134O - Dose-dense adjuvant chemotherapy in early-stage breast cancer patients: End-of-study results from a randomised, phase III trial of the Gruppo Italiano Mammella (GIM)

Background

The GIM 2 trial compared in a 2x2 factorial design the dose dense (DD, every 2 weeks) schedule to the standard interval one (every 3 weeks) and the addition of fluorouracil (F) to epirubicin-cyclophosphamide (EC) and paclitaxel (P) as adjuvant chemotherapy for node-positive breast cancer. In the primary analysis (Del Mastro, Lancet 2015), disease-free survival (DFS) and overall survival (OS) were significantly improved with the DD schedule, while no benefit was observed with the addition of F. Here, we report the end-of-study analysis.

Methods

This was an open-label, phase III trial, done in 81 Italian centres. Node-positive breast cancer patients were randomly allocated 1:1:1:1 to receive either EC-P or FEC-P DD or standard-interval EC-P or FEC-P The primary endpoint was DFS, comparing FEC-P vs. EC-P, and DD vs. standard-interval schedule. Secondary end points included OS and safety.

Results

2091 patients were randomized; 88 patients were enrolled in centres providing only standard-intensity schedule. After a median follow-up of 15.11 years (IQR 8.40-16.33), 343 of 1002 patients (34.2%) and 409 of 1001 patients (40.9%) in the DD and control arm experienced a DFS event, with 15-year DFS of 61% (95% CI 58-64) and 52% (95%CI 49-56), respectively (Hazard Ratio [HR] 0.77, 95% CI 0.67-0.89; p<0.001). 197 (19.7%) and 254 (25.4%) OS events were registered, with 15-years OS of 76% (95%CI 73-79) and 69% (95%CI 65-72) in the DD and control arm, respectively (HR 0.72, 95%CI 0.60-0.86, p<0.001). Addition of F did not significantly improve DFS (HR 1.12, 95%CI 0.98-1.29, p= 0.11) and OS (HR 1.13, 95%CI 0.94-1.36, p=0.18).

In hormone receptor-positive (N=1611), 15-years OS was 76% (95% CI 72-79) with the DD and 71% (95% CI 67-74) with the standard schedule. For hormone receptor-negative (N=335), 15-years OS was 76% (95%CI 69-83) with the DD and 63% (95%CI 55-71) with the standard schedule. Four cases of myelodysplasia/leukaemia were observed.

Conclusions

The final analysis confirmed an improved DFS and OS with the use of DD as compared with the standard schedule. The DD should be considered the standard adjuvant schedule for node-positive breast cancer patients.

Clinical trial identification

NCT00433420.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Bristol-Myers Squibb; Pharmacia, and Dompè Biotec.

Disclosure

L. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal, Invited Speaker, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests, Personal, Invited Speaker, Author for BC text: Pensiero Scientifico Editore; Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pfizer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, Astrazeneca; Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. F. Poggio: Financial Interests, Personal, Invited Speaker: Novartis, Lilly, Pfizer. S. de Placido: Financial Interests, Invited Speaker: Novartis, Roche, Daichii Sankyo, Celgene, AstraZeneca, Pfizer, Eli Lilly, Eisai, MSD. M. Giuliano: Financial Interests, Invited Speaker: Eli Lilly, Novartis, Pfizer, Roche, MSD, Seagen, AstraZeneca. M. De Laurentiis: Financial Interests, Speaker’s Bureau: Amgen, AstraZeneca, Pierre Fabre Pharma; Financial Interests, Invited Speaker: Daichii Sankyo, Eisai, Eli Lilly, Exact Sciences, MSD, Novartis, Pfizer, Roche, Seagen; Financial Interests, Advisory Board: Gilead. O. Garrone: Financial Interests, Personal, Research Grant: Eisai; Financial Interests, Other: Pfizer; Financial Interests, Invited Speaker: Novartis, Amgen. C. Bighin: Financial Interests, Personal, Invited Speaker: Roche, Novartis, Eli Lilly. M. Mansutti: Financial Interests, Invited Speaker: Novartis, Pfizer, AstraZeneca, Eisai, MSD, Eli Lilly. F. Montemurro: Financial Interests, Invited Speaker: Roche, Eli Lilly, Seagen, Novartis, Pfizer, Pierre Fabre. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Pfizer, Takeda, Sandoz, Ipsen, Libbs, Knight. All other authors have declared no conflicts of interest.