- Email: [email protected]
Role of rolapitant in chemotherapy-induced emesis
Comment
*Nicolas Wentzensen, Amy Berrington de Gonzalez Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Drive, National Institutes of Health, Bethesda, MD 20892-9774, USA [email protected]
5 6 7
We declare no competing interests. 1
2
3
4
Maguire K, Westhoff C. The state of hormonal contraception today: established and emerging noncontraceptive health benefits. Am J Obstet Gynecol 2011; 205 (4 suppl): S4–8. Beral V, Doll R, Hermon C, Peto R, Reeves G. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87 303 controls. Lancet 2008; 371: 303–14. Havrilesky LJ, Gierisch JM, Moorman PG, et al. Oral contraceptive use for the primary prevention of ovarian cancer. Evid Rep Technol Assess 2013; 212: 1–514. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. BMJ 1968; 2: 199–205.
8 9
10
Brinton LA, Daling JR, Liff JM, et al. Oral contraceptives and breast cancer risk among younger women. J Natl Cancer Inst 1995; 87: 827–35. Kiley J, Hammond C. Combined oral contraceptives: a comprehensive review. Clin Obstet Gynecol 2007; 50: 868–77. Collaborative Group on Epidemiological Studies on Endometrial Cancer. Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies. Lancet Oncol 2015; published online Aug 5. http://dx.doi.org/10.1016/S1470-2045(15)00212-0. Pike MC, Spicer DV. Hormonal contraception and chemoprevention of female cancers. Endocr Relat Cancer 2000; 7: 73–83. Lu KH, Loose DS, Yates MS, et al. Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome. Cancer Prev Res 2013; 6: 774–81. Walker JL, Powell CB, Chen LM, et al. Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer. Cancer 2015; published online March 27. DOI:10.1002/cncr.29321.
Alice S/Bsip/Science Photo Library
Role of rolapitant in chemotherapy-induced emesis
Published Online August 11, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00096-0 See Articles pages 1071 and 1079
1006
The introduction of two classes of antiemetics has had a major effect on prevention of chemotherapy-induced nausea and vomiting.1 Serotonin (5-HT3) receptor antagonists (eg, ondansetron) in combination with dexamethasone were especially effective at preventing the acute phase of emesis in the first 24 h after chemotherapy of high and moderate emetic potential. Addition of neurokinin-1 (NK-1) receptor antagonists (eg, aprepitant) showed further efficacy, particularly in the delayed phase of emesis, from 24 h to 5 days after chemotherapy.2 Both classes of drugs are available in oral and intravenous formulations, and a fixed combination formulation has been developed.3 A second-generation 5-HT3 receptor antagonist, palonosetron, has a longer duration of action and was more effective than shorter-acting NK-1 receptor antagonists, particularly in moderately emetogenic chemotherapy.4 Rolapitant represents the next generation of NK-1 receptor antagonists, with a long half-life and NK-1 receptor binding for up to 5 days, suggesting that it will also have a longer duration of action. In The Lancet Oncology, Bernardo Rapoport, Lee Schwartzberg, and their colleagues report the findings of three large, phase 3, randomised, active-controlled studies, two in highly emetogenic chemotherapy5 and one in moderately emetogenic chemotherapy,6 in which the efficacy of rolapitant was tested in combination with the 5-HT3 receptor
antagonist granisetron and dexamethasone. In these multinational trials, the primary endpoint was complete control of emesis and no need for rescue medication in acute and delayed phases of emesis, reported by patients’ assessment. Secondary endpoints included nausea. Current evidence-based guidelines for antiemesis with highly emetogenic chemotherapy state that triple antiemetic therapy with a 5-HT3 receptor antagonist, an NK-1 receptor antagonist, and dexamethasone is the standard of care.2 To have a control arm with only two drugs is, therefore, ethically problematic. The only mitigating factor is that sometimes in standard practice only two drugs are used because of a lack of availability of the NK-1 receptor antagonist or the added cost.7 However, there is an issue when trials that aim to register a drug are thought to need a placebo instead of active controls. There is not such an ethical issue with the trial of rolapitant against moderately emetogenic chemotherapy, because palonosetron and steroids have achieved better control of delayed emesis than occurs with highly emetogenic chemotherapy, and the aim of supportive care drugs such as antiemetics should be to use the minimum effective drug doses and combinations to avoid antiemetic side-effects.8 However, as these researchers indicate, a problem with the moderately emetogenic chemotherapy trial is that almost half the patients received chemotherapy based www.thelancet.com/oncology Vol 16 September 2015
Comment
on an anthracycline and cyclophosphamide. Although each of these drugs is classified as moderately emetogenic, the combination was classified as highly emetogenic after initiation of the trial, because without antiemetic prophylaxis at least 90% of patients receiving the regimen without antiemetics would be expected to experience nausea or vomiting. The results of these three studies show that rolapitant improves control of the delayed phase of emesis (>24–120 h after treatment) in patients receiving highly emetogenic chemotherapy, including an anthracycline and cyclophosphamide, and moderately emetogenic chemotherapy.5,6 These trials are among the first to show that addition of an NK-1 receptor antagonist to a 5-HT3 receptor antagonist and a steroid improves prevention of chemotherapy-induced nausea and vomiting more than 24 h after treatment with moderately emetogenic chemotherapy.6 There was less consistency in the acute phase (0–24 h after treatment) of chemotherapy-induced nausea and vomiting, with the moderately emetogenic trial and one of the highly emetogenic studies failing to show a difference between treatment groups in acute emesis, although with better control than placebo over the whole 120 h at-risk period.5,6 This benefit in delayed emesis is achieved without any relevant additional toxicity. In the three studies, some control of nausea was reported; however, as with first-generation NK-1 receptor antagonists (eg, aprepitant), nausea was not as well controlled as was vomiting. It has been suggested that a reason for the poorer control of nausea is that it is part of a multi-component symptom cluster.9 Having shown the benefit of adding rolapitant to granisetron and dexamethasone before highly and moderately emetogenic chemotherapy, the next question is whether longer-acting NK-1 receptor antagonists such as rolapitant will be more effective than first-generation NK-1 receptor antagonists such as aprepitant, which were originally dosed over 3 days but are effective when just given on day 1.10 A trial comparing rolapitant and the shorter-acting NK-1 receptor antagonists is necessary. Combinations with palonosetron would also be instructive. It would be advantageous if such combinations could enable a reduction in the high doses of steroids that are part of current antiemetic regimens. www.thelancet.com/oncology Vol 16 September 2015
An advantage of rolapitant over other NK-1 receptor antagonists is that it is not metabolised by CYP3A4, thereby reducing the chance for possible drug–drug interactions. The dexamethasone dose was reduced in regimens with first-generation NK-1 receptor antagonists and, although not shown to be clinically important, there were potential interactions with drugs as diverse as cytotoxic agents and oral contraceptives. Thus, although these three studies show that rolapitant adds efficacy, particularly in the delayed phase of emesis with moderately and highly emetogenic chemotherapy, rolapitant’s place in routine antiemetic care is yet to be determined. Ian Olver Sansom Institute for Cancer Research, University of South Australia, Adelaide, SA 5001, Australia [email protected] I declare no competing interests. 1 2
3
4
5
6
7
8
9
10
Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008; 358: 2482–94. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Peurgia consensus conference. Ann Oncol 2010; 21 (suppl 5): 232–43. Natale JJ, Spinelli T, Calcagnile S, et al. Drug–drug interaction profile of components of a fixed combination of netupitant and palonosetron: review of clinical data. J Oncol Pharm Pract 2015; published online May 20. DOI:10.1177/1078155215586824. Zhou M, Popovic M, Paetka M, et al. Update on the management of chemotherapy-induced nausea and vomiting: focus on palonosetron. Ther Clin Risk Manag 2015; 11: 713–29. Rapoport BL, Chasen MR, Gridelli C, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol 2015; published online Aug 11. http://dx.doi. org/S1470-2045(15)00035-2. Schwartzberg LS, Modiano MR, Rapoport BL, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol 2015; published online Aug 11. http://dx.doi.org/S14702045(15)00034-0. Yu S, Burke TA, Chan A, et al. Antiemetic therapy in Asia Pacific countries for patients receiving moderately and highly emetogenic chemotherapy: a descriptive analysis of practice patterns, antiemetic quality of care and use of antiemetic guidelines. Support Care Cancer 2015; 23: 273–82. Celio L, Denaro A, Agustoni F, Bajetta E. Palonosetron plus dexamethasone for the prevention of nausea and vomiting due to moderately emetogenic chemotherapy: effect of established risk factors on treatment outcome in a phase III trial. J Support Oncol 2012; 10: 65–71. Olver IN, Eliott JA, Koczwara B. A qualitative study investigating chemotherapy-induced nausea as a symptom cluster. Support Care Cancer 2014; 22: 2749–56. Maru A, Gangadharan VP, Desai CJ, Mohaptra RK, Carides AD. A phase 3 randomized, double-blind study of single-dose fosapreitant for prevention of cisplatin-induced nausea and vomiting: results of an Indian population subanalysis. Indian J Cancer 2013; 50: 285–91.
1007
*Nicolas Wentzensen, Amy Berrington de Gonzalez Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Drive, National Institutes of Health, Bethesda, MD 20892-9774, USA [email protected]
5 6 7
We declare no competing interests. 1
2
3
4
Maguire K, Westhoff C. The state of hormonal contraception today: established and emerging noncontraceptive health benefits. Am J Obstet Gynecol 2011; 205 (4 suppl): S4–8. Beral V, Doll R, Hermon C, Peto R, Reeves G. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87 303 controls. Lancet 2008; 371: 303–14. Havrilesky LJ, Gierisch JM, Moorman PG, et al. Oral contraceptive use for the primary prevention of ovarian cancer. Evid Rep Technol Assess 2013; 212: 1–514. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. BMJ 1968; 2: 199–205.
8 9
10
Brinton LA, Daling JR, Liff JM, et al. Oral contraceptives and breast cancer risk among younger women. J Natl Cancer Inst 1995; 87: 827–35. Kiley J, Hammond C. Combined oral contraceptives: a comprehensive review. Clin Obstet Gynecol 2007; 50: 868–77. Collaborative Group on Epidemiological Studies on Endometrial Cancer. Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies. Lancet Oncol 2015; published online Aug 5. http://dx.doi.org/10.1016/S1470-2045(15)00212-0. Pike MC, Spicer DV. Hormonal contraception and chemoprevention of female cancers. Endocr Relat Cancer 2000; 7: 73–83. Lu KH, Loose DS, Yates MS, et al. Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome. Cancer Prev Res 2013; 6: 774–81. Walker JL, Powell CB, Chen LM, et al. Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer. Cancer 2015; published online March 27. DOI:10.1002/cncr.29321.
Alice S/Bsip/Science Photo Library
Role of rolapitant in chemotherapy-induced emesis
Published Online August 11, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00096-0 See Articles pages 1071 and 1079
1006
The introduction of two classes of antiemetics has had a major effect on prevention of chemotherapy-induced nausea and vomiting.1 Serotonin (5-HT3) receptor antagonists (eg, ondansetron) in combination with dexamethasone were especially effective at preventing the acute phase of emesis in the first 24 h after chemotherapy of high and moderate emetic potential. Addition of neurokinin-1 (NK-1) receptor antagonists (eg, aprepitant) showed further efficacy, particularly in the delayed phase of emesis, from 24 h to 5 days after chemotherapy.2 Both classes of drugs are available in oral and intravenous formulations, and a fixed combination formulation has been developed.3 A second-generation 5-HT3 receptor antagonist, palonosetron, has a longer duration of action and was more effective than shorter-acting NK-1 receptor antagonists, particularly in moderately emetogenic chemotherapy.4 Rolapitant represents the next generation of NK-1 receptor antagonists, with a long half-life and NK-1 receptor binding for up to 5 days, suggesting that it will also have a longer duration of action. In The Lancet Oncology, Bernardo Rapoport, Lee Schwartzberg, and their colleagues report the findings of three large, phase 3, randomised, active-controlled studies, two in highly emetogenic chemotherapy5 and one in moderately emetogenic chemotherapy,6 in which the efficacy of rolapitant was tested in combination with the 5-HT3 receptor
antagonist granisetron and dexamethasone. In these multinational trials, the primary endpoint was complete control of emesis and no need for rescue medication in acute and delayed phases of emesis, reported by patients’ assessment. Secondary endpoints included nausea. Current evidence-based guidelines for antiemesis with highly emetogenic chemotherapy state that triple antiemetic therapy with a 5-HT3 receptor antagonist, an NK-1 receptor antagonist, and dexamethasone is the standard of care.2 To have a control arm with only two drugs is, therefore, ethically problematic. The only mitigating factor is that sometimes in standard practice only two drugs are used because of a lack of availability of the NK-1 receptor antagonist or the added cost.7 However, there is an issue when trials that aim to register a drug are thought to need a placebo instead of active controls. There is not such an ethical issue with the trial of rolapitant against moderately emetogenic chemotherapy, because palonosetron and steroids have achieved better control of delayed emesis than occurs with highly emetogenic chemotherapy, and the aim of supportive care drugs such as antiemetics should be to use the minimum effective drug doses and combinations to avoid antiemetic side-effects.8 However, as these researchers indicate, a problem with the moderately emetogenic chemotherapy trial is that almost half the patients received chemotherapy based www.thelancet.com/oncology Vol 16 September 2015
Comment
on an anthracycline and cyclophosphamide. Although each of these drugs is classified as moderately emetogenic, the combination was classified as highly emetogenic after initiation of the trial, because without antiemetic prophylaxis at least 90% of patients receiving the regimen without antiemetics would be expected to experience nausea or vomiting. The results of these three studies show that rolapitant improves control of the delayed phase of emesis (>24–120 h after treatment) in patients receiving highly emetogenic chemotherapy, including an anthracycline and cyclophosphamide, and moderately emetogenic chemotherapy.5,6 These trials are among the first to show that addition of an NK-1 receptor antagonist to a 5-HT3 receptor antagonist and a steroid improves prevention of chemotherapy-induced nausea and vomiting more than 24 h after treatment with moderately emetogenic chemotherapy.6 There was less consistency in the acute phase (0–24 h after treatment) of chemotherapy-induced nausea and vomiting, with the moderately emetogenic trial and one of the highly emetogenic studies failing to show a difference between treatment groups in acute emesis, although with better control than placebo over the whole 120 h at-risk period.5,6 This benefit in delayed emesis is achieved without any relevant additional toxicity. In the three studies, some control of nausea was reported; however, as with first-generation NK-1 receptor antagonists (eg, aprepitant), nausea was not as well controlled as was vomiting. It has been suggested that a reason for the poorer control of nausea is that it is part of a multi-component symptom cluster.9 Having shown the benefit of adding rolapitant to granisetron and dexamethasone before highly and moderately emetogenic chemotherapy, the next question is whether longer-acting NK-1 receptor antagonists such as rolapitant will be more effective than first-generation NK-1 receptor antagonists such as aprepitant, which were originally dosed over 3 days but are effective when just given on day 1.10 A trial comparing rolapitant and the shorter-acting NK-1 receptor antagonists is necessary. Combinations with palonosetron would also be instructive. It would be advantageous if such combinations could enable a reduction in the high doses of steroids that are part of current antiemetic regimens. www.thelancet.com/oncology Vol 16 September 2015
An advantage of rolapitant over other NK-1 receptor antagonists is that it is not metabolised by CYP3A4, thereby reducing the chance for possible drug–drug interactions. The dexamethasone dose was reduced in regimens with first-generation NK-1 receptor antagonists and, although not shown to be clinically important, there were potential interactions with drugs as diverse as cytotoxic agents and oral contraceptives. Thus, although these three studies show that rolapitant adds efficacy, particularly in the delayed phase of emesis with moderately and highly emetogenic chemotherapy, rolapitant’s place in routine antiemetic care is yet to be determined. Ian Olver Sansom Institute for Cancer Research, University of South Australia, Adelaide, SA 5001, Australia [email protected] I declare no competing interests. 1 2
3
4
5
6
7
8
9
10
Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008; 358: 2482–94. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Peurgia consensus conference. Ann Oncol 2010; 21 (suppl 5): 232–43. Natale JJ, Spinelli T, Calcagnile S, et al. Drug–drug interaction profile of components of a fixed combination of netupitant and palonosetron: review of clinical data. J Oncol Pharm Pract 2015; published online May 20. DOI:10.1177/1078155215586824. Zhou M, Popovic M, Paetka M, et al. Update on the management of chemotherapy-induced nausea and vomiting: focus on palonosetron. Ther Clin Risk Manag 2015; 11: 713–29. Rapoport BL, Chasen MR, Gridelli C, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol 2015; published online Aug 11. http://dx.doi. org/S1470-2045(15)00035-2. Schwartzberg LS, Modiano MR, Rapoport BL, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol 2015; published online Aug 11. http://dx.doi.org/S14702045(15)00034-0. Yu S, Burke TA, Chan A, et al. Antiemetic therapy in Asia Pacific countries for patients receiving moderately and highly emetogenic chemotherapy: a descriptive analysis of practice patterns, antiemetic quality of care and use of antiemetic guidelines. Support Care Cancer 2015; 23: 273–82. Celio L, Denaro A, Agustoni F, Bajetta E. Palonosetron plus dexamethasone for the prevention of nausea and vomiting due to moderately emetogenic chemotherapy: effect of established risk factors on treatment outcome in a phase III trial. J Support Oncol 2012; 10: 65–71. Olver IN, Eliott JA, Koczwara B. A qualitative study investigating chemotherapy-induced nausea as a symptom cluster. Support Care Cancer 2014; 22: 2749–56. Maru A, Gangadharan VP, Desai CJ, Mohaptra RK, Carides AD. A phase 3 randomized, double-blind study of single-dose fosapreitant for prevention of cisplatin-induced nausea and vomiting: results of an Indian population subanalysis. Indian J Cancer 2013; 50: 285–91.
1007