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Phase III randomised trial comparing intense dose-dense chemotherapy to tailored dose-dense chemotherapy in high-risk early breast cancer (GAIN-2)

Volker Möbus, Hans-Joachim Lück, Ekkehart Ladda, Peter Klare, Marcus Schmidt, Andreas Schneeweiss, Eva-Maria Grischke, Grischa Wachsmann, Helmut Forstbauer, Michael Untch, Frederik Marme, Jens-Uwe Blohmer, Christian Jackisch, Jens Huober, Elmar Stickeler, Mattea Reinisch, Theresa Link, Bruno V Sinn, Wolfgang Janni, Carsten Denkert, Jenny Furlanetto, Knut Engels, Christine Solbach, Sabine Schmatloch, Julia Rey, Nicole Burchardi, Sibylle Loibl & GBG And AGO-B

abstract

BACKGROUND
The GAIN-2 trial was designed to identify a superior intense dose-dense (idd) strategy for high-risk patients with early breast cancer. Here, we report an interim analysis, at which the predefined futility boundary was crossed.

PATIENTS AND METHODS
GAIN-2 was an open-label, randomised, multicentre phase III trial. Two thousand eight hundred and eighty seven patients were randomised 1:1 between three courses each of idd epirubicin (E) 150 mg/m, nab-paclitaxel (nP) 330 mg/m and cyclophosphamide (C) 2000 mg/m (iddEnPC) versus four cycles of leucocyte nadir-based tailored and dose-dense EC (dtEC) followed by four cycles of tailored and dose-dense docetaxel (dtD) (dtEC-dtD).

RESULTS
The duration of median follow-up was 45.8 (range 0.0-88.3) months. Trial objectives included invasive disease-free survival (iDFS) as the primary end-point. A total of 593 patients received the treatment as neoadjuvant chemotherapy. At the time of futility interim analysis, 414 events for iDFS were reported. Overall, there was no difference in iDFS between iddEnPC and dtEC-dtD with 4-year iDFS rates of 84.3% (95% confidence interval (CI) 82.0-86.4%). Among all predefined subgroups, hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-), lobular cancer and ≤50 years subgroups predicted for better iDFS in the dtEC-dtD arm. Overall, 88.1% of patients completed all treatment in both arms. Haematological toxicity grade 3/4 and grade 3/4 non-haematological adverse events were significantly higher with iddEnPC (iddEnPC 50.8% vs dtEC-dtD 45.1%, P = 0.002), especially arthralgia and peripheral sensory neuropathy. Two treatment-related deaths occurred during dtEC-dtD, corresponding to a low mortality rate of 0.07%.

CONCLUSIONS
iDFS is equal in both regimens, but tailoring dose-dense chemotherapy improved outcomes in HR+/HER2-, lobular cancer and patients ≤50 years.
   
citation Möbus V, Lück H J, Ladda E, Klare P, Schmidt M, Schneeweiss A, Grischke E M, Wachsmann G, Forstbauer H, Untch M, Marme F, Blohmer J U, Jackisch C, Huober J, Stickeler E, Reinisch M, Link T, Sinn B V, Janni W, Denkert C, Furlanetto J, Engels K, Solbach C, Schmatloch S, Rey J, Burchardi N, Loibl S, GBG and AGO-B . Phase III randomised trial comparing intense dose-dense chemotherapy to tailored dose-dense chemotherapy in high-risk early breast cancer (GAIN-2). Eur J Cancer 2021; 156:138-148.
   
type journal paper/review (English)
date of publishing 24-08-2021
journal title Eur J Cancer (156)
ISSN electronic 1879-0852
pages 138-148
PubMed 34450552
DOI 10.1016/j.ejca.2021.07.033