Rolapitant Gets FDA Approval to Prevent CINV

Richard Gralla

Oncology practitioners now have a new drug in their armamentarium to help prevent chemotherapy-induced nausea and vomiting (CINV) following the FDA’s approval today of the oral agent rolapitant (Varubi) for use in combination with other antiemetic agents to prevent CINV in adults during the delayed phase of chemotherapy treatment.

FDA’s approval was based on data from several phase III trials of rolapitant involving more than 2500 patients receiving various emetogenic chemotherapy agents, including cisplatin, carboplatin, and anthracycline/cyclophosphamide-based regimens.

The data showed that adding rolapitant to a 5-HT3 receptor antagonist and dexamethasone was superior to a 5-HT3 receptor antagonist and dexamethasone alone in preventing delayed CINV in patients receiving chemotherapy regimens that were moderately or highly emetogenic.

“Chemotherapy-induced nausea and vomiting (CINV) remains a major issue that can disrupt patients' lives and sometimes their therapy,” said Amy Egan, MD, deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Today’s approval provides cancer patients with another treatment option for the prevention of the delayed phase of nausea and vomiting caused by chemotherapy.”

Rolapitant is a potent, selective, NK-1 receptor antagonist, with plasma half-life of approximately 7 days. According to the FDA, 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.

“While important strides in preventing nausea and vomiting associated with chemotherapy have been made, still up to half of patients receiving emetogenic cancer chemotherapy can experience delayed CINV,” said Richard J. Gralla, MD, professor of Medicine at Albert Einstein College of Medicine. “Because NK-1 receptors are key drivers of CINV, especially in the delayed Phase, NK-1 receptor antagonists such as Varubi, when combined with a 5-HT3 receptor antagonist and a corticosteroid, provide enhanced protection from CINV, and do so in the delayed timeframe where the most help is needed.”

Two of the pivotal phase III trials considered by the FDA 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 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 = .043).

In patients receiving cisplatin-based chemotherapy, the most frequently reported adverse events 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 moderately emetogenic chemotherapy (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%).

"We look forward to expanding the awareness of CINV and working with healthcare providers to make this important medicine available to patients," said Moulder.

Varubi is marketed by Tesaro Inc., based in Waltham, Massachusetts.