Raftopoulos, H., Cooper, W., O'Boyle, E., Gabrail, N., Boccia, R., & Gralla, R.J. (2015). Comparison of an extended-release formulation of granisetron (APF530) versus palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated with moderately or highly emetogenic chemotherapy: Results of a prospective, randomized, double-blind, noninferiority phase 3 trial. Supportive Care in Cancer, 23, 723–732. 

To compare two dose levels of AFP530 and palonosetron in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) after moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC)

Eligible patients were 18 years of age or older with a confirmed malignancy scheduled to receive single-day MEC or HEC defined by the Hesketh algorithm. Patients were stratified according to their chemotherapy emetogenicity (MEC or HEC) and randomized 1:1:1 to receive APF530 at 250 mg subcutaneously (granisetron 5 mg) plus a placebo IV; APF530 at 500 mg subcutaneously (granisetron 10 mg) plus a placebo IV; or palonosetron IV at 0.25 mg plus a placebo subcutaneously prior to chemotherapy. After cycle 1, all patients were invited to continue in the study. If they consented, they were rerandomized to maintain blinding, but only patients who received IV palonosetron in cycle 1 were actually randomized 1:1 to receive APF530 at 250 or 500 mg subcutaneously for less than or equal to three subsequent cycles. Efficacy measures were determined from patient diaries in which patients recorded emetic episodes, rescue medications, and the severity of nausea for each 24-hour period after chemotherapy.

• N = 1,396 (653 received MEC, 742 received HEC)
• MEAN AGE RANGE = 54.8–58.1 years 
• MALES: 27.2%–12.25%, FEMALES: 62.8%–87.75% (across treatment arms and emetogenicity strata)
• KEY DISEASE CHARACTERISTICS: 63.3%–69.5% patients with breast cancer receiving MEC; 25.4%–32.8% patients with lung cancer; and 25.4%–27.6% patients with breast cancer receiving HEC
• OTHER KEY SAMPLE CHARACTERISTICS: Greater than half of the patients received prior chemotherapy. Eastern Cooperative Oncology Group performance statuses were greater than or equal to 2.

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: 103 centers in the United States, Poland, and India

• PHASE OF CARE: Active antitumor treatment

Prospective, multicenter, randomized, double-blinded, double-dummy, parallel-group, phase 3 trial

• Efficacy measures were determined from diaries in which patients recorded emetic episodes, rescue medications, and the severity of nausea for each 24-hour period after chemotherapy.

The original analysis under the Hesketh criteria for emetogenicity demonstrated that AFP530 at 250 and 500 mg subcutaneously was noninferior to palonosetron as assessed by complete response (CR) in the control of acute CINV after MEC (CR rates of 74.8% and 76.9%, respectively, versus 75% for palonosetron). The result was similar for patients receiving HEC with acute CR rates of 77.7% and 81.3% for APF530 at 250 mg and 500 mg, respectively, versus 80.7% for palonosetron. APF530 at 500 mg subcutaneously also was noninferior to palonosetron in preventing delayed CINV after MEC with a CR rate of 58.5% versus 57.2% for palonosetron. The superiority of APF530 at 250 or 500 mg subcutaneously versus palonosetron at 0.25 mg IV in preventing delayed CINV after HEC in cycle 1 was not determined. However, CR rates were similar for APF530 at 500 mg subcutaneously and palonosetron at 0.25 mg IV. In a post hoc analysis, patients receiving chemotherapy regimens whose antiemetic risk had been revised according to the updated antiemetic practice guidelines (notably cyclophosphamide plus anthracyclines [reclassified from MEC to HEC] and carboplatin-based regimens [reclassified from HEC to MEC]) were reclassified at the request of the U.S. Food and Drug Administration. The results of this reanalysis showed no notable statistic or clinical difference in response rates between APF530 and palonosetron.

A single, subcutaneous APF530 injection offered a convenient alternative to palonosetron for preventing acute and delayed CINV after MEC or HEC with similar safety profiles.

• Measurement/methods not well described
• Other limitations/explanation: Patient diaries and ratings were not clearly described. Chemotherapy was single-day only, and nausea and vomiting was measured for only a 24-hour period.

Single-dose APF530 subcutaneously was noninferior to palonosetron at 0.25 mg IV for controlling acute CINV in patients who received single-day MEC or HEC as determined by CR. This provides another option for antiemetic chemotherapy premedication. Because of changing emetic classifications, antiemetic study interpretation can be a complicated process. The findings of this study cannot be generalized to multiday chemotherapeutic regimens because multiday chemotherapeutic regimens were not included in the design of the study.