Abstract P4-15-11: Advanced HER2 positive breast cancer treated with trastuzumab: Is combination with chemotherapy always needed? Randomized phase III trial SAKK 22/99
Authors: Pagani Olivia , Klingbiel Dirk , Ruhstaller Thomas , Nolè Franco , Eppenberger Serenella , Oehlschlegel Christian , Bernhard Jürg , Brauchli Peter , Hess Dagmar , Mamot Christoph , Munzone Elisabetta , Pestalozzi Bernhard , Rabaglio Manuela , Ribi Karin , Rochlitz Christoph , Rothgiesser Karin , Thürlimann Beat , von Moos Roger , Zaman Khalil , Goldhirsch Aron 
Published: May 2015

Abstract
&lt;Background
In advanced HER2+ breast cancer the impact of combining Trastuzumab (T) and chemotherapy (chemo) versus T alone followed by the addition of chemo at disease progression has not been properly studied.
Study design
The trial compared efficacy, toxicity and quality of life of sequential administration of T followed, at progression, by combination with chemo (T&gt;TChemo) versus the upfront combination of T and chemo (TChemo) in patients with HER2+ advanced breast cancer.
Materials and methods
Eligibility: measurable/evaluable HER2+ advanced disease; ≤2 previous chemo; ECOG performance status &lt;=1. Stratification: degree of HER2 overexpression, estrogen (ER) receptor status, 1st-line vs 2nd/3rd-line therapy, previous anthracyclines, institution. Primary endpoint: time to progression on combined TChemo (TTP-TChemo). Secondary endpoints: response rate, time to 1st progression and to treatment failure, overall survival, toxicity. Substudies: quality of life, predictive value of serum HER2 levels, association of HER2 immunoprofiles with outcome.
The estimated median TTP-TChemo in the control arm (TChemo) was 5-6 months. A 3 months’ increase in the experimental T&gt;TChemo arm was considered meaningful.
The chemo backbone was at investigator’s choice (taxanes, vinorelbine, cisplatin) and could be stopped after 6 cycles in responding patients. T was continued until progression. Treatment after progression under TChemo was by investigators’ decision.
Patients’ characteristics
From Sept 1999–Jan 2013, 175 patients were enrolled. The trial was stopped prematurely due to insufficient accrual. Baseline characteristics were well balanced between arms: median age 55 years (32–79), ER and/or progesterone receptor positive 63%, ≥2 disease sites 91%, dominant bone 36% or dominant visceral disease 66%, 1stline therapy 72%.
Results
At the cutoff date (May 2014) 173 patients were evaluable: median follow up 77.7 months, 29 patients (17%) censored when receiving, at chemo stop, off-protocol treatment before progression (maintenance metronomic chemotherapy or endocrine therapy), 11 patients (6%) had no event at the end of follow-up.
TTP-TChemo was longer than expected in both arms (12.7 months T&gt;TChemo, 10.3 months TChemo) and not significantly different (HR=0.7; 95% CI, 0.5–1.0; p=0.08). In the T&gt;TChemo arm, median TTP before introduction of chemo was 3.7 months (95% CI 2.3–5.1). Overall survival was not significantly different, 35.6 months versus 36.3 months (HR=0.9; 95% CI, 0.6–1.3; p=0.50). Toxicity was mainly chemo related, consistent with the chosen regimen. Cardiac toxicity was mild (no grade 4, 1 cardiac failure NYHA III in the T&gt;TChemo arm). No treatment-related death was reported.
Conclusions
The sequential administration of T and chemo showed a non-significant trend to longer TTP-TChemo compared to upfront combination therapy: it allows to delay chemo use and its toxicity and seems a reasonable approach. TTP-TChemo was better than projected in both arms.
The sequential strategy with double anti-HER2 targeting (T/Pertuzumab) is now under evaluation in 1st-line patients in the SAKK 22/10 trial.
Citation Format: Olivia Pagani, Dirk Klingbiel, Thomas Ruhstaller, Franco Nolè, Serenella Eppenberger, Christian Oehlschlegel, Jürg Bernhard, Peter Brauchli, Dagmar Hess, Christoph Mamot, Elisabetta Munzone, Bernhard Pestalozzi, Manuela Rabaglio, Karin Ribi, Christoph Rochlitz, Karin Rothgiesser, Beat Thürlimann, Roger von Moos, Khalil Zaman, Aron Goldhirsch. Advanced HER2 positive breast cancer treated with trastuzumab: Is combination with chemotherapy always needed? Randomized phase III trial SAKK 22/99 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-11.