TY - JOUR
T1 - Lapatinib-related rash and breast cancer outcome in the ALTTO phase III randomized trial
AU - Sonnenblick, Amir
AU - De Azambuja, Evandro
AU - Agbor-Tarh, Dominique
AU - Bradbury, Ian
AU - Campbell, Christine
AU - Huang, Yingjie
AU - Dueck, Amylou C.
AU - Pritchard, Kathleen I.
AU - Wolff, Antonio C.
AU - Jackisch, Christian
AU - Lang, Istvan
AU - Untch, Michael
AU - Smith, Ian
AU - Boyle, Frances
AU - Xu, Binghe
AU - Gomez, Henry
AU - Perez, Edith A.
AU - Piccart, Martine
AU - Azim, Hatem A.
N1 - Funding Information:
The ALTTO trial was supported by GlaxoSmithKline (GSK) and the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 to the Alliance for Clinical Trials in Oncology, CA025224 to the legacy North Central Cancer Treatment Group (NCCTG), and CA077202 to the National Cancer Information Center (NCIC) Clinical Trials group. NCIC CTG participation was also supported by the Canadian Cancer Society Research Institute under Award Number 015469 and 021039.
Publisher Copyright:
© The Author 2016. Published by Oxford University Press. All rights reserved.
PY - 2016/8
Y1 - 2016/8
N2 - 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.
AB - 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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U2 - 10.1093/jnci/djw037
DO - 10.1093/jnci/djw037
M3 - Article
C2 - 27098150
AN - SCOPUS:84992392061
VL - 108
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
IS - 8
ER -