FDA Approves Varubi for CINV

The FDA has approved Varubi (rolapitant) for use in combination with other antiemetic agents to prevent delayed chemotherapy-induced nausea and vomiting (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,” said Amy Egan, deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research, 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.”

Varubi is a potent, selective, NK-1 receptor antagonist, with plasma half-life of approximately seven 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.

The approval was based on data from several phase 3 trials of Varubi in more than 2,500 patients receiving various emetogenic chemotherapy agents, including cisplatin, carboplatin and anthracycline/cyclophosphamide-based regimens. The data showed that adding Varubi 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.

“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,” Richard J. Gralla, professor of Medicine at Albert Einstein College of Medicine, said in a statement. “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 3 trial considered by the FDA were the identically designed highly emetogenic chemotherapy (HEC) 1 and HEC2 trials, which examined Varubi in highly emetogenic cisplatin-based chemotherapy regimens.

Patients in both trials received 180 mg of oral Varubi or placebo one to two 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 five 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 percent among 264 patients in the Varubi arm compared with 58.4 percent in the 262-patient control arm. In HEC2, CR in the Varubi group (271 patients) versus the control arm (273 patients) was 70.1 versus 61.9 percent.

In patients receiving cisplatin-based chemotherapy, the most frequently reported adverse events were neutropenia (9 percent with Varubi vs 8 percent with control), hiccups (5 percent vs 4 percent) and abdominal pain (3 percent vs 2 percent).

A separate phase 3 trial evaluated the 180-mg dose of rolapitant in 1,332 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 percent in the delayed phase of CINV versus 61.6 percent in patients receiving granisetron plus dexamethasone. AEs occurring in at least 3 percent of patients in the rolapitant arm versus the control arm included decreased appetite (9 percent vs 7 percent), neutropenia (7 percent vs 6 percent), dizziness (6 percent vs 4 percent), dyspepsia (4 percent vs 2 percent), urinary tract infection (4 percent vs 3 percent), stomatitis (4 percent vs 2 percent) and anemia (3 percent vs 2 percent).

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."