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Clinical Trial
. 2016 Apr 20;108(8):djw037.
doi: 10.1093/jnci/djw037. Print 2016 Aug.

Lapatinib-Related Rash and Breast Cancer Outcome in the ALTTO Phase III Randomized Trial

Amir Sonnenblick  1 , Evandro de Azambuja  1 , Dominique Agbor-Tarh  1 , Ian Bradbury  1 , Christine Campbell  1 , Yingjie Huang  1 , Amylou C Dueck  1 , Kathleen I Pritchard  1 , Antonio C Wolff  1 , Christian Jackisch  1 , Istvan Lang  1 , Michael Untch  1 , Ian Smith  1 , Frances Boyle  1 , Binghe Xu  1 , Henry Gomez  1 , Edith A Perez  1 , Martine Piccart  1 , Hatem A Azim Jr  2
Affiliations
Clinical Trial

Lapatinib-Related Rash and Breast Cancer Outcome in the ALTTO Phase III Randomized Trial

Amir Sonnenblick et al. J Natl Cancer Inst. .

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.

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Figures

Figure 1.
Figure 1.
ALTTO rash substudy CONSORT diagram. *Out of 6194 patients randomly assigned to lapatinib-containing arms with safety data, 96 patients did not actually receive any dose of lapatinib, resulting in 6098 eligible for the current analysis.
Figure 2.
Figure 2.
Forest plots showing heterogeneity by rash phenotype in the T+L (trastuzumab/lapatinib combination) treated group. Hazard ratios (HRs) and 95% confidence interval (CIs), represented by the error bars, compared with baseline trastuzumab-alone arm. Others include patients who developed rash after six weeks from starting lapatinib or patients who did not develop rash. P values were two-sided using Wald test from Cox model. CI = confidence interval; DFS = disease-free survival; HR = hazard ratio; L = lapatinib; OS = overall survival; T = trastuzumab.
See this image and copyright information in PMC

References

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