The US Food and Drug Administration (FDA) has approved oncology-focused biopharmaceutical company TESARO Inc's Varubi (rolapitant) in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.
Varubi is a selective and competitive antagonist of human substance P/neurokinin 1 (NK-1) receptors, with a plasma half-life of approximately seven days. Results from three phase 3 trials of Varubi demonstrated a significant reduction in episodes of vomiting or use of rescue medication during the 25 to 120 hour period following administration of highly emetogenic and moderately emetogenic chemotherapy regimens. In addition, patients who received Varubi reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy. A 180 milligram dose of Varubi is to be administered approximately one to two hours prior to chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone. No dosage adjustment is required for dexamethasone, a CYP3A4 substrate, when administering Varubi.
TESARO licensed exclusive rights for the development, manufacture, commercialisation and distribution of Varubi from OPKO Health, Inc.
"The approval of Varubi, our first product, represents a significant milestone in TESARO's evolution into an integrated biopharmaceutical company with strong development and commercialisation capabilities," said Lonnie Moulder, CEO of TESARO.
"Results from the phase 3 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. Patient surveys and our primary market research also point to the high rate of CINV and its potentially debilitating effects. 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."
"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, M.D., professor of medicine at Albert Einstein College of Medicine in New York.
"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."
Chemotherapy-induced nausea and vomiting is a debilitating, yet often preventable, side effect of chemotherapy. Up to 50 per cent of patients undergoing highly or moderately emetogenic chemotherapy experience delayed CINV (25 to 120 hours post chemotherapy)—even when prescribed a 5-HT3 receptor antagonist and corticosteroid.
Blocking both 5-HT3 and NK-1 receptors has been shown to offer better control of nausea and vomiting than inhibiting 5-HT3 receptors alone. Adding a single dose of Varubi to an antiemetic regimen, including a 5-HT3 receptor antagonist and corticosteroid, further improves prevention of CINV in the delayed phase following chemotherapy.
The superior efficacy of Varubi was established in multiple randomized, well-controlled, blinded clinical trials that enrolled more than 2,500 patients. Varubi, when administered in combination with a 5-HT3 receptor antagonist and dexamethasone, was superior to a 5-HT3 receptor antagonist and dexamethasone in preventing CINV in patients receiving either moderately or highly emetogenic chemotherapy.
The clinical profile of Varubi in cisplatin-based highly emetogenic chemotherapy (HEC) was confirmed in two identical phase 3 studies: HEC1 and HEC2. Both trials met their primary endpoint of complete response (CR), and demonstrated statistical superiority of rolapitant 180 mg compared to active control (5-HT3 receptor antagonist + dexamethasone) in the delayed phase (25-120 hours) of CINV. In HEC1, 264 patients received rolapitant 180 mg and 262 received control. The proportion of patients achieving a CR was 72.7 per cent vs. 58.4 per cent (p= < 0.001). In HEC2, 271 patients received rolapitant and 273 received control. The proportion of patients achieving a CR was 70.1 per cent vs. 61.9 per cent (p=0.043). The most common adverse reactions (=3 per cent) among patients receiving cisplatin-based chemotherapy were neutropenia (9 per cent Varubi vs. 8 per cent control), hiccups (5 per cent vs. 4 per cent), and abdominal pain (3 per cent vs. 2 per cent).
A phase 3 trial was also conducted to evaluate rolapitant 180 mg compared to active control in 1,332 patients receiving moderately emetogenic chemotherapy regimens, including anthracycline/cyclophosphamide combinations, carboplatin, irinotecan, pemetrexed, oxaliplatin, and doxorubicin. This trial met its primary endpoint of CR, and demonstrated statistical superiority of rolapitant 180 mg compared to active control (5-HT3 receptor antagonist + dexamethasone) in the delayed phase of CINV. The proportion of patients achieving a CR was 71.3 per cent vs 61.6 per cent (p= < 0.001). The most common adverse reactions (=3 per cent) among patients receiving these chemotherapies were decreased appetite (9 per cent Varubi vs. 7 per cent control), neutropenia (7 per cent vs. 6 per cent), dizziness (6 per cent vs. 4 per cent), dyspepsia (4 per cent vs. 2 per cent), urinary tract infection (4 per cent vs. 3 per cent), stomatitis (4 per cent vs. 2 per cent), and anemia (3 per cent vs. 2 per cent).
Primary data from the three phase 3 studies have recently been published online ahead of print in Lancet Oncology, the analysis of the non-AC MEC population was presented at the 2015 annual meeting for the Multinational Association for Supportive Care in Cancer, and commentary has been provided in Nature Reviews Clinical Oncology.