An FDA Analysis of Survival Outcomes Comparing an Adjuvant Paclitaxel and Trastuzumab Trial to an External Control from Historical Clinical Trials

ABSTRACT Background Although the Adjuvant Paclitaxel and Trastuzumab (APT) trial has been adopted clinically, single-arm trials have limitations, and interest remains whether these patients with small node-negative HER2-positive early breast cancer (EBC) would benefit from more intensive chemotherapy. This analysis explored whether external controls can contextualize single-arm studies to add to clinical decision-making in the use of de-escalated therapy in patients with low-risk HER2-positive EBC. Patients and Methods Patient-level data from five randomized trials supporting drug approval in adjuvant HER2-positive EBC were pooled, and patients with low-risk EBC were selected (n=1770). Patients treated concurrently with trastuzumab and either anthracycline/cyclophosphamide/taxane (ACTH) or taxane/carboplatin (TCH) (n=1366) were matched (1:1) to patients treated with paclitaxel and trastuzumab (TH) in the APT trial (n=406) using propensity scores. Patients treated with anthracycline/cyclophosphamide/taxane (ACT) (n=374) were also matched (1:1) to those treated with TH. Propensity score were estimated using covariates of age, tumor stage, ER status, PR status, and histological grade. Results After matching, the estimated probabilities of invasive disease-free survival (iDFS) at 3 and 5 years were 98·6% and 96·5% in the TH arm, and 96·6% and 92·9% in the ACTH/TCH arm. The estimated probabilities of overall survival (OS) at 3 and 5 years was 99·7% and 99·3% in the TH arm, and 99·0% and 97·4% in the ACTH/TCH arm, respectively. Comparing TH arm to ACT arm in the matched sample, the estimated difference in iDFS was 7·5% (TH 98·8% and ACT 91·3%) at 3 years and 12·6% (TH 96·1% and ACT 83·5%) at 5 years. The estimated difference in OS was 2·6% (TH 100% and ACT 97·4%) at 3 years, and 5·3% (TH 99·3% and ACT 94%) at 5 years. Conclusions Our analyses suggest that patients' outcomes in both arms were in general similar, thus providing additional reassurance regarding de-escalation of therapy.