Abstract PD3-11: Efficacy and safety of subcutaneous or intravenous trastuzumab in patients with HER2-positive early breast cancer after 5 years' treatment-free follow-up: Final analysis from the phase III, open-label, randomized HannaH study

Abstract

Background HannaH (NCT00950300) compared subcutaneous and intravenous trastuzumab (H SC and H IV) as neoadjuvant–adjuvant therapy for HER2-positive breast cancer. The co-primary endpoints of pathological complete response (pCR) and serum trough concentration at predose cycle 8 demonstrated noninferiority between H SC and H IV. Efficacy analyses of event-free survival (EFS) and overall survival (OS) at a median follow-up of 40 months supported this noninferiority. Safety analyses also confirmed the consistency of the safety profile across both arms. In this final follow-up analysis, we report the long-term efficacy and safety outcomes at 5 years of treatment-free follow-up (TFFU; 6 years in total). The correlation between total pCR (tpCR; absence of invasive neoplastic cells in ipsilateral nodes and the breast) and EFS was also explored. Methods Enrolled patients (n=596; pts) were randomized to receive 4 cycles of docetaxel, then 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide concurrently with 3-weekly fixed-dose 600mg H SC or H IV (loading: 8mg/kg; maintenance: 6mg/kg) in the neoadjuvant setting. Post-surgery, pts received an additional 10 cycles of H SC or H IV in the adjuvant setting to complete 1 year of anti-HER2 therapy. EFS (time from randomization to local, regional, or distant recurrence, contralateral breast cancer, or death) and OS were calculated using the Kaplan-Meier method. Adverse events (AEs) and serious AEs were recorded and graded per standard criteria. Results In total, 297 pts were randomized to the H SC arm and 299 to the H IV arm; 294 and 297 pts were included in the respective efficacy analysis populations. Median duration of follow-up (including TFFU) was 70.8 and 71.4 months in the H SC and H IV arms, respectively. EFS and OS were similar across both study arms (Table 1). Pts who achieved tpCR had longer EFS and OS vs. those who did not (Table 1). Table 1 H SCH IVHazard Ratio (95% CI)6-year EFS, % (95% CI)n=294n=297 Overall65 (59;70)65 (60;71)0.98 (0.74;1.29)tpCR status*tpCRn=102n=90 80 (73;88)83 (75;91) no tpCRn=158n=173 57 (49;65)61 (54;69) 6-year OS, % (95% CI)n=294n=297 Overall84 (79;88)84 (79;88)0.94 (0.61;1.45)* Efficacy per protocol population Cardiac AE incidence was low and consistent across study arms (Table 2). Table 2Pts, n (%)H SC (n=297)H IV (n=298)Any AE290 (98)282 (95)≥ Grade 3 AE158 (53)160 (54)Serious AE65 (22)45 (15)Cardiac AE44 (15)42 (14)LVEF decline (≥10%-points from baseline to <50%)11 (3.8)12 (4.2)LVEF, left ventricular ejection fraction Conclusion Long-term efficacy EFS and OS results confirmed the noninferiority of H SC compared with H IV, as demonstrated by pCR and pharmacokinetic endpoints. tpCR was associated with longer EFS and OS. The overall safety profile of H SC was consistent with that of H IV. Citation Format: Jackisch C, Stroyakovskiy D, Pivot X, Ahn J-S, Melichar B, Chen S-C, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Efficacy and safety of subcutaneous or intravenous trastuzumab in patients with HER2-positive early breast cancer after 5 years' treatment-free follow-up: Final analysis from the phase III, open-label, randomized HannaH study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-11.

Development of a Subcutaneous Fixed‐Dose Combination of Pertuzumab and Trastuzumab: Results From the Phase Ib Dose‐Finding Study

“…Therefore, it is expected that the maximal clinical benefit will be achieved at these serum concentrations (with SC pertuzumab 600 mg). Because the approved IV pertuzumab regimen is assumed to saturate HER2 receptor binding, predicting maximum clinical efficacy with an SC pertuzumab dose with a noninferior C trough,ss should be appropriate; a noninferior C trough would ensure at least the same degree of target saturation as with IV administration and therefore ensure similar efficacy, as was seen with the development of both SC trastuzumab and SC rituximab …”

“…Fixed‐dose SC trastuzumab has a similar safety profile to that of IV trastuzumab and is noninferior in terms of pathologic complete response and C trough in patients with early breast cancer, supported by long‐term safety and efficacy results (6‐year event‐free survival and overall survival) in the HannaH (enHANced treatment with NeoAdjuvant Herceptin) study (NCT00950300). Similarly, the SABRINA (Subcutaneous Administration BRIdgiNg for PhAse 3) study (NCT01200758) showed that the SC formulation of rituximab had comparable efficacy and safety to the IV formulation and was demonstrated to be noninferior in terms of PK …”

A Multidisciplinary Perspective on the Subcutaneous Administration of Trastuzumab in HER2-Positive Breast Cancer

“…After a median follow-up of 12.2-12.4 months, the sc formulation was shown to be noninferior to the iv formulation, with pcr being 45.4% and 40.7% respectively (difference of 4.7%; 95% ci: 4.0% to 13.4%; noninferiority margin: -12.5%). Moreover, a 6-year follow-up analysis of the HannaH study showed noninferiority for the 6-year event-free survival and os rates, which were 65% and 84% for the two formulations respectively (event-free hazard ratio: 0.98; 95% ci: 0.74 to 1.29; os hazard ratio: 0.94; 95% ci: 0.61 to 1.45) 20 . In addition, all efficacy outcomes were consistent in the bodyweight subgroups 11,19 .…”