Amir Sonnenblick1, Evandro de Azambuja1, Dominique Agbor-Tarh1, Ian Bradbury1, Christine Campbell1, Yingjie Huang1, Amylou C Dueck1, Kathleen I Pritchard1, Antonio C Wolff1, Christian Jackisch1, Istvan Lang1, Michael Untch1, Ian Smith1, Frances Boyle1, Binghe Xu1, Henry Gomez1, Edith A Perez1, Martine Piccart1, Hatem A Azim2. 1. Department of Medicine, Breast European Adjuvant Study Team (BrEAST) Data Centre, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium (AS, EdA, MP, HAAJr); Frontier Science (Scotland) Ltd, Grampian View, Kincraig, Kingussie, UK (DAt, IB, CC); Novartis Pharmaceuticals Corporation, East Hanover, NJ (YH); Alliance Statistics and Data Center, Mayo Clinic, Section of Biostatistics, Scottsdale, AZ (ACD); Sunnybrook Odette Cancer Centre, the University of Toronto and the NCIC Clinical Trials Group, Toronto, Ontario, Canada (KIP); The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (ACW); Sana Klinikum Offenbach, Offenbach, Germany (CJ); National Institute of Oncology, Budapest, Hungary (IL); Helios Klinikum Berlin-Buch, Berlin, Germany (MU); Royal Marsden Hospital NHS Trust, Sutton/Surrey, UK (IS); Patricia Ritchie Centre for Cancer Care and Research, The University of Sydney, Mater Hospital, North Sydney, Australia (FB); Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China (BX); Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru (HG); Mayo Clinic, Jacksonville, FL (EAP). 2. Department of Medicine, Breast European Adjuvant Study Team (BrEAST) Data Centre, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium (AS, EdA, MP, HAAJr); Frontier Science (Scotland) Ltd, Grampian View, Kincraig, Kingussie, UK (DAt, IB, CC); Novartis Pharmaceuticals Corporation, East Hanover, NJ (YH); Alliance Statistics and Data Center, Mayo Clinic, Section of Biostatistics, Scottsdale, AZ (ACD); Sunnybrook Odette Cancer Centre, the University of Toronto and the NCIC Clinical Trials Group, Toronto, Ontario, Canada (KIP); The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (ACW); Sana Klinikum Offenbach, Offenbach, Germany (CJ); National Institute of Oncology, Budapest, Hungary (IL); Helios Klinikum Berlin-Buch, Berlin, Germany (MU); Royal Marsden Hospital NHS Trust, Sutton/Surrey, UK (IS); Patricia Ritchie Centre for Cancer Care and Research, The University of Sydney, Mater Hospital, North Sydney, Australia (FB); Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China (BX); Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru (HG); Mayo Clinic, Jacksonville, FL (EAP) hatemazim@icloud.com.
Abstract
BACKGROUND: Previously we have shown that early development of rash is associated with a higher chance of achieving pathological complete response to neoadjuvant lapatinib. In the current analysis, we investigate its impact on survival in the ALTTO phase III adjuvant trial. METHODS: In ALTTO, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomly assigned to adjuvant trastuzumab, lapatinib, their sequence, or their combination for a total duration of one year. We evaluated whether the development of early lapatinib-related rash (ie, within 6 weeks) is associated with disease-free (DFS) and overall survival (OS). Landmark analysis at eight weeks and time-dependent analysis were tested in a multivariable model stratifying on trial's stratification factors. All statistical tests were two-sided. RESULTS: Out of 6098 lapatinib-treated patients, 3973(65.2%) were included in the landmark analysis, of whom 1389 (35.0%) had developed early rash. After median follow-up of 4.5 years, the development of early rash was associated with a trend of improved DFS (multivariable: hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.73 to 1.03,P= .10) and statistically significantly improved OS (multivariable: HR = 0.63, 95% CI = 0.48 to 0.82,P< .001) compared with subjects without early rash. Compared with patients randomly assigned to trastuzumab (n = 2051), patients who were randomly assigned to trastuzumab/lapatinib combination and developed early rash (n = 692) had superior DFS (multivariable: HR = 0.72, 95% CI = 0.55 to 0.92,P= .01) and OS (multivariable: HR = 0.59, 95% CI = 0.39 to 0.90,P= .01). Time-dependent analysis suggests that the occurrence of rash is predictive of lapatinib benefit, both when given in combination or sequential to trastuzumab. CONCLUSIONS: Our results indicate that early development of rash identifies patients who derive superior benefit from lapatinib-based therapy.
BACKGROUND: Previously we have shown that early development of rash is associated with a higher chance of achieving pathological complete response to neoadjuvant lapatinib. In the current analysis, we investigate its impact on survival in the ALTTO phase III adjuvant trial. METHODS: In ALTTO, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomly assigned to adjuvant trastuzumab, lapatinib, their sequence, or their combination for a total duration of one year. We evaluated whether the development of early lapatinib-related rash (ie, within 6 weeks) is associated with disease-free (DFS) and overall survival (OS). Landmark analysis at eight weeks and time-dependent analysis were tested in a multivariable model stratifying on trial's stratification factors. All statistical tests were two-sided. RESULTS: Out of 6098 lapatinib-treated patients, 3973(65.2%) were included in the landmark analysis, of whom 1389 (35.0%) had developed early rash. After median follow-up of 4.5 years, the development of early rash was associated with a trend of improved DFS (multivariable: hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.73 to 1.03,P= .10) and statistically significantly improved OS (multivariable: HR = 0.63, 95% CI = 0.48 to 0.82,P< .001) compared with subjects without early rash. Compared with patients randomly assigned to trastuzumab (n = 2051), patients who were randomly assigned to trastuzumab/lapatinib combination and developed early rash (n = 692) had superior DFS (multivariable: HR = 0.72, 95% CI = 0.55 to 0.92,P= .01) and OS (multivariable: HR = 0.59, 95% CI = 0.39 to 0.90,P= .01). Time-dependent analysis suggests that the occurrence of rash is predictive of lapatinib benefit, both when given in combination or sequential to trastuzumab. CONCLUSIONS: Our results indicate that early development of rash identifies patients who derive superior benefit from lapatinib-based therapy.
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