Pattern of Rash, Diarrhea, and Hepatic Toxicities Secondary to Lapatinib and Their Association With Age and Response to Neoadjuvant Therapy: Analysis From the NeoALTTO Trial

Abstract

Purpose We investigated the pattern of rash, diarrhea, and hepatic adverse events (AEs) secondary to lapatinib and their association with age and pathologic complete response (pCR) in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALLTO) phase III trial. Patients and Methods Patients with HER2-positive early breast cancer were randomly assigned to receive lapatinib (Arm A), trastuzumab (Arm B), or their combination (Arm C) for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery. We investigated the frequency and time to developing each AE according to age (≤ 50 v > 50 years) and their association with pCR in a logistic regression model adjusted for age, hormone receptors, tumor size, nodal status, planned breast surgery, completion of lapatinib administration, and treatment arm. Results Only patients randomly assigned to arms A and C were eligible (n = 306). Younger patients (≤ 50 years) experienced significantly more rash compared with older patients (74.4% v 47.9%; P < .0001). Diarrhea and hepatic AEs were observed in 78.8% and 41.2% of patients, respectively, with no differences in rate or severity or time of onset according to age. Early rash (ie, before starting paclitaxel) was independently associated with a higher chance of pCR, mainly in patients older than 50 years (odds ratio [OR] = 3.76; 95% CI, 1.69 to 8.34) but not in those ≤ 50 years (OR = 0.92; 95% CI, 0.45 to 1.88; P for interaction = .01). No significant association was observed between pCR and diarrhea or hepatic AEs. Conclusion Our results indicate that the frequency and clinical relevance of lapatinib-related rash is largely dependent on patient age.

Lapatinib-associated mucocutaneous toxicities are clinical predictors of improved progression-free survival in patients with human epidermal growth factor receptor (HER2)-positive advanced breast cancer

“…3a). Furthermore, a recent study reported the association between pathological CR and early rash in elderly patients, which would partly support the present study's observations [20]. Figure 3b shows the associations between multiple AEs and PFS.…”

“…(-) negative, (?) positive development of toxicities with lapatinib response in patients with HER2-positive breast cancer [20]. For more than half a decade, lapatinib in combination with capecitabine, compared with capecitabine alone, has improved time to progression in patients resistant to trastuzumab, anthracycline, and taxanes [1].…”

Dual Blockade with AFatinib and Trastuzumab as NEoadjuvant Treatment for Patients with Locally Advanced or Operable Breast Cancer Receiving Taxane–Anthracycline Containing Chemotherapy—DAFNE (GBG-70)

“…However, skin toxicity and diarrhea appeared less in the DAFNE study compared with the lapatinib arms of NeoALTTO (grade 3 skin disorders 6.5%-6.6%; grade 3 diarrhea 21.1%-23.4%). Similar to the results of the DAFNE study no significant correlation was seen between the occurrence of such toxicities associated with lapatinib and pCR in the GeparQuinto study (29); however, this is in opposite to a positive correlation observed in NeoALTTO (30). The main weakness of the DAFNE study is the nonrandomized design and the relatively low sample size.…”

Cytochrome P450 3A4 and CYP3A5-Catalyzed Bioactivation of Lapatinib

“…Clinically significant ALT elevations have been reported in 1.6%-14.3% of patients receiving lapatinib (Moy et al, 2009;Azim et al, 2013). Lapatinib-induced hepatotoxicity is idiosyncratic in nature and is predominately hepatocellular; fewer cases of cholestasic or mixed liver injury have been reported (Spraggs et al, 2012).…”