FDA Approves Intravenous Rolapitant for Delayed Chemotherapy-Induced Nausea and Vomiting

On October 25, the U.S. Food and Drug Administration (FDA) approved intravenous (IV) rolapitant (Varubi) 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. Delayed nausea and vomiting can occur anytime between 25 and 120 hours following chemotherapy, and is often extremely debilitating.

Rolapitant is a highly selective and competitive antagonist of human substance P/neurokinin 1 (NK-1) receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV). With a long plasma half-life of approximately 7 days, a single dose of rolapitant, as part of an antiemetic regimen, significantly improved complete response (CR) rates in the delayed phase of CINV. Results from three phase III trials of rolapitant oral tablets 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 rolapitant reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy. Results from a bioequivalence trial demonstrated comparability of the IV and oral formulations of rolapitant.

Rolapitant IV is supplied in ready-to-use vials and does not require refrigerated storage or mixing. Rolapitant IV is to be administered up to 2 hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone. No dosage adjustment is required for dexamethasone, a CYP3A4 substrate, and rolapitant is the first intravenously administered NK-1 receptor antagonist approved by the FDA that does not contain polysorbate 80.

“Many health-care providers tend to believe that CINV is no longer an unmet need, but the reality is that more than half of patients treated with emetogenic chemotherapy experience delayed CINV, even when prescribed standard preventative therapies, such as a 5-HT3 receptor antagonist and dexamethasone,” said Lee Schwartzberg, MD, Professor of Medicine at University of Tennessee Health Science Center. “The FDA approval of rolapitant IV gives doctors and nurses a new option to help protect their patients from these often preventable side effects.”

Results of Three Phase III Studies

The superior efficacy of rolapitant was established in multiple global randomized, well-controlled, double-blinded clinical trials that enrolled more than 2,500 patients. Rolapitant, when administered in combination with 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 either moderately or highly emetogenic chemotherapy.

The clinical profile of rolapitant in cisplatin-based highly emetogenic chemotherapy (HEC) was confirmed in two identical phase III studies: HEC1 and HEC2. Both trials met their primary endpoint of complete response (CR), and demonstrated statistical superiority of rolapitant (180 mg oral) compared to active control (5-HT3 receptor antagonist plus dexamethasone) in the delayed phase (25–120 hours) of CINV.

In HEC1, 264 patients received rolapitant and 262 received active control. The proportion of patients achieving a CR was 72.7% vs 58.4% (P = < .001).

In HEC2, 271 patients received rolapitant and 273 received active control. The proportion of patients achieving a CR was 70.1% vs 61.9% (P = .043). The most common adverse reactions (≥ 3%) among patients receiving cisplatin-based chemotherapy were neutropenia (9% rolapitant vs 8% control), hiccups (5% vs 4%), and abdominal pain (3% vs 2%).

A phase III trial was also conducted to evaluate rolapitant (180 mg oral) compared to active control in 1,332 patients receiving moderately emetogenic chemotherapy regimens, including anthracycline/cyclophosphamide combinations; carboplatin; irinotecan; pemetrexed (Alimta); oxaliplatin; and doxorubicin. This trial met its primary endpoint of CR, and demonstrated statistical superiority of rolapitant compared to active control (5-HT3 receptor antagonist plus dexamethasone) in the delayed phase of CINV. The proportion of patients achieving a CR was 71.3% vs 61.6% (P ≤ .001). The most common adverse reactions (≥ 3%) among patients receiving these chemotherapies were decreased appetite (9% rolapitant vs 7% control); 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%).

In addition to the phase III program, a bioequivalence study was conducted in healthy volunteers to compare the exposure of the 166.5-mg dose of IV rolapitant to the exposure of a 180-mg dose of oral rolapitant. Study participants were randomized to receive a single dose of either 166.5 mg of intravenous rolapitant administered over 30 minutes (n = 61) or 180 mg of oral rolapitant (n = 62). The primary endpoint of this pivotal study was bioequivalence, defined by estimating whether the 90% confidence intervals for the ratio of the area under the curves of the two formulations are entirely included within the acceptance range of 80% to 125%. Safety and tolerability were also assessed for both formulations. The safety profile was consistent with previous clinical trials with oral rolapitant, except for infusion-site reactions observed with the IV formulation.  

The full prescribing information for rolapitant IV is available at http://www.varubirx.com/en.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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