Cardiac Safety of NEPA, a Fixed-Dose Antiemetic Combination, Administered Prior to Anthracycline-Based Chemotherapy

Background:

Cardiotoxicity is a well-known risk associated with anthracyclines, a widely prescribed class of chemotherapeutic agents. While the cumulative dose represents the greatest risk factor, concomitant use of other chemotherapy, such as cyclophosphamide can also contribute to this risk. As supportive care agents may be necessary to manage side effects associated with anthracycline treatment, it is critical that these agents do not contribute to the potential for cardiac adverse effects. NEPA is a unique fixed-dose antiemetic combination of netupitant (NETU), a new highly-selective NK₁ receptor antagonist (RA) and palonosetron (PALO), an established pharmacologically distinct 5-HT₃RA with a clean cardiac safety profile (Morganroth, ESMO 2007). Superiority of NEPA over oral PALO in preventing chemotherapy-induced nausea and vomiting associated with anthracycline-cyclophosphamide (AC) chemotherapy was recently demonstrated in a large multicycle study in solid tumors (Aapro, ASCO 2014). Because AC is also part of treatment utilized for hematologic malignancies, such as the CHOP combination, an evaluation of the cardiac safety of NEPA in this study is relevant to the hematology setting.

Methods:

This multinational, randomized, double-blind, parallel group study compared a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) versus a single oral 0.50 mg dose of PALO in chemotherapy-naïve patients receiving AC chemotherapy for solid tumors during cycle 1 and during a multicycle extension. All patients also received oral dexamethasone on Day 1 (12 mg in the NEPA arm and 20 mg in the PALO arm). Cardiac safety was evaluated by cardiac adverse events, ECG changes, cardiac troponin levels (a biomarker used for early detection of cardiotoxicity) and left ventricular ejection fraction (LVEF, by ECHO).

Results:

1450 and 1286 patients were included in the safety population for cycle 1 (n = 725 each group) and the multicycle extension (n = 635 NEPA, 651 PALO), respectively; 76% of all patients completed at least 4 cycles. Treatment groups were comparable with the majority of patients being female (98%) and white (80%), with a mean age of 54 years.

The percentage of patients with at least one treatment-emergent adverse event (AE) classified as a cardiac disorder was similar for both groups in cycle 1 (2.6% NEPA vs. 2.1% PALO) and during the multicycle extension (5.0% vs. 4.6%). Overall, four AEs (n = 1 NEPA, n = 3 PALO) were classified as serious while none were considered related to study treatment. The percent of patients with treatment-emergent ECG abnormalities was comparable between groups. In cycle 1, the most frequently reported abnormalities were flat T waves (12.6% and 12.1% for NEPA and PALO, respectively). ST depression was the same in both groups (6.5%). The mean changes in QTcF were small and similar between groups and returned to baseline at 120 hours. The percentage of patients with increases from baseline of > 60 ms in QTcF were 0.7% and 1.1% for NEPA and PALO, respectively. This pattern for ECG abnormalities and QTcF changes was similar in the multicycle extension with no differences seen between groups. Similar proportions of patients had high troponin levels (ie, >0.12 ng/mL) in cycle 1 (0.1% NEPA vs. 0.3% PALO) and in the multicycle extension (3.4% NEPA vs. 2.9% PALO). Of these, 0.4% NEPA and 0.7% PALO had troponin values greater than 0.50 ng/mL. In the majority of cases, the high values developed in cycles 5 and 6. Mean LVEF changes from screening to end of study were negligible and comparable between groups.

Conclusions:

In this large study of 1450 patients, there was no indication of increased cardiac safety concerns with the NEPA combination relative to PALO after single or repeated cycles of anthracycline-based chemotherapy. Consequently, clinicians can utilize this highly effective convenient, fixed-dose antiemetic drug combination with the knowledge that NEPA is not expected to contribute to the potential for cardiotoxicity seen with anthracyclines or other chemotherapies.