title: A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer brain metastases.
abstract: Brain metastases are common in patients with advanced, Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer. We evaluated the maximum tolerated dose (MTD) and feasibility of lapatinib given concurrently with whole brain radiotherapy (WBRT). Eligible patients had (HER2)-positive breast cancer and ≥1 brain metastasis. Patients received lapatinib 750 mg twice on day one followed by 1000, 1250, or 1500 mg once daily. WBRT (37.5 Gy, 15 fractions) began 1-8 days after starting lapatinib. Lapatinib was continued through WBRT. Following WBRT, patients received trastuzumab 2 mg/kg weekly and lapatinib 1000 mg once daily. The regimen would be considered feasible if <3/27 pts treated at the MTD experienced a dose-limiting toxicity (DLT). Thirty-five patients were enrolled; 17 % had central nervous disease (CNS) only. During dose escalation, no patients receiving 1,000 or 1,250 mg and two of five patients receiving 1,500 mg experienced DLTs (grade 3 mucositis and rash). Overall, 7/27 patients at 1,250 mg (MTD) had DLTs: grade 3 rash (n = 2), diarrhea (n = 2), hypoxia (n = 1), and grade 4 pulmonary embolus (n = 2). Among 28 evaluable patients, the CNS objective response rate (ORR) was 79 % [95% confidence interval (CI) 59-92 %] by pre-specified volumetric criteria; 46 % remained progression-free (CNS or non-CNS) at 6 months. The study did not meet the pre-defined criteria for feasibility because of toxicity, although the relationship between study treatment and some DLTs was uncertain. Given the high ORR, concurrent lapatinib-WBRT could still be considered for future study with careful safety monitoring.
authors.affiliation: Harvard Medical School, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA, nlin@partners.org.
authors.forename: Nancy U
authors.initials: NU
authors.lastname: Lin
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Freedman
authors.forename: Naren
authors.initials: N
authors.lastname: Ramakrishna
authors.forename: Jerry
authors.initials: J
authors.lastname: Younger
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Storniolo
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Bellon
authors.forename: Steven E
authors.initials: SE
authors.lastname: Come
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Gelman
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Harris
authors.forename: Mark A
authors.initials: MA
authors.lastname: Henderson
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Macdonald
authors.forename: Anand
authors.initials: A
authors.lastname: Mahadevan
authors.forename: Emily
authors.initials: E
authors.lastname: Eisenberg
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Ligibel
authors.forename: Erica L
authors.initials: EL
authors.lastname: Mayer
authors.forename: Beverly
authors.initials: B
authors.lastname: Moy
authors.forename: April F
authors.initials: AF
authors.lastname: Eichler
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy* / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000532:radiotherapy; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D011788:Quality of Life; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human