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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Discussion
The MAGIC trial is the first phase 3 efficacy trial in the prevention of CINV in patients receiving HEC using the current guideline-recommended 3-drug antiemetic regimen in both treatment arms.18 Ondansetron was chosen as the appropriate 5-HT3 RA comparator because no other 5-HT3 RA has shown superiority to ondansetron in delayed-phase CINV following HEC. Furthermore, ondansetron is indicated for prevention of nausea and vomiting associated with initial and repeat courses of chemotherapy, including high-dose cisplatin.19 The MAGIC trial primary endpoint was met for the overall study population; in the context of a 3-drug regimen, APF530 demonstrated superior control of delayed-phase CINV following HEC compared with standard-of-care ondansetron.18 As reported previously, significant benefits were also observed with the APF530 regimen over the ondansetron regimen in terms of rescue medication use, patient satisfaction with antiemetic therapy, and nausea frequency in the overall study population.18
Cisplatin is generally regarded as one of the most emetogenic chemotherapeutic agents. For this reason, cisplatin is often evaluated separately in clinical trials, and was a stratification factor in the MAGIC trial. Consistent with the previously reported significant results,18 trends in the cisplatin stratum analysis favored the APF530 regimen, compared with the ondansetron regimen, in delayed- and overall-phase CR (treatment difference: 10.6%).18 Numerical trends presented here favoring the APF530 regimen over the ondansetron regimen were observed in CC and TR, two more stringent measures of CINV control that account for incidence of nausea. Furthermore, among women in the cisplatin stratum, a population at increased risk for CINV, the numerically higher CR, CC, and TR persisted in the APF530 arm, compared with the ondansetron arm.
The APF530 regimen was generally well tolerated in the cisplatin stratum, and no new safety signals were identified. The most common TEAEs were ISRs, mostly mild or moderate and resolving by study end. The double-dummy design resulted in ISRs in the ondansetron arm due to TEG-POE vehicle as the dummy APF530 injection. Transient ISRs have been observed with other agents administered SC, and are expected.20,21 Excluding ISRs, TEAEs were generally consistent with those observed for the 5-HT3 RA class.22
,This analysis of patients randomized to receive cisplatin-based HEC in the MAGIC trial is exploratory and was not sufficiently powered to detect between-arm differences. Five total patients did not go on to receive cisplatin ≥50 mg/m2 as intended at randomization (2 APF530, 3 ondansetron); however, this is not uncommon in large clinical trials and represents less than 2% of patients in this analysis.
Recent phase 3 studies in patients receiving cisplatin-based HEC showed significant improvement in CINV prevention with the current guideline-recommended 3-drug regimen over the traditional 2-drug regimen (5-HT3 RA + dexamethasone).8,23 Results presented here, in a similar population receiving cisplatin-based HEC, suggest that in the context of a 3-drug antiemetic regimen in both treatment arms, APF530 provides additional benefit in CINV prevention compared with the standard of care, ondansetron. Furthermore, a recent phase 3 trial in patients receiving cisplatin or AC-based HEC demonstrated significant improvement in nausea when olanzapine was added to a traditional 3-drug regimen of a 5-HT3 RA, NK-1 RA, and dexamethasone.24 These compelling data support the addition of olanzapine as a fourth agent to the CINV treatment regimen to provide further control of nausea, which has been one of the more difficult components of CINV to control to date.
APF530 is the only 5-HT3 RA to demonstrate superiority over another as part of the guideline-recommended regimen in a 3-drug versus 3-drug phase 3 efficacy trial examining antiemetic efficacy following HEC. Results from the MAGIC trial, this exploratory analysis, and previous studies in MEC and HEC provide clinically meaningful benefits in preventing both acute- and delayed-phase CINV following guideline-specified MEC or HEC regimens. Consequently, APF530 was approved for use in combination with other antiemetics for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of MEC or AC combination chemotherapy regimens.13 Both the superior control of delayed-phase CINV following HEC demonstrated by the MAGIC trial18 and the consistent trends in the cisplatin stratum indicate a particular benefit for high-risk patients receiving high doses of cisplatin.
Acknowledgments
Joanna K Sandilos Rega, PhD, of SciStrategy Communications provided medical writing assistance, supported by Heron Therapeutics Inc, the maker of the study drug.
