Abstract PD4-08: An FDA analysis of survival outcomes comparing adjuvant paclitaxel and trastuzumab trial (APT) to an external control from historical clinical trials
Authors: Amiri-Kordestani Laleh , Xie Diqiong , Bloomquist Erik , Tang Shenghui , Pazdur Richard , Sridhara Rajeshwari , Tolaney Sara M , Winer Eric P , Beaver Julia A 
Published: March 2020

Abstract
Background: The Adjuvant Paclitaxel and Trastuzumab (APT) trial was a single-arm trial in patients with small node-negative HER2-positive early breast cancer (EBC). Although the regimen used in the APT trial has been adopted clinically, single-arm trials have limitations, and interest remains if these patients, particularly those with T1c or T2 disease would benefit from more intensive chemotherapy.
Methods: Patient-level data from five randomized trials (BCIRG 006, NSABP-B31, HERA, N-9831, and APHINITY) submitted to FDA to support drug approval in adjuvant HER2-positive EBC were pooled (n=19087). Patients treated concurrently with trastuzumab and either anthracycline/cyclophosphamide/taxane (ACTH) (n=932), or taxane/carboplatin (TCH) (n=434), 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 on the APT trial. Propensity score models included age, tumor size (Tim/T1a, T1b, T1c, T2), grade, and hormone receptor status. Invasive disease-free survival (iDFS) and overall survival (OS) were compared between patients treated with ACTH or TCH and patients treated with TH from the APT trial, and between patients treated with ACT and TH.
Results: After matching, 305 patients were included from the APT trial and 305 patients from the trastuzumab containing external control (ACTH or TCH). One hundred and sixty-nine patients from the APT trial were also matched to 169 patients from the ACT external control. The propensity score matching adequately balanced the patients’ baseline age and disease characteristics (Table 1). The iDFS and OS results are shown in Table 2. Similar results were observed when comparing patients who received ACTH versus TH, and comparing patients who received TCH versus TH. Similar results were also seen in trastuzumab-based treatment subgroups based on tumor size.
Conclusions: External controls can be useful to contextualize single arm studies. These exploratory analyses further support the use of de-escalated therapy in patients with low-risk HER2-positive EBC.
Table 1: Demographics and Disease CharacteristicsAPT (TH) N = 305External Control (ACTH/TCH) N = 305Std. Mean Diff (%)Age (Yrs), Mean (Std)54.6 (10.7)54.7 (9.8)1.1Primary Tumor Size (cm), Mean (Std)1.3 (0.6)1.4 (0.6)19.7Tumor Stage, n (%)T1ami16 (5.3)11 (3.6)-8.0T1b93 (30.5)95 (31.2)1.4T1c162 (53.1)166 (54.4)2.6T234 (11.2)33 (10.8)-1.1Grade, n (%)G119 (6.2)20 (6.6)1.3G2107 (35.1)95 (31.2)-8.4G3179 (58.7)190 (62.3)7.4ER+, n (%)198 (64.9)200 (65.6)1.4PR+, n (%)158 (51.8)157 (51.5)-0.7HR+, n (%)204 (66.9)202 (66.2)-1.4
APT (TH) N = 169External Control (ACT) N = 169Std. Mean Diff (%)Age (Yrs), Mean (Std)51.9 (10)52.5 (8.9)6.7Tumor Size (cm), Mean (Std)1.5 (0.6)1.6 (0.6)24.3Tumor Stage, n (%)T1ami6 (3.6)6 (3.6)0T1b30 (17.8)25 (14.8)-8.0T1c103 (61.0)109 (64.5)7.4T230 (17.8)29 (17.2)-1.6Grade, n (%)G13 (1.8)3 (1.8)0G252 (30.8)52 (30.8)0G3114 (67.5)114 (67.5)0ER+, n (%)100 (59.2)93 (55.0)-8.4PR+, n (%)81 (47.9)79 (46.8)-2.4HR+, n (%)103 (61.0)100 (59.2)-3.6
Table 2: iDFS and OSAPT (TH) (%)External Control (ACTH/TCH) (%)iDFS3 yrs98.6 (96.4, 99.5)96.6% (93.7, 98.1)5 yrs96.5 (93.6, 98.1)92.9% (88.2, 95.8)OS3 yrs99.7 (97.6, 100.0)99.0% (96.9, 99.7)5 yrs99.3 (97.2%, 99.8)97.4 (94.5, 98.7)APT (TH) (%)External Control (ACT) (%)iDFS3 yrs98.8 (95.3, 99.7)91.3 (85.7, 94.7)5 yrs96.1 (91.5, 98.2)83.5 (76.5, 88.6)OS3 yrs100 (NA, NA)97.4 (93.3, 99.0)5 yrs99.3 (95.3, 99.9)94.0 (88.8, 96.8)
Citation Format: Laleh Amiri-Kordestani, Diqiong Xie, Erik Bloomquist, Shenghui Tang, Richard Pazdur, Rajeshwari Sridhara, Sara M Tolaney, Eric P Winer, Julia A Beaver. An FDA analysis of survival outcomes comparing adjuvant paclitaxel and trastuzumab trial (APT) to an external control from historical clinical trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-08.