FDA Approves Rolapitant for CINV

The FDA has approved rolapitant (Varubi) for use in combination with other antiemetic agents to prevent delayed CINV from initial and repeat chemotherapy regimens, including highly emetogenic chemotherapy.

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

The approval was based on data from several phase III trials of rolapitant in 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.

“Results from the phase III trials of Varubi demonstrated that patients receiving emetogenic chemotherapy agents, including platinum and cyclophosphamide-containing regimens, benefitted from the addition of Varubi to their antiemetic regimen. Data from multiple well-controlled trials demonstrate that patients who receive only a 5-HT3 receptor antagonist and dexamethasone often continue to suffer from nausea and vomiting for several days following chemotherapy administration,” Lonnie Moulder, CEO of Tesaro, the manufacturer of the drug, said in a statement.

Rolapitant is a potent, selective NK-1 receptor antagonist, with a 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 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 = .043).

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 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 its announcement, Tesaro noted that because rolapitant inhibits CYP2D6, it is contraindicated with CYP2D6 substrates, such as thioridazine.

Commenting on Tesaro's plans for rolapitant going forward, Moulder said, "We look forward to expanding the awareness of CINV and working with healthcare providers to make this important medicine available to patients during the fourth quarter."

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%).