Phase I study of intermittent high-dose lapatinib alternating with capecitabine for HER2-positive breast cancer with central nervous system metastases.

e14016 Background: Central nervous system (CNS) metastasis is an unmet clinical challenge. While lapatinib (L) and capecitabine (C) have modest efficacy in the treatment of brain metastases (BM) from HER2+ breast cancer (HER2+BC), intratumoral penetration of L in human HER2+ BM is suboptimal (Morikawa A et al. Neuro-Oncol 2015), and L+C has overlapping toxicity. High dose L improves efficacy in preclinical models (Vivanco I et al. Cancer Disc 2012, Morikawa A et al. SABCS 2016). Methods: This multi-center phase I trial of intermittent high dose (IHD) L alternating with C in HER2+BC patients (pts) with CNS metastasis was designed based on Norton-Simon modeling and our preclinical data. An accelerated titration was used. The primary objective was to determine the maximum tolerated dose (MTD) of IHD L given twice a day (BID) 3 days on/11 days off, sequentially with fixed dose C at 1500mg BID given 7 days on/7 days off. The exploratory objectives included evaluation of clinical efficacy and circulating tumor cells (CTC). 4 dose levels were planned for IHD L: 1000mg BID, 1500mg BID, 2000mg BID, and 2500mg BID. Proactive use of anti-diarrheal medications was employed. Key eligibility criteria included HER2+BC with progression of disease in the brain, LM, or spinal cord (SC). There were no limits on prior therapy including standard dose L, intrathecal therapy (IT), and radiotherapy (RT) to the CNS and C was allowed if exposure was > 6 months prior. Results: The study enrolled 11 pts: 4 BM only, 5 LM, and 2 SC pts. 9/11 pts had prior RT. 3/5 LM pts had prior IT. 2 DLTs were G3 vomiting and G3 nausea (despite supportive measures per protocol);the MTD was L at 1500mg BID. The most frequent treatment emergent toxicities (>20%) were G2 vomiting, G1-2 diarrhea, G1 abdominal pain, G1-2 fatigue, G1 headache, G1-2nausea, and G1 palmar-plantar erythrodysesthesia. 3 pts with BM and/or LM remained on therapy for > 6 months with an exceptional responder currently on treatment > 1.5 yrs. CTCs in cerebrospinal fluid were detected in 3/3 pts examined, and changes paralleled the clinical course. Conclusions: IHD L alternating with C is a tolerable regimen for HER2+ CNS metastasis with potential clinical benefit. Clinical trial information: NCT02650752.