APF530 for nausea and vomiting prevention following cisplatin: phase 3 MAGIC trial analysis
Background APF530 is approved for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with initial and repeat moderately emetogenic chemotherapy or anthracycline plus cyclophosphamide (AC) regimens, based on phase 3 trials.
Objective To evaluate APF530 for CINV among cisplatin-stratum patients in the phase 3 MAGIC trial.
Methods Stratification was by planned receipt of cisplatin, with randomization to APF530 500 mg SC or ondansetron 0.15 mg/kg IV. Patients received fosaprepitant 150 mg IV plus dexamethasone 12 mg IV (day 1) and oral dexamethasone 8 mg (once, day 2; twice daily, days 3-4). The primary endpoint was delayed-phase complete response (CR). Other endpoints included CR, complete control (CC), and total response (TR) across phases, time to first rescue medication use, proportion of patients with no rescue medication use, and nausea frequency. Adverse event (AE) assessments included injection-site reactions (ISRs). This analysis evaluated cisplatin-stratum patients.
Results 264 of 942 randomized patients were included in the cisplatin stratum, 252 in the efficacy analyses (124 APF530, 128 ondansetron). Delayed-phase CR was numerically higher with APF530 than ondansetron, with a 10.6% treatment difference (APF530: 65.3% [81/124]; ondansetron: 54.7% [70/128]; P = .085). Similar trends favored APF530 for CC, TR, rescue medication use, and nausea endpoints. APF530 was well tolerated; most AEs were ISRs, generally mild or moderate.
Limitations Exploratory analysis, not powered to detect significant between-arm differences.
Conclusions Consistent with significant results in the overall population, APF530 showed clinical benefits in CINV control in patients scheduled for cisplatin-based regimens.
Funding Heron Therapeutics Inc, maker of the study drug, APF530.
Accepted for publication February 13, 2017
Correspondence Lee Schwartzberg, MD, FACP; lschwartzberg@westclinic. com
Disclosures Dr Schwartzberg has received consulting fees from Heron Therapeutics, the maker of the study drug, outside of the submitted work. Dr Mosier has received personal fees for statistical analysis from EMB Statistical Solutions LLC, outside the submitted work. Dr Geller received personal fees from Heron Therapeutics, during the conduct of the study. Dr Klepper received consulting fees from Heron Therapeutics during the conduct of the study, and consulting fees from Heron Therapeutics, outside the submitted work. Dr Schnadig is the scientific advisor and consultant to Medical Affairs Team at Heron Therapeutics. Dr Vogelzang is a consultant to Heron Therapeutics.
Citation JCSO 2017;15(2):82-88
©2017 Frontline Medical Communications
doi https://doi.org/10.12788/jcso.0331
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Despite available antiemetic therapies, chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC), particularly in the delayed phase (>24-120 h after chemotherapy), continues to impair patient quality of life and chemotherapy compliance.1 Cisplatin-based chemotherapy, classified as HEC at any dose,2 is widely used to treat cancers such as non–small-cell and small
5-hydroxytryptamine type 3 (5-HT3) receptor antagonists (RAs; eg, granisetron, ondansetron, dolasetron, and palonosetron) have been the cornerstone of CINV therapy for decades and remain an integral part of contemporary antiemetic treatment regimens. Most current antiemetic guidelines for HEC recommend a 3-drug regimen, comprising a 5-HT3 RA, a neurokinin 1 (NK-1) RA, and a corticosteroid (dexamethasone).2,6,7 A regimen of olanzapine (antipsychotic), palonosetron (5-HT3 RA), and dexamethasone (corticosteroid) has been recommended as an alternative option. Recently, the oral fixed-dose combination of netupitant and palonosetron (NEPA) was approved and has shown efficacy in the cisplatin setting.8,9 However, the administration of oral medication to patients experiencing CINV and those with head and neck cancer may be difficult.10 Alternative antiemetic treatments that provide CINV control into the delayed phase and with a convenient route of administration, are needed.
APF530 is a novel extended-release granisetron formulation that provides sustained release of therapeutic concentrations for ≥5 days. The Biochronomer tri(ethylene glycol) poly(orthoester) (TEG-POE) vehicle releases granisetron slowly by polymer hydrolysis after it has been injected subcutaneously (SC) into the abdomen or upper arm.11,12 In 2016, the US Food and Drug Administration approved APF530 in combination with other antiemetics for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC) combination chemotherapy regimens based on data from 2 pivotal phase 3 trials.13
,A phase 3 trial demonstrated noninferiority of APF530 (500 mg, SC) to palonosetron (0.25 mg, intravenously [IV]), each with dexamethasone (corticosteroid), in the control of acute-phase CINV after MEC or HEC, and delayed-phase CINV after MEC (classified by Hesketh criteria).14,15 Furthermore, APF530 provided sustained CINV control over multiple cycles of chemotherapy.16 Numerically higher complete response (CR: no emesis, no rescue medication use) rates were observed with APF530, compared with palonosetron, in the delayed phase after HEC (APF530 500 mg, 67.1%; palonosetron 0.25 mg, 64.3%).15
A reanalysis of study endpoints by newer emetogenicity classification guidelines from the American Society of Clinical Oncology (ASCO)7 maintained overall study conclusions.17 Notably, the numerically higher CR rates with APF530 in the delayed phase following HEC were enhanced (APF530 500 mg, 55.8%; palonosetron 0.25 mg, 50.5%), suggesting a need for further examination in this setting. The subsequent APF530 phase 3 MAGIC trial (Modified Absorption of Granisetron In the prevention of CINV; NCT02106494), compared APF530 (500 mg, SC) with ondansetron (0.15 mg/kg, IV), each with fosaprepitant (NK-1 RA) and dexamethasone in patients receiving HEC. The primary endpoint was met: the APF530 regimen demonstrated superior delayed-phase CR compared with the ondansetron regimen (64.7% vs 56.6%; 95% confidence interval [CI]:
1.7-14.4; P = .014; 8.0% absolute improvement).18
APF530 also demonstrated a significant benefit over ondansetron for other endpoints including nausea control, rescue medication use, and satisfaction with antiemetic therapy.18 APF530 is the first and only 5-HT3 RA to demonstrate superiority over another in a phase 3 efficacy trial using a guideline-recommended 3-drug regimen for both arms.
A prespecified MAGIC trial analysis of the primary endpoint by intent to receive cisplatin (≥50 mg/m2, Yes/No) demonstrated a pronounced treatment benefit in terms of delayed-phase CR rates with the APF530 regimen among patients in the cisplatin (≥50 mg/m2, Yes) stratum (CR: 65.3% vs 54.7%; 95% CI: -1.4-22.7; 10.6% absolute improvement).18 These results are compelling, since cisplatin represents a particularly emetogenic class of chemotherapy; a more in-depth analysis of additional MAGIC trial endpoints for these patients would be of clinical interest, and is presented here. Efficacy endpoints in this analysis include CR in the overall and acute phases, complete control (CC) and total response (TR) rates, rescue medication use, nausea frequency, and safety.
Methods
Study design and patients
The MAGIC trial was a prospective, randomized, multicenter, placebo-controlled, double-blind, double-dummy phase 3 trial conducted at 77 centers across the United States. The study protocol was reviewed and approved by the institutional review board at each participating center, and conducted according to the Declaration of Helsinki. The study design, previously presented in detail,18 is reviewed briefly here.
