Type of information: Granting of a Market Authorisation in Japan
Product name: Stivarga®
Therapeutic area: Cancer - Oncology - Rare diseases
- multi-kinase inhibitor. Stivarga® (regorafenib) is an oral multi-kinase inhibitor that inhibits various kinases within the mechanisms involved in tumor growth and progression - angiogenesis, oncogenesis and the tumor microenvironment. In preclinical studies, Stivarga inhibits several angiogenic VEGF receptor tyrosine kinases that play a role in tumor neoangiogenesis (the growth of new blood vessels). In addition to VEGFR 1-3 it also inhibits various oncogenic and tumor microenvironment kinases including TIE-2, RAF-1, BRAF, BRAFV600, KIT, RET, PDGFR, and FGFR, which individually and collectively impact upon tumor growth, formation of a stromal microenvironment and disease progression.
- Stivarga® is already approved in more than 90 countries worldwide for metastatic colorectal cancer (CRC), including Japan, and in more than 80 countries globally for the treatment of metastatic gastrointestinal stromal tumors (GIST), including Japan.
Company: Bayer Healthcare (Germany)
Disease: hepatocellular carcinoma
- • On June 26, 2017, Bayer announced that the Ministry of Health, Labour and Welfare (MHLW) in Japan has granted marketing authorization for Stivarga® (regorafenib) tablets for the second-line treatment of patients with unresectable hepatocellular carcinoma who have progressed after treatment with cancer chemotherapy. Since 1990, the annual mortality rate of liver cancer in Japan has increased by over 50%. Globally it is the second leading cause of cancer-related deaths.
- The approval is based on data from the international, multicenter, placebo-controlled Phase III RESORCE trial. In the trial, regorafenib plus best supportive care (BSC) was shown to provide a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo plus BSC (HR 0.63; 95% CI 0.5-0.79; p<0.0001), which translates to a 37% reduction in the risk of death over the trial period.
- The most common treatment-emergent adverse events (regorafenib vs. placebo group) were palmar-plantar erythrodysesthesia syndrome (53% vs. 8%), diarrhea (41% vs. 15%), fatigue (40% vs. 32%) and hypertension (31% vs. 6%).
- Additional regulatory filings for Stivarga® in hepatocellular carcinoma are under review in countries around the world. Stivarg®a in hepatocellular carcinoma has been approved by the FDA in the U.S (see below).
- • On June 22, 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Stivarga®. The CHMP adopted a new indication as follows: "Stivarga® is indicated as monotherapy for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib."
- • On April 27, 2017, the FDA expanded the approved use of Stivarga® (regorafinib) to include treatment of patients with hepatocellular carcinoma who have been previously treated with the drug sorafenib. This is the first FDA-approved treatment for a liver cancer in almost a decade.
- The safety and efficacy of Stivarga® for treatment of hepatocellular carcinoma were studied in a randomized trial of 573 patients with hepatocellular carcinoma whose tumors had progressed after receiving sorafenib (RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma trial (NCT 01774344)] . The trial measured the overall survival, progression-free survival and the percent of patients whose tumors completely or partially shrank after treatment (overall response rate). The median overall survival for patients taking Stivarga® was 10.6 months, compared to 7.8 months for patients taking a placebo. The median progression-free survival for patients taking Stivarga® was 3.1 months compared to 1.5 months for patients taking a placebo. The overall response rate for patients taking Stivarga® was 11 percent, compared to 4 percent of patients taking placebo.Common side effects of Stivarga® include pain (including gastrointestinal and abdominal pain), hand-foot skin reaction, fatigue, diarrhea, decreased appetite, high blood pressure (hypertension), infection, difficulty speaking (dysphonia), high levels of bilirubin in the blood (hyperbilirubinemia), fever, inflammation of the mucous membranes (mucositis), weight loss, rash and nausea. Stivarga® is associated with serious risks, including liver damage (hepatotoxicity), infections, heavy bleeding (hemorrhage), holes in the stomach or intestines (gastrointestinal perforation or fistula), skin damage (dermatologic toxicity), hypertension, problems with blood flow to the heart (cardiac ischemia and infarction), temporary brain swelling(reversible posterior leukoencephalopathy syndrome) and wound healing complications.
- This application was granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.
- • On June 4, 2015, the FDA has granted orphan drug designation for Stivarga® (regorafenib) for the treatment of hepatocellular carcinoma.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2017-04-27
Favourable opinion UE: 2017-06-22
Favourable opinion USA:
Orphan status USA: 2015-06-04
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: