Mary Lynne Hedley, PhD
The EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of oral rolapitant (Varuby; Varubi in US) for the prevention of delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy, according to Tesaro, the manufacturer of the agent.
The positive opinion will now be reviewed by the European Commission and a final approval decision for use in the European Union (EU) is expected in about 2 months. Rolapitant was previously approved by the FDA in September 2015.
“Chemotherapy-induced nausea and vomiting (CINV) remains a significant unmet need, with more than half of patients treated with emetogenic chemotherapy experiencing this debilitating side effect for up to 5 days,” Mary Lynne Hedley, PhD, president and COO of Tesaro, said in a statement. “The positive CHMP opinion for Varuby is an important milestone for the company. Varuby is positioned to be Tesaro’s first commercial product in Europe, and we look forward to bringing this important medicine to patients as quickly as possible.”
Rolapitant is a potent, selective NK-1 receptor antagonist, with a plasma half-life of approximately 7 days. Activation of NK-1 receptors plays a central role in CINV induced by certain chemotherapies, particularly in the delayed phase, defined as the period from 24 hours to up to 120 hours after the start of chemotherapy.
The application for rolapitant in the EU is based on data from 4 clinical trials, including 3 studies with patients receiving cisplatin-based highly emetogenic chemotherapy (HEC) and 1 study with patients receiving moderately emetogenic chemotherapy (MEC).
Two pivotal phase III trials of rolapitant were the identically designed highly emetogenic chemotherapy (HEC) 1 and HEC2 trials, which examined rolapitant in highly emetogenic cisplatin-based chemotherapy regimens.
Patients in both HEC trials received 180 mg of oral rolapitant or placebo 1 to 2 hours before HEC administration. All patients also received 10 μg/kg IV of the 5HT3-antagonist granisetron and 20 mg of oral dexamethasone on day 1, and 8 mg of oral dexamethasone twice daily on days 2 to 4 of cycle 1, which lasted a minimum of 14 days. Patients could receive the same study drug as cycle 1 in up to 5 subsequent cycles.
Both trials achieved the primary endpoint of complete response (CR) in the delayed phase of CINV, defined as 25 to 120 hours after treatment initiation. In HEC1, CR was 72.7% among 264 patients in the rolapitant arm compared with 58.4% in the 262-patient control arm (P
<.001). In HEC2, CR in the rolapitant group (n = 271) versus the control arm (n = 273) was 70.1% versus 61.9% (P
In patients receiving cisplatin-based chemotherapy, the most frequently reported adverse events (AEs) were neutropenia (9% with rolapitant vs 8% with control), hiccups (5% vs 4%), and abdominal pain (3% vs 2%).
A separate phase III trial evaluated the 180-mg dose of rolapitant in 1332 patients receiving MEC regimens. The design was similar to the HEC trials, with patients receiving rolapitant or placebo prior to MEC, and both groups also receiving granisetron and dexamethasone. MEC regimens included anthracycline/cyclophosphamide combinations, carboplatin, irinotecan, pemetrexed, oxaliplatin, and doxorubicin. The primary endpoint was CR.
In the rolapitant arm, CR was 71.3% in the delayed phase of CINV versus 61.6% in patients receiving granisetron plus dexamethasone (P
<.001). AEs occurring in ≥3% of patients in the rolapitant arm versus the control arm included decreased appetite (9% vs 7%), neutropenia (7% vs 6%), dizziness (6% vs 4%), dyspepsia (4% vs 2%), urinary tract infection (4% vs 3%), stomatitis (4% vs 2%), and anemia (3% vs 2%).
“Tesaro has an exciting pipeline of oncology therapeutics, and with the positive CHMP opinion for Varuby today and our planned product launches in Europe this year, we are globalizing our mission of providing transformative therapies to people bravely facing cancer,” Orlando Oliveira, senior vice president and general manager of Tesaro International, said in a statement.
“Following today’s positive CHMP opinion, and subject to final approval and completion of pricing and reimbursement discussions, Tesaro plans to launch Varuby in Europe beginning in the first half of 2017, on a country-by-country basis. Our international organization now spans 17 European countries and is well prepared to make this treatment available in each country as soon as possible,” Oliveira added.