O Pagani1, D Klingbiel2, T Ruhstaller3, F Nolè4, S Eppenberger5, C Oehlschlegel6, J Bernhard7, P Brauchli2, D Hess8, C Mamot9, E Munzone4, B Pestalozzi10, M Rabaglio11, S Aebi12, K Ribi7, C Rochlitz13, K Rothgiesser2, B Thürlimann14, R von Moos15, K Zaman16, A Goldhirsch4. 1. Institute of Oncology and Breast Unit of Southern Switzerland, Bellinzona. 2. Swiss Group for Clinical Cancer Research, Coordinating Center, Bern. 3. Breast Center, St. Gallen, Switzerland. 4. European Institute of Oncology, Milano, Italy. 5. Molecular Pathology, University Hospital, Basel. 6. Pathology, Kantonsspital, San Gallen. 7. International Breast Cancer Study Group Coordinating Center, Bern. 8. Department of Internal Medicine, Kantonsspital, St.Gallen. 9. Oncology, Kantonsspital, Aarau, Switzerland. 10. Oncology, University Hospital, Zurich. 11. Breast Unit, Inselspital, Bern. 12. Medical Oncology, Inselspital Bern, now at Luzerner Kantonsspital. 13. Oncology, University Hospital, Basel. 14. Breast Center, St.Gallen. 15. Department of Medicine, Kantonsspital, Chur. 16. Breast Centre, University Hospital, Lausanne, Switzerland.
Abstract
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.
RCT Entities:
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.
Authors: Maria Mitsogianni; Ioannis P Trontzas; Georgia Gomatou; Stephanie Ioannou; Nikolaos K Syrigos; Elias A Kotteas Journal: Oncol Lett Date: 2021-02-12 Impact factor: 2.967
Authors: Sabine Schmid; Dirk Klingbiel; Stefan Aebi; Aron Goldhirsch; Christoph Mamot; Elisabetta Munzone; Franco Nolè; Christian Oehlschlegel; Olivia Pagani; Bernhard Pestalozzi; Christoph Rochlitz; Beat Thürlimann; Roger von Moos; Patrik Weder; Khalil Zaman; Thomas Ruhstaller Journal: BMC Cancer Date: 2019-09-10 Impact factor: 4.430
Authors: Serenella Eppenberger-Castori; Dirk Klingbiel; Thomas Ruhstaller; Daniel Dietrich; Daniel Alexander Rufle; Karin Rothgiesser; Olivia Pagani; Beat Thürlimann Journal: BMC Cancer Date: 2020-02-11 Impact factor: 4.430