Stivarga (regorafenib) - 3 indications

• the treatment of metastatic colorectal cancer; approved September 2012
• the treatment of gastrointestinal stromal tumor; approved February 2013
• the treatment of hepatocellular carcinoma; approved April 2017

General Information

Stivarga (regorafenib) is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.

Stivarga is specifically indicated for the following conditions:

• the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy
• for patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor who have been previously treated with imatinib mesylate and sunitinib malate
• for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

Stivarga is supplied as tablets for oral administration. The recommended dose is 160 mg Stivarga (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity.

Take Stivarga at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat. Do not take two doses of Stivarga on the same day to make up for a missed dose from the previous day.

Mechanism of Action

Stivarga (regorafenib) is a potent oral multi-kinase inhibitor with a kinase inhibition profile targeting angiogenic, stromal and oncogenic receptor tyrosine kinases (TK). This distinct anti-angiogenic profile includes inhibition of both VEGFR2 and TIE2 TK.

Side Effects

Adverse effects associated with the use of Stivarga may include, but are not limited to, the following:

• asthenia/fatigue
• decreased appetite and food intake
• hand-foot skin reaction (palmar-plantar erythrodysesthesia)
• diarrhea
• mucositis
• weight loss
• infection
• hypertension
• dysphonia

The Stivarga drug label comes with the following Black Box Warning: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has occurred in clinical trials. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

Indication 1 - metastatic colorectal cancer

approved September 2012

Clinical Trial Results

The FDA approval of Stivarga for colorectal cancer was based in part on an international, multi-center, randomized, double-blind, placebo-controlled trial in 760 subjects with previously treated metastatic colorectal cancer. The subjects received 160 mg Stivarga orally once daily plus Best Supportive Care (BSC) or placebo plus BSC for the first 21 days of each 28-day cycle. Stivarga was administered with a low-fat breakfast (less than 30% fat). The primary efficacy endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS) and objective tumor response rate. The median overall survival was 6.4 months for the Stivarga arm versus 5.0 months for the placebo arm (p=0.0102). The median PFS was 2.0 months versus 1.7 months and the overall tumor response rate was 5 (1%) versus 1 (0.4%) for the Stivarga arm versus the placebo arm, respectively.

Indication 2 - gastrointestinal stromal tumor

approved February 2013

Clinical Trial Results

The FDA approval of Stivarga for GIST was based on an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial in 199 subjects with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST), who had been previously treated with imatinib mesylate and sunitinib malate. The subjects received 160 mg regorafenib orally once daily plus best supportive care (BSC) or placebo plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) based on disease assessment by independent radiological review using modified RECIST 1.1 criteria. The percentage of subjects with death or progression was 62% in the Stivarga arm versus 96% in the placebo arm. The median PFS was 4.8 months versus 0.9 months for the Stivarga and placebo arms, respectively.

Indication 3 - hepatocellular carcinoma

approved April 2017

Clinical Trial Results

The FDA approval of Stivarga for the treatment of HCC was based on a randomized trial of 573 patients with HCC whose tumors had progressed after receiving sorafenib. The trial measured the length of time the patients lived after receiving treatment (overall survival), the length of time tumors did not grow after treatment (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.