New formulation, new drug? The importance of assessing the safety of new supportive care formulations in oncology
Authors: K. Jordan
Journal: Annals of Oncology (2018)

The discovery and development of new medicines is a long, complex and rigorous process with every step aimed at bringing effective medicines to patients as quickly as possible, while ensuring the highest possible level of safety. In oncology, one of the primary goals of supportive care is to avoid or eliminate the adverse effects associated with anticancer therapy. Therefore a supportive care drug has to be effective and safe, with minimal side-effects, thereby improving the overall quality of life for patients. Recent research revealing that adherence to guideline recommendations for antiemetic prophylaxis is suboptimal [1.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: 1986-1992Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 2.Clark-Snow R. Affronti M.L. Rittenberg C.N. Chemotherapy-induced nausea and vomiting (CINV) and adherence to antiemetic guidelines: results of a survey of oncology nurses.Support Care Cancer. 2017; Google Scholar] suggests that clinicians may not be as focused on supportive care agents as they are on anticancer treatments. The European Society for Medical Oncology (ESMO) recently issued a position paper, advocating for holistic patient-centered care, including supportive and palliative care, to be personalized and integrated with anticancer treatment by a multidisciplinary team, from the time of diagnosis and throughout the continuum of disease [3.Jordan K. Aapro M. Kaasa S. et al.Position paper on supportive and palliative care.Ann Oncol. 2018; 29: 36-43Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar]. Patient-reported outcomes should also be encouraged as monitoring these closely has been shown to be associated with better quality of life, fewer hospitalizations and even increased survival compared with usual care [4.Basch E. Deal A.M. Dueck A.C. et al.Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment.JAMA. 2017; 318: 197-198Crossref PubMed Scopus (1056) Google Scholar]. While prevention of chemotherapy-induced nausea and vomiting (CINV) has been revolutionized over the past 25 years, antiemetic research continues with the goal of optimizing CINV control for every patient [5.Jordan K. Jahn F. Aapro M. Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review.Ann Oncol. 2015; 26: 1081-1090Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar]. Emerging from the most recent research is the first combination antiemetic (NEPA), designed to simplify dosing for patients by combining an NK1 receptor antagonist (RA), netupitant, with a 5-HT3 RA, palonosetron. Clinical studies leading to the approval of oral NEPA demonstrated superiority of NEPA plus dexamethasone (DEX) over palonosetron plus DEX in preventing CINV in patients receiving various emetogenic chemotherapy [6.Hesketh P.J. 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: 1340-1346Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 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: 1328-1333Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. In addition, a single dose of NEPA was non-inferior to a 3-day aprepitant regimen in preventing CINV in patients receiving highly emetogenic chemotherapy (HEC) in a recent phase III trial [8.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: 452-458Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. The safety of oral NEPA was also well-established in the phase II/III clinical program in single or repeated cycles [9.Gralla R.J. Bosnjak S.M. 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: 1333-1339Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 10.Aapro M. Hesketh P.J. Jordan K. et al.Safety of an oral fixed combination of netupitant and palonosetron (NEPA): pooled data from the phase II/III clinical program.Oncologist. 2016; 21: 494-502Crossref PubMed Scopus (13) Google Scholar]. NEPA might have the potential to overcome some barriers interfering with administration of guideline-recommended antiemetics should healthcare providers perceive the recommended multi-agent prophylactic combinations to be too complex. Providing alternate drug formulations offers numerous advantages: it improves the ability of clinicians to manage specific administration-related challenges, offers options for patients who may have a preference, and addresses the varying country-specific regulatory, commercial, or reimbursement associated challenges and preferences. A fixed intravenous (i.v.) combination formulation of NEPA was subsequently developed using a water-soluble phosphorylated pro-drug of netupitant called fosnetupitant. A pharmacokinetic study was done and confirmed the bioequivalence of the selected dose of fosnetupitant in the i.v. formulation (235 mg) with the dose of netupitant in the oral NEPA formulation (300 mg) for area under the plasma concentration curve. In this issue of Annals of Oncology, Schwartzberg et al. [11.Schwartzberg L. Roeland E. Andric Z. et al.Phase III safety study of intravenous NEPA: a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy.Ann Oncol. 2018; 29: 1535-1540Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar] report the results of a subsequent phase III study conducted to evaluate the safety and tolerability of a single dose of i.v. NEPA administered with DEX over initial and repeated cycles of HEC. One might ask, 'with demonstrated bioequivalence to the approved formulation, is another study really needed or of interest?' A recent case in point was the approval of the i.v. formulation of rolapitant, another novel NK1 RA. The approval of i.v. rolapitant was based solely on demonstrated pharmacokinetic bioequivalence of the new i.v. formulation with the approved oral formulation [12.Wang X. Zhang Z. Powers D. et al.Bioequivalence of intravenous and oral rolapitant: results from a randomized, open-label pivotal study.J Clin Pharmacol. 2017; 57: 1600-1606Crossref PubMed Scopus (16) Google Scholar]. In the first month on the market, anaphylaxis, anaphylactic shock and other serious hypersensitivity reactions were reported during or soon after administration of i.v. rolapitant, leading the Food & Drug Administration to mandate an update to the product label with warnings/precautions regarding the potential for these events [13.Varubi® (Rolapitant) Injectable Emulsion, for Intravenous Use. US Prescribing Information. TESARO, Inc, Waltham, MA2018Google Scholar, 14.U.S. Food & Drug Administration, Safety Alerts for Human Medicinal Products. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm592592.htm (27 February 2018, date last accessed).Google Scholar] and leading the manufacturer to suspend its commercial distribution. In light of these recent findings the results of the i.v. NEPA study become even more pertinent. Importantly, this study assessed the safety of i.v. NEPA over multiple cycles. An oral NEPA treatment group was included to help interpret any unexpected safety finding in the i.v. NEPA group. A total of 404 chemotherapy-naïve patients completed 1312 cycles, with 667 exposures to i.v. NEPA. Schwartzberg et al. report the key safety findings as follows: the incidence and type of treatment-emergent adverse events (AEs) were similar for both treatment groups with the majority of AEs mild/moderate in intensity. There was no increased incidence of AEs, whether treatment-related or not, in subsequent cycles in either treatment group. Before the recent reports of infusion site reactions associated with i.v. rolapitant, similar reactions were reported for fosaprepitant [15.Emend® (fosaprepitant) for injection, for intravenous use. US Prescribing Information. Merck & Co, Inc., Whitehouse Station, NJ, USA 2017.Google Scholar, 16.Grunberg S. Chua D. Maru A. et al.Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with cisplatin therapy: randomized, double-blind study protocol – EASE.J Clin Oncol. 2011; 29: 1495-1501Crossref PubMed Scopus (178) Google Scholar], with a precaution/warning statement regarding the potential for hypersensitivity reactions in the product label [15.Emend® (fosaprepitant) for injection, for intravenous use. US Prescribing Information. Merck & Co, Inc., Whitehouse Station, NJ, USA 2017.Google Scholar]. Reassuringly, there were no injection site reactions considered to be related to i.v. NEPA over repeated cycles and no instance of anaphylaxis with either formulation of NEPA, though one instance of hypersensitivity was reported (0.5%) for a patient receiving oral NEPA. Post-marketing surveillance of these events will be important. Given the inherent purpose of a supportive care drug, it is important for clinicians to thoughtfully consider the benefit/risk profile of these agents in the context of their purpose and each patient's situation. Not only do these drugs need to be effective at preventing or minimizing the side-effects for which they are intended, but they should have few, if any, side-effects associated with them. While the advances in supportive care have been substantial over the past 20 years, the multitude of options creates new challenges for clinicians. With the number of currently available supportive care interventions and guidelines, such as antiemetics, recommending multi-agent regimens, it is important to consider potential drug–drug interactions when making decisions. Is it possible to take into account all possible interactions and potential side-effects and be reassured that it is safe for the patient? Moreover, one wonders when it is necessary to administer four drugs, as is the case for the olanzapine antiemetic regimen [17.Hesketh P.J. Kris M.G. Basch E. et al.Antiemetic: American Society of Clinical Oncology: Clinical Practice Guideline Update.J Clin Oncol. 2017; 35: 3240-3261Crossref PubMed Scopus (364) Google Scholar], in order to prevent two symptoms, nausea and vomiting? The initiatives by various organizations advocating for integrating supportive care into the broader treatment plan for patients, along with implementation of patient-reported outcomes should help. Additionally, studies such as those reported by Schwartzberg et al. at least offer reassurance about the initial safety of new agents or new formulations of supportive care agents. None declared.