TY - JOUR
T1 - Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99
AU - Pagani, Olivia
AU - Klingbiel, D.
AU - Ruhstaller, T.
AU - Nolè, F.
AU - Eppenberger, S.
AU - Oehlschlegel, C.
AU - Bernhard, J.
AU - Brauchli, P.
AU - Hess, D.
AU - Mamot, C.
AU - Munzone, E.
AU - Pestalozzi, B.
AU - Rabaglio, M.
AU - Aebi, S.
AU - Ribi, K.
AU - Rochlitz, C.
AU - Rothgiesser, K.
AU - Thürlimann, B.
AU - von Moos, R.
AU - Zaman, K.
AU - Goldhirsch, A.
AU - Swiss Group for Clinical Cancer Research (SAKK)
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Background: HER2-targeted therapy plus chemotherapy is standard treatment in advanced HER2+ breast cancer. Trastuzumab alone followed by addition of chemotherapy at disease progression versus upfront combination therapy has not been elucidated. Patients and methods: One-hundred seventy-five patients with measurable/evaluable HER2+ advanced disease without previous HER2-directed therapy were randomized to trastuzumab alone followed, at disease progression, by the combination with chemotherapy (Arm A) or upfront trastuzumab plus chemotherapy (Arm B). Chemotherapy could be stopped after ≥ 6 cycles in responding patients, trastuzumab was continued until progression. The primary endpoint of this superiority trial was time to progression (TTP) on combined trastuzumab-chemotherapy (Combination-TTP) in both arms. Secondary endpoints included response rate, TTP, overall survival, quality of life and toxicity. Results: Combination-TTP was longer than expected in both arms, 12.2 months in Arm A and 10.3 months in Arm B and not significantly different (hazard ratio [HR] 0.7; 95% CI 0.5-1.1; P = 0.1). Overall survival was also not significantly different (HR 0.9; 95% CI 0.6-1.5; P = 0.55). In Arm A, the median TTP before introduction of chemotherapy was 3.7 months (95% CI 2.3-5.4), yet at 2 years 6% of patients were still on trastuzumab alone. Patients without visceral disease had a Combination-TTP of 21.8 months in arm A, compared with 10.1 months in arm B (unplanned analysis HR 2.1, 95% CI 1.1-4.2, P = 0.03). Patients with visceral disease showed no difference. Toxicity was chemotherapy-related. Conclusion: The outcome of patients receiving sequential trastuzumab-chemotherapy or upfront combination was similar. We failed to demonstrate superiority of the sequential approach. These results nevertheless suggest chemotherapy and its toxicity can be deferred, especially in patients with indolent, non-visceral disease. Despite a larger non-inferiority confirmatory study would be needed, these findings represent an additional proof of concept that de-escalation strategies can be discussed in individual patients.
AB - Background: HER2-targeted therapy plus chemotherapy is standard treatment in advanced HER2+ breast cancer. Trastuzumab alone followed by addition of chemotherapy at disease progression versus upfront combination therapy has not been elucidated. Patients and methods: One-hundred seventy-five patients with measurable/evaluable HER2+ advanced disease without previous HER2-directed therapy were randomized to trastuzumab alone followed, at disease progression, by the combination with chemotherapy (Arm A) or upfront trastuzumab plus chemotherapy (Arm B). Chemotherapy could be stopped after ≥ 6 cycles in responding patients, trastuzumab was continued until progression. The primary endpoint of this superiority trial was time to progression (TTP) on combined trastuzumab-chemotherapy (Combination-TTP) in both arms. Secondary endpoints included response rate, TTP, overall survival, quality of life and toxicity. Results: Combination-TTP was longer than expected in both arms, 12.2 months in Arm A and 10.3 months in Arm B and not significantly different (hazard ratio [HR] 0.7; 95% CI 0.5-1.1; P = 0.1). Overall survival was also not significantly different (HR 0.9; 95% CI 0.6-1.5; P = 0.55). In Arm A, the median TTP before introduction of chemotherapy was 3.7 months (95% CI 2.3-5.4), yet at 2 years 6% of patients were still on trastuzumab alone. Patients without visceral disease had a Combination-TTP of 21.8 months in arm A, compared with 10.1 months in arm B (unplanned analysis HR 2.1, 95% CI 1.1-4.2, P = 0.03). Patients with visceral disease showed no difference. Toxicity was chemotherapy-related. Conclusion: The outcome of patients receiving sequential trastuzumab-chemotherapy or upfront combination was similar. We failed to demonstrate superiority of the sequential approach. These results nevertheless suggest chemotherapy and its toxicity can be deferred, especially in patients with indolent, non-visceral disease. Despite a larger non-inferiority confirmatory study would be needed, these findings represent an additional proof of concept that de-escalation strategies can be discussed in individual patients.
KW - Advanced breast cancer
KW - Chemotherapy
KW - Combination therapy
KW - HER2+ breast cancer
KW - Sequential therapy
KW - Trastuzumab
UR - http://www.scopus.com/inward/record.url?scp=85019584288&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019584288&partnerID=8YFLogxK
U2 - 10.1093/annonc/mdw622
DO - 10.1093/annonc/mdw622
M3 - Article
C2 - 27998961
AN - SCOPUS:85019584288
VL - 28
SP - 305
EP - 312
JO - Annals of Oncology
JF - Annals of Oncology
SN - 0923-7534
IS - 2
ER -