Abstract P2-11-07: Duration of fasting before taking lapatinib is associated with skin toxicity in neoadjuvant treatment of HER2 positive breast cancer: A cohort study from JBCRG-16/Neo-LaTH
Authors: Tsuda M , Ishiguro H , Toriguchi N , Masuda N , Bando H , Ohgami M , Homma M , Morita S , Yamamoto N , Kuroi K , Takano T , Shimizu S , Toi M 
Published: March 2017

Abstract
Background: In neoadjuvant dual HER2 blockade, over 30% of patients fail to complete treatment as planned because of lapatinib-induced diarrhea, rash, and hepatotoxicity. Lapatinib bioavailability, which affects both efficacy and toxicity, is influenced by prandial conditions.
Methods: To investigate the association between lapatinib dosage timing and toxicity, we reviewed the medical records of patients who were enrolled in the JBCRG-16/Neo-LaTH randomized phase II multicenter trial evaluating the efficacy and safety of neoadjuvant 1000 mg/day lapatinib (La) and trastuzumab (T) therapy for 6 or 12 weeks followed by 750 mg/day La, T and weekly paclitaxel for 12 weeks in Japanese patients with primary HER2 positive breast cancer. Lapatinib dosage timing was divided into three groups: after overnight fasting, between meals, and at bedtime. We also measured serum lapatinib concentrations at steady state and dosage timing on the day prior to pharmacokinetic blood sampling. The primary endpoint was to investigate the association between lapatinib dosage timing and frequency of ≥grade 2 diarrhea. The secondary endpoint was to assess the association between dosage timing and other toxicities, pharmacokinetics, efficacy, and treatment discontinuation. Statistical analyses performed included one-way ANOVA, Welch's test and logistic regression.
Results: Out of 213 patients enrolled in JBCRG-16/Neo LaTH, we obtained dosage timing data from 143 (67%) patients: 16 (11%) after overnight fasting, 53 (37%) between meals, and 74 (52%) at bedtime. Serum lapatinib concentrations were obtained in 34/143 (24%) of patients. Dosage timing was not associated with ≥grade 2 diarrhea (8/16 (50%) after overnight fasting, 18/53 (34%) between meals, and 26/74 (35%) at bedtime; p = 0.48). However, multivariate analysis revealed that the after overnight fasting group is less likely to develop acne-like rash during La + T treatment regardless of age, BMI, or treatment.
Multivariate logistic regression analysis of factors predicting rash during La + T treatmentFactor Adjusted odds ratio95% confidence intervalp valueAge (years)≥55Reference &lt;552.671.18-6.310.018*BMI (kg/m2)≥23Reference &lt;231.040.45-2.390.933La + T duration6 weeksReference 12 weeks3.621.49-9.770.004*Concurrent endocrine treatmentYesReference No2.170.94-5.150.068Dosage timingAfter overnight fastingReference Others3.681.16-11.90.027*BMI cut off is based on Asian criteria for overweight status. La: Lapatinib, T: Trastuzumab, *statistically significant
In addition, serum lapatinib trough concentration and it's variability were significantly reduced in the after overnight fasting group (mean ± standard deviation (SD) = 0.35 ± 0.15 µg/ml, coefficient of variation (CV) = 42.7%) as compared to the others (mean ± SD = 0.77 ± 0.44 µg/ml, CV = 57.8%) (p&lt;0.01) . The chance of pCR was not associated with dosage timing (8/16 (50%) after overnight fasting, 24/53, (45%) between meals, and 38/74 (51%) at bedtime; p = 0.79).
Conclusions: These data suggest that overnight fasting stabilizes the bioavailability of lapatinib, which may aid in managing lapatinib-induced rash without diminishing its therapeutic efficacy.
Citation Format: Tsuda M, Ishiguro H, Toriguchi N, Masuda N, Bando H, Ohgami M, Homma M, Morita S, Yamamoto N, Kuroi K, Takano T, Shimizu S, Toi M. Duration of fasting before taking lapatinib is associated with skin toxicity in neoadjuvant treatment of HER2 positive breast cancer: A cohort study from JBCRG-16/Neo-LaTH [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-07.