New antiemetics: facing the current challenge

New antiemetics: facing the current challenge Revolution starts with evolution. Progress regarding emesis has been highlighted by the American Society of Clinical Oncology Committee (https://www.asco.org/about-asco/press-center/news-releases/asco-50th-anniversary-poll-names-top-5-advances-past-50-years) as one of the five leading advances in cancer during the past 50 years. A new generation of antiemetics is approved by the FDA every 10 years leading to a significant enhancement of a no emesis response rate for patients undergoing chemotherapy. We must remember that 100% of cancer-treated patients were impacted by emesis in the seventies, whereas today, ‘only’ 10%–20% of patients are affected [1, 2]. Before the development of setrons (5HT3 receptor antagonists) there was a daily fight by the patient against vomiting. The NK1 inhibitor’s development has radically altered the face of the emesis battle and we can now effectively assess nausea and individual risk factors [3–5]. Two new antiemetics (NK1 inhibitors) have been recently approved by the FDA: Rolapitant which has a very long half-life (180 h) that may cover the entire delayed phase up to 7 days [6]. Netupitant with a long half-life (96 h), combined with palonosetron, should be reduced to a single capsule 1 h before starting chemotherapy [7–9]. Both have a galenic oral route, leading to a reduction in the out-patient stay and nurse’s care involvement. In their non-inferiority trial, Li et al., has compared a fixed combination of netupitant and palonosetron (NEPA) combined with steroids, versus an aprepitant regimen combined with steroids and granisetron [10], in order to assess the efficacy of a new NK1 inhibitor when compared with the previous antiemetic reference. The results highlighted in their article conclude in favour of the non-inferiority of NEPA. This is the first time, to our knowledge, that a new NK1 inhibitor generation has been compared with the old-fashioned prophylaxis. In previous registration studies, NEPA has been compared with an aprepitant–ondansetron regimen, but this was in a non-pre-planned analysis [8, 9]. All the previously reported studies only compared the new NK1 inhibitors with the association of steroids and setrons. In fact, this association was the control arm of the aprepitant pivotal studies [11]. The response rate levels reached by an aprepitant combined with a standard combination, in some trials have led a 100% protection of breast cancer patients treated with an AC regimen [12]. Some comments should be addressed by the authors: Why conduct a non-inferiority trial? Statistical efficacy as regards nausea. Patient’s characteristics. Cost. Moreover, we must keep in mind that modern medicine likes comparisons and the use of evidence based data. There are very few topics in oncology that have a treatment response rate that can reach 100%. An aprepitant NK1 inhibitor has been available for some time in the cisplatin and Anthracycline–cyclophosphamide (AC) antiemetic prophylaxis [13]. All the recently reported guidelines, published by the various oncological societies, have included all NK1-inhibitors in the prophylaxis of cisplatin, AC regimen and carboplatin [14–16]. With the article by Zhang et al., and their results, the non-inferiority trial opens the door to new perspectives. The challenges we will have to assume with the new antiemetics, in the near future are: nausea assessment and prevention, improvement and individual adaptation of prophylaxis related to individual risk factors, specificities of acute, delayed but also anticipatory phase (including the role of long half-life NK1 inhibitors) and of course, efficacy in anticancer regimens other than cisplatin (AC, moderate emesis chemotherapies, radiotherapy etc.). The long half-life should certainly prompt a new prophylaxis regimen. Patients undergoing weekly or daily chemotherapy targeted treatment, via oral route administration, will only need to take this antiemetic once a week. Compliance to supportive drugs should be improved by taking the medication only on the day before chemotherapy. The interesting impact on the delayed phase should reduce the frequency of emergency visits or consultations. The easy administration will also improve the physician’s interest in emesis, as well as, the major knowledge guidelines and compliance, in order to enhance a no emesis efficacy in daily practice [17]. The global cost of emesis would also be reduced and compared with the price of these new drugs. These are basic questions that should now not only be detailed in superiority trials versus an aprepitant regimen but also between newly created prophylaxis. This trial currently presents a new window of opportunity. It is time now to have the courage to conduct further trials in response to daily questions regarding antiemetics, and to use this new generation of medication towards an effective cancer course. The objective is now to reach a 100% response rate and prevent any vomiting or nausea for this patient population. The first step of revolution is the evolution. Funding None declared. Disclosure I, Florian Scotté, corresponding author, hereby declare Honoraria for advisory boards or consulting with Helsinn, Tesaro, Vifor France, MSD and Norgine. References 1 Gralla RJ, Itri LM, Pisko SE et al.   Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med  1981; 305( 16): 905– 909. Google Scholar CrossRef Search ADS PubMed  2 Grunberg SM, Warr D, Gralla RJ et al.   Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity–state of the art. Support Care Cancer  2011; 19( S1): S43– S47. Google Scholar CrossRef Search ADS PubMed  3 Vidall C, Fernández-Ortega P, Cortinovis D et al.   Impact and management of chemotherapy/radiotherapy-induced nausea and vomiting and the perceptual gap between oncologists/oncology nurses and patients: a cross-sectional multinational survey. Support Care Cancer  2015; 23( 11): 3297– 3305. Google Scholar CrossRef Search ADS PubMed  4 Dranitsaris G, Molassiotis A, Clemons M et al.   The development of a prediction tool to identify cancer patients at high risk for chemotherapy-induced nausea and vomiting. Ann Oncol  2017; 28( 6): 1260– 1267. Google Scholar CrossRef Search ADS PubMed  5 Scotté F. Identifying predictive factors of chemotherapy-induced nausea and vomiting (CINV): a novel approach. Ann Oncol  2017; 28( 6): 1165– 1167. Google Scholar CrossRef Search ADS PubMed  6 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; 16( 9): 1079– 1089. Google Scholar CrossRef Search ADS PubMed  7 Aapro M, Rugo H, Rossi G et al.   A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol  2014; 25( 7): 1328– 1333. Google Scholar CrossRef Search ADS PubMed  8 Gralla RJ, Bosnjak SM, Hontsa A et al.   A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol  2014; 25( 7): 1333– 1339. Google Scholar CrossRef Search ADS PubMed  9 Hesketh PJ, Rossi G, Rizzi G et al.   Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol  2014; 25( 7): 1340– 1346. Google Scholar CrossRef Search ADS PubMed  10 Zhang L, Lu S, Feng J et al.   A randomized phase III study evaluating the efficacy of single-dose NEPA, a fixed antiemetic combination of netupitant and palonosetron, versus an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC). Ann Oncol  2018; 29( 2): 452– 458. 11 Hesketh PJ, Grunberg SM, Gralla RJ et al.   The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol  2003; 21( 22): 4112– 4119. Google Scholar CrossRef Search ADS PubMed  12 Grunberg SM, Dugan M, Muss H et al.   Effectiveness of a single-day three-drug regimen of dexamethasone, palonosetron, and aprepitant for the prevention of acute and delayed nausea and vomiting caused by moderately emetogenic chemotherapy. Support Care Cancer  2009; 17( 5): 589– 594. Google Scholar CrossRef Search ADS PubMed  13 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 Perugia consensus conference. Ann Oncol  2010; 21(Suppl 5): v232– v243. Google Scholar CrossRef Search ADS PubMed  14 Roila F, Molassiotis A, Herrstedt J et al.   2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting in advanced cancer patients. Ann Oncol  2016; 27( 5): v119– v133. Google Scholar CrossRef Search ADS PubMed  15 Hesketh PJ, Kris MG, Basch E et al.   Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol  2017; 35( 28): 3240– 3261. Google Scholar CrossRef Search ADS PubMed  16 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Antiemesis [v1.2017]. https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf (15 November 2017, date last accessed). 17 Aapro M, Molassiotis A, Dicato M et al.   The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol  2012; 23( 8): 1986– 1992. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

New antiemetics: facing the current challenge

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
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1569-8041
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10.1093/annonc/mdx748
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Abstract

Revolution starts with evolution. Progress regarding emesis has been highlighted by the American Society of Clinical Oncology Committee (https://www.asco.org/about-asco/press-center/news-releases/asco-50th-anniversary-poll-names-top-5-advances-past-50-years) as one of the five leading advances in cancer during the past 50 years. A new generation of antiemetics is approved by the FDA every 10 years leading to a significant enhancement of a no emesis response rate for patients undergoing chemotherapy. We must remember that 100% of cancer-treated patients were impacted by emesis in the seventies, whereas today, ‘only’ 10%–20% of patients are affected [1, 2]. Before the development of setrons (5HT3 receptor antagonists) there was a daily fight by the patient against vomiting. The NK1 inhibitor’s development has radically altered the face of the emesis battle and we can now effectively assess nausea and individual risk factors [3–5]. Two new antiemetics (NK1 inhibitors) have been recently approved by the FDA: Rolapitant which has a very long half-life (180 h) that may cover the entire delayed phase up to 7 days [6]. Netupitant with a long half-life (96 h), combined with palonosetron, should be reduced to a single capsule 1 h before starting chemotherapy [7–9]. Both have a galenic oral route, leading to a reduction in the out-patient stay and nurse’s care involvement. In their non-inferiority trial, Li et al., has compared a fixed combination of netupitant and palonosetron (NEPA) combined with steroids, versus an aprepitant regimen combined with steroids and granisetron [10], in order to assess the efficacy of a new NK1 inhibitor when compared with the previous antiemetic reference. The results highlighted in their article conclude in favour of the non-inferiority of NEPA. This is the first time, to our knowledge, that a new NK1 inhibitor generation has been compared with the old-fashioned prophylaxis. In previous registration studies, NEPA has been compared with an aprepitant–ondansetron regimen, but this was in a non-pre-planned analysis [8, 9]. All the previously reported studies only compared the new NK1 inhibitors with the association of steroids and setrons. In fact, this association was the control arm of the aprepitant pivotal studies [11]. The response rate levels reached by an aprepitant combined with a standard combination, in some trials have led a 100% protection of breast cancer patients treated with an AC regimen [12]. Some comments should be addressed by the authors: Why conduct a non-inferiority trial? Statistical efficacy as regards nausea. Patient’s characteristics. Cost. Moreover, we must keep in mind that modern medicine likes comparisons and the use of evidence based data. There are very few topics in oncology that have a treatment response rate that can reach 100%. An aprepitant NK1 inhibitor has been available for some time in the cisplatin and Anthracycline–cyclophosphamide (AC) antiemetic prophylaxis [13]. All the recently reported guidelines, published by the various oncological societies, have included all NK1-inhibitors in the prophylaxis of cisplatin, AC regimen and carboplatin [14–16]. With the article by Zhang et al., and their results, the non-inferiority trial opens the door to new perspectives. The challenges we will have to assume with the new antiemetics, in the near future are: nausea assessment and prevention, improvement and individual adaptation of prophylaxis related to individual risk factors, specificities of acute, delayed but also anticipatory phase (including the role of long half-life NK1 inhibitors) and of course, efficacy in anticancer regimens other than cisplatin (AC, moderate emesis chemotherapies, radiotherapy etc.). The long half-life should certainly prompt a new prophylaxis regimen. Patients undergoing weekly or daily chemotherapy targeted treatment, via oral route administration, will only need to take this antiemetic once a week. Compliance to supportive drugs should be improved by taking the medication only on the day before chemotherapy. The interesting impact on the delayed phase should reduce the frequency of emergency visits or consultations. The easy administration will also improve the physician’s interest in emesis, as well as, the major knowledge guidelines and compliance, in order to enhance a no emesis efficacy in daily practice [17]. The global cost of emesis would also be reduced and compared with the price of these new drugs. These are basic questions that should now not only be detailed in superiority trials versus an aprepitant regimen but also between newly created prophylaxis. This trial currently presents a new window of opportunity. It is time now to have the courage to conduct further trials in response to daily questions regarding antiemetics, and to use this new generation of medication towards an effective cancer course. The objective is now to reach a 100% response rate and prevent any vomiting or nausea for this patient population. The first step of revolution is the evolution. Funding None declared. Disclosure I, Florian Scotté, corresponding author, hereby declare Honoraria for advisory boards or consulting with Helsinn, Tesaro, Vifor France, MSD and Norgine. References 1 Gralla RJ, Itri LM, Pisko SE et al.   Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med  1981; 305( 16): 905– 909. Google Scholar CrossRef Search ADS PubMed  2 Grunberg SM, Warr D, Gralla RJ et al.   Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity–state of the art. Support Care Cancer  2011; 19( S1): S43– S47. Google Scholar CrossRef Search ADS PubMed  3 Vidall C, Fernández-Ortega P, Cortinovis D et al.   Impact and management of chemotherapy/radiotherapy-induced nausea and vomiting and the perceptual gap between oncologists/oncology nurses and patients: a cross-sectional multinational survey. Support Care Cancer  2015; 23( 11): 3297– 3305. Google Scholar CrossRef Search ADS PubMed  4 Dranitsaris G, Molassiotis A, Clemons M et al.   The development of a prediction tool to identify cancer patients at high risk for chemotherapy-induced nausea and vomiting. Ann Oncol  2017; 28( 6): 1260– 1267. Google Scholar CrossRef Search ADS PubMed  5 Scotté F. Identifying predictive factors of chemotherapy-induced nausea and vomiting (CINV): a novel approach. Ann Oncol  2017; 28( 6): 1165– 1167. Google Scholar CrossRef Search ADS PubMed  6 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; 16( 9): 1079– 1089. Google Scholar CrossRef Search ADS PubMed  7 Aapro M, Rugo H, Rossi G et al.   A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol  2014; 25( 7): 1328– 1333. Google Scholar CrossRef Search ADS PubMed  8 Gralla RJ, Bosnjak SM, Hontsa A et al.   A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol  2014; 25( 7): 1333– 1339. Google Scholar CrossRef Search ADS PubMed  9 Hesketh PJ, Rossi G, Rizzi G et al.   Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol  2014; 25( 7): 1340– 1346. Google Scholar CrossRef Search ADS PubMed  10 Zhang L, Lu S, Feng J et al.   A randomized phase III study evaluating the efficacy of single-dose NEPA, a fixed antiemetic combination of netupitant and palonosetron, versus an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC). Ann Oncol  2018; 29( 2): 452– 458. 11 Hesketh PJ, Grunberg SM, Gralla RJ et al.   The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol  2003; 21( 22): 4112– 4119. Google Scholar CrossRef Search ADS PubMed  12 Grunberg SM, Dugan M, Muss H et al.   Effectiveness of a single-day three-drug regimen of dexamethasone, palonosetron, and aprepitant for the prevention of acute and delayed nausea and vomiting caused by moderately emetogenic chemotherapy. Support Care Cancer  2009; 17( 5): 589– 594. Google Scholar CrossRef Search ADS PubMed  13 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 Perugia consensus conference. Ann Oncol  2010; 21(Suppl 5): v232– v243. Google Scholar CrossRef Search ADS PubMed  14 Roila F, Molassiotis A, Herrstedt J et al.   2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting in advanced cancer patients. Ann Oncol  2016; 27( 5): v119– v133. Google Scholar CrossRef Search ADS PubMed  15 Hesketh PJ, Kris MG, Basch E et al.   Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol  2017; 35( 28): 3240– 3261. Google Scholar CrossRef Search ADS PubMed  16 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Antiemesis [v1.2017]. https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf (15 November 2017, date last accessed). 17 Aapro M, Molassiotis A, Dicato M et al.   The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol  2012; 23( 8): 1986– 1992. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

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