New Antiemetic Compares Favorably With Standard for Cisplatin Regimens

Lee Schwartzberg, MD

An investigational extended-release formulation of the antiemetic granisetron achieved a complete response more often than did ondansetron in cancer patients receiving highly emetogenic cisplatin-based chemotherapy, a new analysis of a randomized trial showed.¹

The proportion of patients who had complete response in the delayed phase of chemotherapy administration was 64.8% with APF530 compared with 56.3% of patients randomized to ondansetron. Secondary endpoints—including complete response in the acute phase and overall, complete control, and total response—all favored the investigational antiemetic, as reported at the 2016 Society of Gynecologic Oncology Annual Meeting.

The findings were consistent with those of the overall trial, which showed a statistically significant improvement in complete response with APF530. As a post-hoc analysis, the results in the cisplatin-treated subgroup lacked statistical power to demonstrate significant differences between treatment groups.

“Relatively few studies have looked at management of chemotherapy-induced nausea and vomiting (CINV) in patients treated with platinum-based regimens,” said Lee Schwartzberg, MD, a medical oncologist at the West Clinic in Memphis, Tennessee. “The data from this trial provided an opportunity to do that, and we found that the results were the same as in the overall trial, which was driven by a majority of patients who were receiving AC (doxorubicin/cyclophosphamide) chemotherapy.”

APF530 consists of 2% granisetron in a proprietary viscous bioerodible vehicle that undergoes controlled hydrolysis after administration to effect extended release of granisetron for prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). A single subcutaneous dose of APF530 has been shown to achieve and maintain therapeutic levels of granisetron for at least 5 days.²

Schwartzberg and colleagues reported findings from a subgroup analysis of the phase III MAGIC trial, which compared APF530 and ondansetron—each in combination with the neurokinin-1 receptor antagonist fosiprepitant and dexamethasone—in 942 patients receiving highly emetogenic chemotherapy regimens for cancer. The trial had a primary endpoint of complete response (CR), defined as no emesis and no use of rescue medication for CINV during the delayed phase (24-120 hours).

As reported at the 2015 meeting of the American Society of Clinical Oncology, the primary analysis showed that the APF530 treatment group had a significantly higher rate of CR: 64.7% vs. 56.6% (P = .014). The positive results made APF530 the first 5-HT3 receptor antagonist to demonstrate superiority versus another drug in the class when administered as part of the guideline-recommended regimen in a three-drug versus three-drug phase III efficacy trial.

The posthoc subgroup analysis comprised 251 patients treated with cisplatin-based chemotherapy, the most common combination being cisplatin plus gemcitabine (27.1%). The type of cancer for the indicated chemotherapy was not recorded.

As in the overall trial, the primary endpoint for the subgroup analysis was CR during the delayed phase. Secondary endpoints included CR in the acute phase and overall; complete control (CR plus no more than mild nausea); and total response (CR and no nausea).

The analysis yielded a primary outcome (8.5% absolute difference in favor of APF530) almost identical to that of the overall trial (8.0% absolute difference). Acute-phase complete response rates were 84.0% with APF530 and 80.2% with ondansetron, and overall complete response rates were 60.8% and 54.8%.

For the endpoint of complete control, all comparisons favored the APF530 group: delayed phase (61.6% vs 53.2%); overall (58.4% vs 50.8%), and acute phase (84.0% vs 76.2%). Total response rates were 48.0% for APF530 and 45.2% for ondansetron in the delayed phase, 48.0% versus 44.4% overall, and 81.6% versus 73.8% during the acute phase.

As an exploratory objective, Schwartzberg and colleagues also evaluated response among female patients who accounted for 45% of the subgroup. The analysis showed that most of the endpoints were numerically greater for APF530 as compared with the total subgroup. Absolute differences in complete response were 10.3% in the delayed phase, 10.0% overall, and 8.9% in the acute phase.

“Women tend to have more CINV than men, and platinum-based chemotherapy regimens are often used to treat gynecologic malignancies,” said Schwartzberg. “We found that women on platinum-based chemotherapy regimens actually fared numerically better than the rest of the subgroup and the overall study population.”

A spokesperson for Heron Therapeutics said the company is awaiting final word from the FDA on an application for approval. The company is seeking approval for use of APF530 in the management of CINV associated with both highly emetogenic and moderately emetogenic chemotherapy regimens.

References

1. Schwartzberg L, Mosier M, Payne Y, et al. Phase III trial of APF530 versus ondansetron, each with a neurokinin I antagonist and corticosteroid, for prevention of chemotherapy-induced nausea and vomiting in highly emetogenic chemotherapy regimens (MAGIC Trial): outcomes in cisplatin-based regimens. Presented at: 2016 SGO Annual Meeting. March 19-22, 2016. San Diego, CA. Abstract 5988.
2. Gabrail N, Yanagihara R, Spaczynski M, et al. Pharmacokinetics, safety, and efficacy of APF530 (extended-release granisetron) in patients receiving moderately or highly emetogenic chemotherapy: results of two phase II trials. Cancer Manag Res. 2015; 7:83-92.

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