Interim cardiac safety analysis of NCCTG N9831 Intergroup adjuvant trastuzumab trial

Abstract

556 Background: NCCTG N9831 is a 3-arm randomized Phase III trial comparing safety and efficacy of AC followed by weekly paclitaxel (T) (Arm A) vs the same chemotherapy with 1 yr of trastuzumab (H) either after (Arm B) or starting with T (Arm C). Clinical and asymptomatic cardiac tolerability is the focus of this abstract. Methods: Women with normal left ventricular ejection fraction (LVEF) assessed by MUGA or echocardiogram scan were eligible. LVEF evaluation was repeated post-AC, 6, 9 and 18 months post entry. Clinical cardiac evaluation occurred as a continuum. A Cardiac Safety DMC reviewed asymptomatic and symptomatic LVEF changes monthly. Interim analyses were planned after 100, 300, and 500 evaluable pts per arm began post-AC therapy and were followed for additional 6 months. Primary endpoint was proportion of cardiovascular (CV) events in each arm (congestive heart failure (CHF) and definite or probable cardiac deaths). A difference of 4% would trigger suspension or closure of the H-containing study arms. Results: 3rd interim analysis comparing the cardiac safety on Arms A and B included 1126 women (544 on Arm A and 572 on Arm B) who had a satisfactory post-AC cardiac evaluation (7.3% on Arm A and 3.3% on Arm B were unsatisfactory (significant cardiac symptoms, LVEF below facility’s lower limit of normal, or LVEF drop >15 percentage points) and prohibited from taking H). There were 0 (0%; 95% CI: 0–0.7%) CV events on Arm A and 13 (2.2%; 95% CI: 1.2–3.8%) CV events on Arm B. Among the 13 CV events on Arm B, 12 pts had confirmed cases of CHF and 1 pt experienced a cardiac death. Follow-up data on pts experiencing CV events has been gathered and will be presented. The 3rd interim cardiac analysis comparing cardiac events in Arms A and C expected Spring 2005. Conclusions: There is an increase in cardiac toxicity with H but it remains less than the threshold of 4% prospectively designated as a stopping rule. By that criteria, AC → T vs AC → T → H manifests acceptable cardiac safety data in the adjuvant treatment setting. Enrollment continues for all arms anticipating completion in Spring 2005. Long-term follow-up is needed to determine the impact of the adverse CV events reported at this time. Supported by the Breast Cancer Research Foundation, Genentech, NIH CA25224. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Bristol-Myers Squibb, Eli Lilly, Genentech, Pfizer