child-Pugh B: 2%

- Etiology included Hepatitis B (38%), Hepatitis C (21%), Non-Alcoholic Steato Hepatitis (NASH, 7%)

- Absence of both macroscopic vascular invasion and extra-hepatic tumour spread: 19%

- Barcelona Clinic Liver Cancer (BCLC) stage B: 13%; BCLC stage C: 87%

- Loco-regional transarterial embolisation or chemoinfusion procedures: 61%

- Radiotherapy prior to regorafenib treatment: 15%

- Median duration of sorafenib treatment: 7.8 months

The addition of Regorafenib to BSC resulted in a statistically significant improvement in OS compared to placebo plus BSC with a hazard ratio of 0.624 [95% CI 0.498, 0.782], p=0.000017 stratified log rank test, and a median OS of 10.6 months vs. 7.8 months (see Table 7 and Figure 4).

Table 7: Efficacy Results from the RESORCE study

^§ Best Supportive Care

* Hazard ratio < 1 favours Regorafenib

** based on investigator's assessment of tumour response by modified RECIST

# Response rate (complete or partial response), Disease Control Rate (complete response, partial response and stable disease maintained for 6 weeks)

Figure 4: Kaplan-Meier curve of Overall survival

Figure 5: Kaplan-Meier curve of Progression Free survival (mRECIST)

Paediatric population

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Absorption

Regorafenib reaches mean peak plasma levels of about 2.5 mg/l at about 3 to 4 hours after a single oral dose of 160 mg given as 4 tablets each containing 40 mg. Following single doses of 60 mg or 100 mg, the average relative bioavailability of tablets compared to an oral solution was 69% and 83%, respectively.

The concentrations of regorafenib and its major pharmacologically active metabolites (M-2 and M-5) were highest when given after a low-fat (light) breakfast, compared to either a high-fat breakfast or fasting condition. The exposure for regorafenib was increased by 48% when administered with a high-fat breakfast, and 36% when administered with a low fat breakfast, compared to fasting. The exposure of metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) is higher when regorafenib is given with a low fat breakfast, compared to fasting condition and lower when given with a high fat meal, compared to fasting condition.

Distribution

Plasma concentration-time profiles for regorafenib as well as for the major circulating metabolites showed multiple peaks across the 24-hour dosing interval, which are attributed to enterohepatic circulation. In vitro protein binding of regorafenib to human plasma proteins is high (99.5%). In vitro protein binding of M-2 and M-5 is higher (99.8% and 99.95%, respectively) than that of regorafenib. Metabolites M-2 and M-5 are weak substrates of P-gp. Metabolite M-5 is a weak BCRP-substrate.

Biotransformation

Regorafenib is metabolized primarily in the liver by oxidative metabolism mediated by CYP3A4, as well as by glucuronidation mediated by UGT1A9. Two major and six minor metabolites of regorafenib have been identified in plasma. The main circulating metabolites of regorafenib in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), which are pharmacologically active and have similar concentrations as regorafenib at steady state. M-2 is further metabolised by oxidative metabolism mediated by CYP3A4, as well as by glucuronidation mediated by UGT1A9.

Metabolites may be reduced or hydrolysed in the gastrointestinal tract by microbial flora, allowing reabsorption of the unconjugated active substance and metabolites (enterohepatic circulation).

Elimination

Following oral administration, mean elimination half-life for regorafenib and its metabolite M-2 in plasma ranges from 20 to 30 hours in different studies. The mean elimination half-life for the metabolite M-5 is approximately 60 hours (range from 40 to 100 hours).

Approximately 90% of the radioactive dose was recovered within 12 days after administration, with about 71% of the dose excreted in faeces (47% as parent compound, 24% as metabolites), and about 19% of the dose excreted in urine as glucuronides. Urinary excretion of glucuronides decreased below 10% under steady-state conditions. Parent compound found in faeces could be derived from intestinal degradation of glucuronides or reduction of metabolite M-2 (N-oxide), as well as unabsorbed regorafenib.

M-5 may be reduced to M-4 in the gastrointestinal tract by microbial flora, allowing reabsorption of M-4 (enterohepatic circulation). M-5 is finally excreted via M-4 as M-6 (carboxylic acid) in faeces.

Linearity/non-linearity

Systemic exposure of regorafenib at steady-state increases dose proportionally up to 60 mg and less than proportionally at doses greater than 60 mg. Accumulation of regorafenib at steady state results in about a 2-fold increase in plasma concentrations, which is consistent with the elimination half-life and dosing frequency. At steady state, regorafenib reaches mean peak plasma levels of about 3.9 mg/L (8.1 micromolar) after oral administration of 160 mg regorafenib and the peak-to-trough ratio of mean plasma concentrations is less than 2.

Both metabolites, M-2 and M-5, exhibit non-linear accumulation, which might be caused by entero-hepatic recycling or saturation of the UGT1A9 pathway. Whereas plasma concentrations of M-2 and M-5 after a single dose of regorafenib are much lower than those of parent compound, steady-state plasma concentrations of M-2 and M-5 are comparable to those of regorafenib.

Hepatic impairment

The exposure of regorafenib and its metabolites M-2 and M-5 is comparable in patients with mild hepatic impairment (Child-Pugh A) and patients with normal hepatic function.

Limited data in patients with moderate hepatic impairment (Child-Pugh B) indicate similar exposure, compared to patients with normal hepatic function after a single 100 mg dose of regorafenib. There are no data for patients with Child-Pugh C (severe) hepatic impairment. Regorafenib is mainly eliminated via the liver, and exposure might be increased in this patient population.

Renal impairment

Available clinical data and physiology-based pharmacokinetic modelling indicate similar steady-state exposure of regorafenib and its metabolites M-2 and M-5 in patients with mild or moderate renal impairment, compared to patients with normal renal function. In patients with severe renal impairment compared to patients with normal renal function, regorafenib exposure was similar while exposure to M-2 and M-5 was decreased by about 30% under steady-state conditions, which is not considered relevant.

The pharmacokinetics of regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease. However, physiology-based pharmacokinetic modelling does not predict any relevant change in exposure in these patients.

Elderly

Age did not affect the regorafenib pharmacokinetics over the studied age range (29 - 85 years).

Gender

The pharmacokinetics of regorafenib is not influenced by gender.

Ethnic differences

The exposure of regorafenib in various Asian populations (Chinese, Japanese, Korean) is within the same range as seen in Caucasians.

Cardiac electrophysiology/QT prolongation

No QTc prolonging effects were observed after administration of 160 mg regorafenib at steady state in a dedicated QT study in male and female cancer patients.

Not applicable.

This medicinal product may pose a risk to the environment.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.