Evandro de Azambuja1, Andrew P Holmes2, Martine Piccart-Gebhart3, Eileen Holmes2, Serena Di Cosimo4, Ramona F Swaby5, Michael Untch6, Christian Jackisch7, Istvan Lang8, Ian Smith9, Frances Boyle10, Binghe Xu11, Carlos H Barrios12, Edith A Perez13, Hatem A Azim14, Sung-Bae Kim15, Sherko Kuemmel16, Chiun-Sheng Huang17, Peter Vuylsteke18, Ruey-Kuen Hsieh19, Vera Gorbunova20, Alexandru Eniu21, Lydia Dreosti22, Natalia Tavartkiladze23, Richard D Gelber24, Holger Eidtmann25, José Baselga26. 1. Institut Jules Bordet and Breast European Adjuvant Study Team, Brussels, Belgium. Electronic address: evandro.azambuja@bordet.be. 2. Frontier Science (Scotland) Ltd, Grampian View, Kincraig, Kingussie, UK. 3. Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. 4. Istituto Nazionale del Tumori, Milan, Italy; SOLTI Breast Cancer Research Group, Spain. 5. GlaxoSmithKline, Collegeville, PA, USA. 6. Clinic for Gynaecology, Gynaecologic Oncology and Obstetrics and Breast Cancer Centre, HELIOS Klinikum Berlin, Buch, Germany. 7. Sana Klinikum Offenbach, Offenbach, Germany. 8. National Institute of Oncology, Budapest, Hungary. 9. Royal Marsden Hospital, London, UK; Institute of Cancer Research, London, UK. 10. Patricia Ritchie Centre for Cancer Care and Research, The University of Sydney, Mater Hospital, North Sydney, NSW, Australia. 11. Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China. 12. PUC-RS School of Medicine, Porto Alegre, Brazil. 13. Mayo Clinic, Jacksonville, FL, USA. 14. Institut Jules Bordet and Breast European Adjuvant Study Team, Brussels, Belgium. 15. Asian Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 16. Kliniken Essen-Mitte, Essen, Germany. 17. National Taiwan University Hospital, Taipei, Taiwan. 18. Clinique St-Elisabeth, Namur, Belgium. 19. Mackay Memorial Hospital, Taipei, Taiwan. 20. Kashirskoye Shosse, Moscow, Russia. 21. Cancer Institute "Prof Dr Ion Chiricuta", Cluj-Napoca, Romania. 22. Department of Medical Oncology, University of Pretoria, Pretoria, South Africa. 23. Odessa Oncology Centre, Odessa, Ukraine. 24. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Frontier Science and Technology Research Foundation, Boston, MA, USA. 25. University Hospital Kiel, Kiel, Germany. 26. Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Abstract
BACKGROUND: Findings from the randomised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved rates of pathological complete response compared with either drug alone. Here, we report data for the prespecified secondary endpoints of event-free and overall survival, and assess the association between these outcomes and pathological complete response. METHODS: We enrolled women with HER2-positive early breast cancer and randomly assigned them to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m(2)). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m(2) plus epirubicin 100 mg/m(2) plus cyclophosphamide 500 mg/m(2)) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pathological complete response. Secondary endpoints included event-free and overall survival (intention-to-treat analysis), and the association between pathological complete response and event-free or overall survival (analysed by landmark analysis at 30 weeks after randomisation). Follow-up is ongoing, and the trial is registered with ClinicalTrials.gov, number NCT00553358. FINDINGS:455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of 3·77 years (IQR 3·50-4·22), 3-year event-free survival was 78% (95% CI 70-84) in the lapatinib group, 76% (68-82) in the trastuzumab group, and 84% (77-89) in the combination group. Event-free survival did not differ between the lapatinib and trastuzumab groups (HR 1·06, 95% CI 0·66-1·69, p=0·81), nor between the combination and trastuzumab groups (0·78, 0·47-1·28, p=0·33). Median survival follow-up was 3·84 years (IQR 3·60-4·24), and 3-year overall survival was 93% (95% CI 87-96) for lapatinib, 90% (84-94) for trastuzumab, and 95% (90-98) for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups (HR 0·86, 95% CI 0·45-1·63, p=0·65), nor between the combination and trastuzumab groups (0·62, 0·30-1·25, p=0·19). Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not (HR 0·38, 95% CI 0·22-0·63, p=0·0003), as was 3-year overall survival (0·35, 0·15-0·70, p=0·005). Adverse events occurred in 149 (99%) patients receiving lapatinib, 142 (96%) patients receiving trastuzumab, and 147 (99%) patients receiving combination therapy. The most common adverse events were diarrhoea, rash or erythema, hepatic adverse events, and neutropenia (not related to FEC administration), and were consistent with known safety profiles of lapatinib and trastuzumab. Three primary and eight secondary cardiac events occurred, with no significant difference in incidence between treatment groups for primary or any cardiac events. INTERPRETATION: Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response. FUNDING: GlaxoSmithKline.
RCT Entities:
BACKGROUND: Findings from the randomised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved rates of pathological complete response compared with either drug alone. Here, we report data for the prespecified secondary endpoints of event-free and overall survival, and assess the association between these outcomes and pathological complete response. METHODS: We enrolled women with HER2-positive early breast cancer and randomly assigned them to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m(2)). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m(2) plus epirubicin 100 mg/m(2) plus cyclophosphamide 500 mg/m(2)) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pathological complete response. Secondary endpoints included event-free and overall survival (intention-to-treat analysis), and the association between pathological complete response and event-free or overall survival (analysed by landmark analysis at 30 weeks after randomisation). Follow-up is ongoing, and the trial is registered with ClinicalTrials.gov, number NCT00553358. FINDINGS: 455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of 3·77 years (IQR 3·50-4·22), 3-year event-free survival was 78% (95% CI 70-84) in the lapatinib group, 76% (68-82) in the trastuzumab group, and 84% (77-89) in the combination group. Event-free survival did not differ between the lapatinib and trastuzumab groups (HR 1·06, 95% CI 0·66-1·69, p=0·81), nor between the combination and trastuzumab groups (0·78, 0·47-1·28, p=0·33). Median survival follow-up was 3·84 years (IQR 3·60-4·24), and 3-year overall survival was 93% (95% CI 87-96) for lapatinib, 90% (84-94) for trastuzumab, and 95% (90-98) for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups (HR 0·86, 95% CI 0·45-1·63, p=0·65), nor between the combination and trastuzumab groups (0·62, 0·30-1·25, p=0·19). Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not (HR 0·38, 95% CI 0·22-0·63, p=0·0003), as was 3-year overall survival (0·35, 0·15-0·70, p=0·005). Adverse events occurred in 149 (99%) patients receiving lapatinib, 142 (96%) patients receiving trastuzumab, and 147 (99%) patients receiving combination therapy. The most common adverse events were diarrhoea, rash or erythema, hepatic adverse events, and neutropenia (not related to FEC administration), and were consistent with known safety profiles of lapatinib and trastuzumab. Three primary and eight secondary cardiac events occurred, with no significant difference in incidence between treatment groups for primary or any cardiac events. INTERPRETATION: Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response. FUNDING: GlaxoSmithKline.
Authors: Gerald S Falchook; Jennifer J Wheler; Aung Naing; Sarina A Piha-Paul; Siqing Fu; Apostolia M Tsimberidou; David S Hong; Filip Janku; Ralph Zinner; Yunfang Jiang; Mei Huang; Quan Lin; Kristin Parkhurst; Razelle Kurzrock Journal: Invest New Drugs Date: 2014-11-04 Impact factor: 3.850
Authors: Tessa G Steenbruggen; Mette S van Ramshorst; Marleen Kok; Sabine C Linn; Carolien H Smorenburg; Gabe S Sonke Journal: Drugs Date: 2017-08 Impact factor: 9.546
Authors: A S Coates; E P Winer; A Goldhirsch; R D Gelber; M Gnant; M Piccart-Gebhart; B Thürlimann; H-J Senn Journal: Ann Oncol Date: 2015-05-04 Impact factor: 32.976
Authors: David Cameron; Martine J Piccart-Gebhart; Richard D Gelber; Marion Procter; Aron Goldhirsch; Evandro de Azambuja; Gilberto Castro; Michael Untch; Ian Smith; Luca Gianni; Jose Baselga; Nedal Al-Sakaff; Sabine Lauer; Eleanor McFadden; Brian Leyland-Jones; Richard Bell; Mitch Dowsett; Christian Jackisch Journal: Lancet Date: 2017-02-17 Impact factor: 79.321
Authors: Roberto Salgado; Carsten Denkert; Christine Campbell; Peter Savas; Paolo Nuciforo; Paolo Nucifero; Claudia Aura; Evandro de Azambuja; Holger Eidtmann; Catherine E Ellis; Jose Baselga; Martine J Piccart-Gebhart; Stefan Michiels; Ian Bradbury; Christos Sotiriou; Sherene Loi Journal: JAMA Oncol Date: 2015-07 Impact factor: 31.777
Authors: Aman U Buzdar; Vera J Suman; Funda Meric-Bernstam; Ann Marilyn Leitch; Matthew J Ellis; Judy C Boughey; Gary W Unzeitig; Melanie E Royce; Kelly K Hunt Journal: JAMA Oncol Date: 2019-01-01 Impact factor: 31.777