Pattern of rash, diarrhea, and hepatic toxicities secondary to neoadjuvant lapatinib and their association with age and pathological complete response (pCR) in breast cancer (BC) patients: Analysis from the NeoALTTO trial

BACKGROUND: We investigated the pattern of lapatinib-specific adverse events (AEs); rash, diarrhea, and hepatic AEs in BC patients (pts) and their association with age and pCR. MATERIAL AND METHODS: NeoALTTO (BIG 1−06/EGF106903) is a multicenter phase 3 neoadjuvant trial in which pts with HER2+ early BC were randomized to either: lapatinib (arm A); trastuzumab (arm B); or the combination (arm C) for 6 weeks followed by the addition of paclitaxel for 12 more weeks prior to surgery. In the current analysis, only pts randomized to arm A or C were included. Per protocol, lapatinib was discontinued if pts developed: > grade (Gr) 2 hepatic AEs (elevated liver enzymes and/or bilirubin), Gr4 rash or persistent Gr3−4 diarrhea. We investigated the time to developing and frequency of each AE by CTCAE Gr version 3 according to age (50 vs. 50), and the association between each AE and pCR in a logistic regression model adjusted for age, hormone receptor status, tumor size, nodal status, planned breast surgery at diagnosis and treatment arm. RESULTS: 306 pts were included. The median time in weeks to developing rash, diarrhea, and hepatic AEs was 2 (IQR: 1.1−4.2), 2.1 (0.4−7.7), and 6.8 (4.1–10.3), respectively. Younger pts (50 years) experienced significantly more rash compared to older pts (74.4% vs. 47.9%, p < 0.0001). 4% of pts experienced Gr3−4 rash, with low treatment discontinuation and dose reduction rates; 1.3% and 5.8%, respectively. No differences were found according to age regarding the frequency or severity of diarrhea and hepatic AEs. Diarrhea occurred in 78.8% of pts (n = 241), of whom 28% were Gr3−4 (22% of all pts). 28.1% of pts required dose reduction due to diarrhea and 5% discontinued therapy for this reason. Hepatic AEs occurred in 41.2% of pts (n = 126), of whom 36% were Gr3−4 (14.3% of all pts). 10% of pts discontinued therapy (n = 33) and required dose reduction (n = 31) due to hepatic AEs. In a logistic regression model, pts who developed early rash (i.e. before starting paclitaxel) had a significantly higher chance of achieving pCR (OR: 1.71, 95% CI 1.01–2.88, p = 0.044) compared to pts who did not develop an early rash (44.2% vs. 31.8%). No significant association was observed between pCR and diarrhea or hepatic AEs. CONCLUSIONS: Rash is more common in young pts receiving lapatinib. In addition, early development of rash is associated with a higher chance of achieving pCR, independent of age, treatment arm and other clinicopathologic features.