Target-specific, histology-independent, randomized discontinuation study of
lapatinib in patients with HER2-amplified solid tumors.
Author(s): Galsky MD, Von Hoff DD, Neubauer M, Anderson T, Fleming M, Nagarwala Y, Mahoney
JM, Midwinter D, Vocila L, Zaks TZ.
Affiliation(s): Mount Sinai Medical Center/Tisch Cancer Institute, 1 Gustave L Levy Place, New
York, NY 10029, USA. Matthew.galsky@mssm.edu
Publication date & source: 2012, Invest New Drugs. , 30(2):695-701
BACKGROUND: To explore the activity of lapatinib with a novel trial design
focused on the drug target rather than on histology.
METHODS: Patients with HER2 amplified gastro-esophageal, bladder, ovarian, or
uterine tumors were enrolled into a double-blinded randomized discontinuation
study of lapatinib 1,500 mg PO daily. The planned sample size was 250 patients
with HER2 amplified tumors, with the goal of randomizing 100 patients with stable
disease (SD) at week 12 to either lapatinib or placebo. Patients responding after
12 weeks continued on lapatinib; those who progressed were discontinued from
study. The primary objectives were response rate after 12 weeks and the
percentage of patients who remained progression free 12 weeks after randomization
to placebo versus lapatinib. Secondary objectives were duration of response and
determination of the incidence of HER2 amplification in multiple tumor types.
RESULTS: A total of 141 patients were screened and 32 patients with HER2
amplified tumors were enrolled. At week 12, 1 (3%) patient had a complete
response, 9 (28%) had stable disease, 20 (63%) had progressive disease, and 2
(6%) were unknown. Only 7 patients with SD underwent randomization. The low
response rate coupled with slow screening and enrollment led to early study
closure.
CONCLUSIONS: Basing trial eligibility on the presence of a genetic target, versus
histologic classification, is challenging. While HER2 amplifications appear to be
prevalent in select non-breast tumors, lapatinib monotherapy is associated with
modest activity. The target-specific histology-independent randomized
discontinuation design still merits consideration for targets clearly implicated
in "oncogene addiction".
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