In three phase III studies reported in The Lancet Oncology, the addition of the neurokinin-1 (NK-1) receptor antagonist rolapitant to serotonin (5-HT3) receptor antagonist and dexamethasone treatment significantly improved complete response rates in the prevention of chemotherapy-induced nausea and vomiting in patients with cancer who were receiving moderately emetogenic chemotherapy or anthracycline-cyclophosphamide regimens (which are now considered highly emetogenic) and in those receiving highly emetogenic cisplatin-based regimens.1,2
Unlike currently available NK-1 receptor antagonists (eg, aprepitant, netupitant), rolapitant is not an inducer or inhibitor of CYP3A4, reducing the potential for drug-drug interactions with other agents metabolized by CYP3A4 and the need to modify the dosage of such agents.
Moderately Emetogenic Chemotherapy
In a double-blind trial reported by Lee S. Schwartzberg, MD, and colleagues, patients from 170 sites in 23 countries were randomized between March 2012 and September 2013 to receive oral rolapitant 180 mg or placebo 1 to 2 hours before administration of moderately emetogenic chemotherapy or anthracycline-cyclophosphamide regimens. All patients received oral granisetron 2 mg and oral dexamethasone 20 mg on day 1 (except for those receiving taxanes, who received dexamethasone according to the package insert) and granisetron 2 mg on days 2 and 3. Treatment was given for up to 6 cycles, with a minimum of 14 days.
A total of 666 patients in each group received at least one dose of study drug and were included in the modified intention-to-treat population. Among them, anthracycline-cyclophosphamide regimens were received by 344 patients in the rolapitant group and 359 in the control group. The primary endpoint was the proportion of patients achieving a complete response, defined as no emesis or use of rescue medication in the delayed phase (> 24–120 hours) after initiation of chemotherapy in cycle 1.
Delayed-Phase Outcomes
During the delayed phase, complete response was observed in 71% of the rolapitant group vs 62% of the control group (odds ratio [OR] = 1.6, P = .0002), including 67% vs 60% among patients receiving anthracycline-cyclophosphamide regimens (OR = 1.4, P = .04) and 76% vs 64% among those receiving other moderately emetogenic regimens (OR = 1.8, P = .0008).
Acute and Overall Phases
During the acute phase (0–24 hours), complete response was achieved in 83% vs 80% (P = .1425), including 77% vs 77% among patients receiving anthracycline-cyclophosphamide regimens (P = .9659) and 91% vs 84% among those receiving other regimens (P = .0163).
During the overall phase (0–124 hours), complete response was achieved in 69% vs 58% (P < .0001), including 63% vs 55% among patients receiving anthracycline-cyclophosphamide regimens (P = .0332) and 75% vs 61% among those receiving other regimens (P = .0003).
Adverse Events
The incidence of adverse events during cycle 1 was similar in the rolapitant and control groups, with the most frequently reported treatment-related adverse events being fatigue (3% vs 2%) and constipation (3% vs 3%). Adverse events led to discontinuation of treatment in 2% vs 2%. The most common grade 3 or 4 adverse event in the rolapitant group was neutropenia (5% vs 3%). No serious adverse events were considered related to treatment.
Highly Emetogenic Chemotherapy
In two identically designed double-blind phase III trials (HEC-1 and HEC-2) reported in a single article by Bernardo L. Rapoport, MD, and colleagues, patients from 155 sites in 26 countries were randomized between February 2012 and March 2014 to receive oral rolapitant 180 mg or placebo at 1 to 2 hours before administration of cisplatin-based highly emetogenic chemotherapy. All patients received intravenous granisetron 10 μg/kg and oral dexamethasone 20 mg on day 1 and oral dexamethasone 8 mg twice daily on days 2 to 4 for up to 6 cycles, with a minimum of 14 days. The study protocols were developed before widespread implementation of guidelines recommending the addition of an NK-1 receptor antagonist to 5-HT3 receptor antagonist and dexamethasone treatment in patients receiving highly emetogenic chemotherapy.
A total of 526 patients in HEC-1 (264 rolapitant and 262 control patients) and 544 in HEC-2 (271 rolapitant and 273 control patients) received at least one dose of study drug and were included in the modified intention-to-treat population. HEC-1 included greater proportions of women, patients from North America, and those with ovarian cancer; HEC-2 included greater proportions of patients with lung or stomach cancer. The primary endpoint was the proportion of patients achieving complete response, defined as no emesis or use of rescue medication, in the delayed phase (> 24–120 hours after initiation of chemotherapy) in cycle 1.
Delayed-Phase Outcomes
Significantly greater proportions of patients in the rolapitant groups achieved complete response during the delayed phase in both HEC-1 (73% vs 58%, OR = 1.9, P = .0006) and HEC-2 (70% vs 62%, OR = 1.4, P = .0426) and in the pooled population (71% vs 60%, OR = 1.6, P = .0001).
Acute and Total Phases
For the acute phase, rolapitant was associated with a significantly higher complete response rate in HEC-1 (84% vs 74%, P = .0051) but not in HEC-2 (83% vs 79%, P = .2331) and with significant benefit in the pooled population (84% vs 77%, P = .0045). For the total phase (0–120 hours), rolapitant was associated with a significantly higher complete response rate in HEC-1 (70% vs 56%, P = .0013) but not in HEC-2 (68% vs 60%, P = .0840) and with significant benefit in the pooled population (69% vs 59%, P = .0005).
Adverse Events
The incidence of adverse events was similar in the rolapitant and control groups. The most commonly reported treatment-related adverse events during cycle 1 were headache, hiccups, constipation, and dyspepsia (all < 1% vs < 1%). The most common grade ≥ 3 adverse events in cycle 1 were neutropenia (3% vs 5% in HEC-1, 6% vs 5% in HEC-2), anemia (< 1% vs < 1% in HEC-1, 3% vs < 1% in HEC-2), and leukopenia (2% vs < 1% in HEC-1, < 1% vs < 1% in HEC-2). No serious adverse events were considered related to treatment.
In both studies, the investigators concluded: “Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the at-risk period (120 h) after administration of [moderately or highly] emetogenic cisplatin-based chemotherapy [or regimens containing an anthracycline and cyclophosphamide].” ■
Disclosure: The studies were funded by Tesaro, Inc. For full disclosures of the study authors, visit www.thelancet.com.
References
1. Schwartzberg LS, et al: Lancet Oncol 16:1071-1078, 2015.
2. Rapoport BL, et al: Lancet Oncol 16:1079-1089, 2015.
