Lapatinib-Related Rash and Breast Cancer Outcome in the ALTTO Phase III Randomized Trial
Amir Sonnenblick1, Evandro de Azambuja1, Dominique Agbor-Tarh1
1Department 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).
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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