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Nausea and Vomiting Treatment Rolapitant Submitted for FDA Review

Positive phase III data presented at ASCO meeting

A new drug application (NDA) has been submitted to the FDA for oral rolapitant (Tesaro, Inc.), an investigational neurokinin-1 (NK-1) receptor antagonist developed for the prevention of chemotherapy-induced nausea and vomiting (CINV).

The NDA was supported by data from four controlled studies in patients receiving emetogenic chemotherapy. One study enrolled patients receiving moderately emetogenic chemotherapy (MEC), and three studies enrolled patients receiving cisplatin-based highly emetogenic chemotherapy (HEC). Results from each of the three phase III studies of rolapitant were presented at the American Society for Clinical Oncology (ASCO) annual meeting in June 2014.

The first phase III trial of rolapitant was an international, randomized, double-blind, active-controlled study that enrolled 1,369 cancer patients receiving MEC, approximately half of whom were receiving anthracycline-based therapy for breast cancer. The patients were randomly assigned to receive either control treatment, which consisted of a 5-HT3 receptor antagonist plus dexamethasone, or oral rolapitant 200 mg plus control.

Patients who received rolapitant had a significantly higher complete response (CR) rate, defined as no emesis and no use of rescue medication, for the primary endpoint of a complete response during the delayed phase compared with control treatment (71.3% vs. 61.6%, respectively; P < 0.001). CR rates were higher for rolapitant-treated patients than for control patients in the acute (83.5% vs. 80.3%, respectively; P = 0.143) and overall (68.6% vs. 57.8%; P < 0.001) phases. The rolapitant group also achieved higher rates of complete protection, defined as no emesis, no use of rescue medication, and no significant nausea, in both the delayed (64.3% vs. 56.9%; P = 0.006) and overall phases (62.0% vs. 53.2%; P = 0.001).

The second phase 3 trial of rolapitant was an international, randomized, double-blind, active-controlled study that enrolled 532 patients receiving HEC, defined as regimens that contained cisplatin at a dose equal to or greater than 60 mg/m2. Patients were randomly assigned to receive either control therapy (a 5-HT3 receptor antagonist plus dexamethasone) or oral rolapitant 200 mg plus control.

Patients who received rolapitant had a significantly higher CR rate compared with control patients for the primary endpoint of CR during the delayed (72.7% vs. 58.4%, respectively; P < 0.001), acute (83.7% vs. 73.7%; P = 0.005), and overall (70.1% vs. 56.5%; P = 0.001) phases. In addition, rolapitant-treated patients had a significantly higher rate of no significant nausea in the overall phase (71.6% vs. 63.0%; P = 0.037). The rolapitant group also achieved higher rates of no nausea in both the delayed (53.0% vs. 41.6%; P = 0.009) and overall phases (49.6% vs. 39.3%; P = 0.018).

The third phase III trial of rolapitant was an international, randomized, double-blind, active-controlled study that enrolled 555 patients receiving HEC. The patients were randomly assigned to receive either control therapy (a 5-HT3 receptor antagonist plus dexamethasone) or oral rolapitant 200 mg plus control.

Patients treated with rolapitant had a significantly higher CR rate compared with the control group during the delayed phase (70.1% vs. 61.9%, respectively; P = 0.043). CR rates were also higher for rolapitant-treated patients in the acute (83.4% vs. 79.5%; P = 0.233) and overall (67.5% vs. 60.4%; P = 0.084) phases. The rolapitant group also achieved higher rates of no nausea in both the delayed (58.3% vs. 46.9%; P = 0.007) and overall phases (55.0% vs. 44.0%; P = 0.009).

Rolapitant is a selective NK-1 receptor antagonist with an extended plasma half-life that is being developed for the prevention of CINV. NK-1 receptors are highly concentrated in the brain and bind neurokinin substance P. The activation of NK-1 receptors plays a central role in nausea and vomiting induced by emetogenic stimuli, including certain cancer chemotherapies.

CINV is estimated to affect more than 70% of cancer patients undergoing emetogenic chemotherapy and, if not prevented, may result in the delay or discontinuation of chemotherapy treatment. Prolonged nausea and vomiting may result in unwanted weight loss, dehydration, and malnutrition as well as hospitalization.

Sources: Tesaro; September 8, 2014; and Tesaro; June 1, 2014.

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