Abstract P4-01-25: Safety analysis after 11 years of follow-up of the randomized phase III trial SAKK22/99: upfront chemotherapy in advanced HER2 positive breast cancer
Authors: Rabaglio Manuela , Dietrich Daniel , Scheibe Bernhard , Ruhstaller Thomas , Nole Franco , Eppenberger Serenella , Oehlschlegel Christian , Hess Dagmar , Mamot Christoph , Munzone Elisabetta , Pestalozzi Bernhard , Aebi Stefan , Vetter Marcus , Thuerlimann Beat , von Moos Roger , Zaman Khalil , Pagani Olivia 
Published: March 2023

Abstract
Background: The SAKK 22/99 is a phase III randomized clinical trial launched by the Swiss Group for Clinical Cancer Research and the European Institute of Oncology in Milan in 99 for women with HER2-positive advanced breast cancer (ABC). 175 patients were randomized 1:1 from Sept 99 to Jan 2013 to receive first-line trastuzumab (T) alone followed at disease progression by the combination with chemo (Arm A) vs the upfront combination of T and chemo (Arm B). The results were published in 2017 (O. Pagani et al Ann Onc 28: 305–312, 2017). The outcome was similar for sequential T-chemo or upfront combination The patients’ treatment and FU continued until March 2022 and we now report the safety data after 135.2 months of median FU.
Patients and methods: at the time of study termination 1 patient with SD was still receiving T alone in the study and T was continued after trial closure. The safety analyses include 86 pts allocated to arm A and 88 to arm B. 1 pt did not receive any trial treatment and was excluded from this analyses. 19 of the 86 patients in arm A stopped trial treatment after T alone, 67 continued with T+ chemo. Baseline characteristics were well balanced and are summarized in Table 1. Treatment The T loading dose of 4 mg/kg/iv was followed by 2 mg/kg/iv weekly. In the 1st-line population (84) chemo was weekly paclitaxel (90 mg/m2/iv-3/4 weeks). After amendment 1 chemo was at investigator’s choice (taxanes, vinorelbine, platin) according to label indications and could be stopped after 24 weeks (6–8 cycles) in responding patients or after unacceptable toxicity.
Results: 7 patients in arm A (8%) and 11 in arm B (13%) stopped trial treatment due to toxicities (Fisher’s exact test, p=0.46). 3 of the 7 patients in arm A stopped under T alone and 4 under T+chemo (all paclitaxel weekly) Treatment durations of these 7 and 11 patients were 7.7 months (range 0.5 – 49) in arm A and 5.5 months (range 0.6 – 31 months) in arm B, respectively. Cardiovascular toxicities: The most common toxicities were thromboembolic events, blood pressure disorders and arrhythmia. 6 patients (7%) in arm A and 10 (11%) in arm B had cardiac events (Fisher’s exact test, p=0.43). G1-3 toxicities occurred in 2 (2%), 2 (2%) and 2 (2%) patients of arm A and in 5 (7%), 2 (2%) and 3 (3%) of arm B. We observed no grade 4 events. Split by treatment phase in arm A, G1-3 toxicities were seen in in 1 (1%), 2 (2%) and 1 (1%) patient under T alone (N=86) and in 1 (1%), 0 (0%) and 2 (3%) under T+chemo (N=67). LVEF-decline: 78 patients in arm A and 74 in arm B had sequential LVEF measurements. A decline ≥ 10% was found in 35 patients (45%) in arm A and in 20 (27%) in arm B (Fisher’s exact test, p=0.028). Among the 35 patients in arm A, 12 had the decline under T alone, 14 under T+chemo, and 9 under both T alone and T+chemo. A decline ≥ 20% was found in 10 patients (13%) in arm A and in 3 (4%) in arm B (Fisher’s exact test, p=0.08). Among the 10 patients in arm A, 7 had the decline under T alone, 3 under T+chemo. Sensory neuropathy 43 patients (50%) in arm A and 48 (54%) in arm B had neuropathy (Fisher’s exact test, p=0.65). G1-3 toxicity in arm A was developed by 26 (30%), 11 (13%) and 6 (7%) patients, respectively; in arm B 30 (34%), 12 (14%) and 6 (7%). No grades 4 events occurred. Conclusion: After more than 11 years of follow-up, no relevant toxicities were found in these patients receiving T for ABC. In particular, the incidence and grade of cardiac toxicity was low. The decline in LVEF was numerically higher in the arm A and in particular in the T alone group, but was not clinically relevant. Our data potentially suggest that T+chemo followed by T maintenance could have less cardiotoxicity than T followed by T+chemo. The possible causes for the difference in LVEF decline between the two arms are unclear, but could be related to treatment duration. The women in Arm A shows a trend to longer therapy: Median treatment duration (months) in Arm A was 7.92 (0.46 - 135.98) vs 6.62 (0.56 - 71.28) in Arm B. This long-term analysis confirms the favorable safety and good tolerability of the reported regimes.

Table 2: Treatment duration
Citation Format: Manuela Rabaglio, Daniel Dietrich, Bernhard Scheibe, Thomas Ruhstaller, Franco Nole, Serenella Eppenberger, Christian Oehlschlegel, Dagmar Hess, Christoph Mamot, Elisabetta Munzone, Bernhard Pestalozzi, Stefan Aebi, Marcus Vetter, Beat Thuerlimann, Roger von Moos, Khalil Zaman, Olivia Pagani. Safety analysis after 11 years of follow-up of the randomized phase III trial SAKK22/99: upfront chemotherapy in advanced HER2 positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-25.