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Rolapitant Improves Quality of Life of Patients Receiving Highly Or Moderately Emetogenic Chemotherapy

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Rolapitant Improves Quality of Life of Patients Receiving Highly Or Moderately Emetogenic Chemotherapy Support Care Cancer (2017) 25:85–92 DOI 10.1007/s00520-016-3388-7 ORIGINAL ARTICLE Rolapitant improves quality of life of patients receiving highly or moderately emetogenic chemotherapy Martin Chasen1 & Laszlo Urban2 & Ian Schnadig3 & Bernardo Rapoport4 & Dan Powers5 & Sujata Arora5 & Rudolph Navari6 & Lee Schwartzberg7 & Cesare Gridelli8 Received: 4 April 2016 /Accepted: 17 August 2016 /Published online: 24 August 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract with no impact on daily life (total score >108 [range 18–126]). Purpose Addition of rolapitant to standard antiemetic therapy We performed a prespecified analysis of the MEC/ improved protection against chemotherapy-induced nausea anthracycline-cyclophosphamide (AC) study and a post hoc and vomiting (CINV) in phase 3 trials of patients receiving analysis of two pooled cisplatin-based HEC studies. highly emetogenic chemotherapy (HEC) or moderately Results In the pooled HEC studies, rolapitant significantly emetogenic chemotherapy (MEC). Here, we assessed the im- improved the FLIE total score (114.5 vs 109.3, p<0.001), pact of CINV on the daily lives of patients receiving HEC or nausea score (55.3 vs 53.5, p<0.05), and vomiting score MEC using the Functional Living Index-Emesis (FLIE). (59.2 vs 55.8, p<0.001) versus control; similar results were Methods In three double-blind phase 3 studies, patients re- observed in the MEC/AC study for FLIE total score (112.7 vs ceiving HEC or MEC were randomized 1:1 to receive oral 108.6, p < 0.001), nausea score (54.1 vs 52.3, p<0.05), and rolapitant 180 mg or placebo prior to chemotherapy plus 5- vomiting score (58.6 vs 56.3, p < 0.001). A higher proportion hydroxytryptamine type 3 receptor antagonist and dexameth- of patients reported no impact on daily life with rolapitant than asone therapy. Patients completed the FLIE questionnaire on with control in the MEC/AC study (73.2 vs 67.4, p=0.027). day 6 of cycle 1. Endpoints included FLIE total score, nausea Conclusions Compared with control, rolapitant improved and vomiting domain scores, and the proportion of patients quality of life in patients receiving HEC or MEC. Keywords Rolapitant . Neurokinin-1 receptor antagonist . * Martin Chasen Quality of life . Functional Living Index-Emesis . [email protected] Chemotherapy-induced nausea and vomiting (CINV) . Antiemetic 1 Palliative Care, William Osler Health Services. 2100 Bovaird Drive East, Brampton, ON L6R 3J7, Canada 2 Matrahaza University Hospital. Mátraháza, Kékestető 3233, Introduction Hungary 3 Compass Oncology, US Oncology Research, Tualatin Office II. Chemotherapy-induced nausea and vomiting (CINV) is a de- 12960 SW 65th Ave Ste. 435, Tualatin, OR 97062, USA bilitating side effect of anticancer treatments associated with 4 Medical Oncology Center of Rosebank. 129 Oxford Rd, Corner substantial reductions in health-related quality of life (QoL) Northwold, Saxonwold, Johannesburg 2196, South Africa [1–3]. Without antiemetic prophylaxis, >90 % of patients re- 5 TESARO, Inc. 1000 Winter St North, Suite 3300, ceiving highly emetogenic chemotherapy (HEC) and 30– Waltham, MA 02451, USA 90 % of patients receiving moderately emetogenic chemother- 6 Indiana University School of Medicine–South Bend. 202 apy (MEC) experience emesis [4]. Prior to the adoption of Lincolnway East, Suite #105, Mishawaka, IN 46544, USA current antiemetic prophylaxis strategies, patients consistently 7 West Clinic. Memphis, TN 38120, USA ranked nausea and vomiting among the most distressing side 8 Division of Medical Oncology, San Giuseppe Moscati Hospital. effects of chemotherapy, ranking these side effects worse than Condtrada Amoretta, 8, Avellino 83100, Italy fatigue, depression, or the impact of chemotherapy on their 86 Support Care Cancer (2017) 25:85–92 family or partner [5, 6]. The risk of developing CINV is pri- report on the impact of CINV on patients’ daily lives marily related to the emetogenic potential of the chemothera- using the FLIE in an analysis of the rolapitant phase 3 peutic regimen, although factors including chemotherapy trials. dose, number of treatment cycles, and patient age and sex may affect the risk [7]. Uncontrolled CINV can result in malnutrition, dehy- dration, and electrolyte imbalance [8] and has been asso- Methods ciated with the development of anticipatory nausea and vomiting with the potential to compromise adherence to Three global, multicenter, randomized, parallel-group, treatment [8, 9]. Fortunately, substantial progress in our double-blind phase 3 studies (clinicaltrials.gov identifiers understanding of the neural mechanisms underlying CINV NCT01500213, NCT01499849, and NCT01500226) were has led to the development of highly effective therapeutic conducted in compliance with the International approaches [9]. The use of 5-hydroxytryptamine type 3 Conference on Harmonisation and Good Clinical (5-HT3) receptor antagonists (RAs), particularly when Practice (GCP) guidelines [20, 21]. Detailed methods combined with dexamethasone, has been found to effec- and results regarding the incidence of CINV were previ- tively reduce CINV in patients treated with HEC or MEC, ously reported [20, 21]. although CINV control was greatest in the acute phase Patients were required to be aged ≥18 years and to (≤24 h following chemotherapy) [4]; symptoms may per- have a Karnofsky performance score ≥60, a predicted life sist in the delayed phase (>24–120 h after chemotherapy expectancy of ≥4 months, and adequate bone marrow, administration) in up to 50 % of patients [10–13]. The kidney, and liver function. Eligibility for the HEC studies addition of a neurokinin-1 (NK-1) RA to a 5-HT3 RA required patients to be naive to cisplatin and scheduled and dexamethasone has improved CINV control through- to receive their first course of cisplatin ≥60 mg/m2. out the delayed phase, and this three-drug combination is Eligibility for the MEC/AC study required patients to the recommended antiemetic prophylaxis regimen for pa- be naive to MEC and HEC and scheduled to receive tients receiving HEC and select patients with CINV risk their first course of one or more of the following agents factors receiving MEC [4]. Despite substantial progress, alone or in combination: intravenous cyclophosphamide complete control of CINV, particularly nausea, in the de- (<1500 mg/m2), doxorubicin, epirubicin, carboplatin, layed phase has proven difficult [14, 15]. Furthermore, idarubicin, ifosfamide, irinotecan, daunorubicin, and/or delayed-phase CINV has been found to have a greater intravenous cytarabine (>1 g/m2). The study protocol impact on QoL than CINV experienced only in the acute prespecified that ≥50 % of patients enrolled in the phase [1, 2]. MEC/AC study would receive AC-based chemotherapy The Functional Living Index-Emesis (FLIE) is a validated [21]. questionnaire designed to specifically address the impact of Prior to receiving study drug, patients were not permitted to CINVon patients’ daily lives [16, 17]. Validation of the FLIE use any of the following medications: 5-HT3 RAs, phenothi- instrument is a sensitive and reliable measure of the impact azines, benzamides, domperidone, cannabinoids, NK-1 RAs, of CINV on QoL [16, 17]. Furthermore, use of the FLIE has or benzodiazepines within 48 h; palonosetron within 7 days; demonstrated that beyond a reduction in the physical symp- or systemic corticosteroids or sedative antihistamines (e.g., toms of nausea and vomiting, effective antiemetic prophylaxis dimenhydrinate or diphenhydramine) within 72 h of day 1, reduces the negative impact of CINV on patients’ daily lives with the exception of premedication for chemotherapy (e.g., [8, 18]. taxanes). Patients with established nausea, vomiting, or both Rolapitant (VARUBI®, TESARO, Inc.) is a highly se- were permitted to take rescue medication; those who used lective, long-acting NK-1 RA indicated in combination rescue medication were considered failures for the efficacy with other antiemetic agents in adults for the prevention endpoint of complete response (no emesis and no use of res- of delayed nausea and vomiting associated with initial and cue medication). repeat courses of emetogenic cancer chemotherapy [19]. Results of two phase 3 cisplatin-based HEC studies (HEC-1 and HEC-2) [20] and one phase 3 MEC or Treatment anthracycline and cyclophosphamide (AC)-based chemo- therapy study [21] demonstrated that a single oral dose of Patients were stratified by sex and randomly assigned (1:1) to rolapitant (180 mg) taken before chemotherapy with a 5- either rolapitant 180 mg (rolapitant group) or placebo (control HT3 RA and dexamethasone resulted in superior protec- group). All patients received 5-HT3 RA and dexamethasone tion against CINV in the delayed phase compared with therapy (Fig. 1). Treatment blinding was maintained through- placebo plus a 5-HT3 RA and dexamethasone. Here, we out the studies. Support Care Cancer (2017) 25:85–92 87 MITT population Rolapitant 180 mg orally day 1 + Granisetron 10 µg/kg intravenously day 1 + n Dexamethasone 20 mg orally day 1 + HEC1 ( =264) n Dexamethasone 8 mg orally twice daily days 2–4 HEC2 ( =271) HEC trials HEC1 (n=266), HEC2 (n=278) HEC1: N=532, HEC2: N=555 Randomized 1:1 Placebo orally day 1 + Granisetron 10 µg/kg intravenously day 1 + n Dexamethasone 20 mg orally day 1 + HEC1 ( =262) n Dexamethasone 8 mg orally twice daily days 2–4 HEC2 ( =273) HEC1 (n=266), HEC2 (n=277) Rolapitant 180 mg orally day 1 + Granisetron 2 mg orally days 1–3 + MEC/AC (n=666) Dexamethasone 20 mg orally day 1 (n=684) MEC/AC trial N=1369 Randomized 1:1 Placebo orally day 1 + Granisetron 2 mg orally days 1–3 + MEC/AC (n=666) Dexamethasone 20 mg orally day 1 (n=685) Fig. 1 Treatment schema. In the HEC and MEC/AC trials, patients chemotherapy administration on day 1; granisetron 2 mg orally was received a single oral dose of rolapitant 180 mg or matching placebo administered once daily on days 2 and 3. In the HEC and MEC/AC capsules 1–2 h prior to the administration of chemotherapy.
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