Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified
Matthew D Galsky1, Daniel D Von Hoff, Marcus Neubauer
1Mount Sinai Medical Center/Tisch Cancer Institute, 1 Gustave L Levy Place, New York, NY 10029, USA. Matthew.galsky@mssm.edu
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".
Insights
Lapatinib showed modest activity in HER2-amplified gastro-esophageal, bladder, ovarian, and uterine tumors. A novel trial design targeting HER2 was challenging due to low response rates and enrollment issues.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Investigating lapatinib's efficacy using a novel trial design focused on drug targets rather than histology.
- Assessing lapatinib in HER2-amplified gastro-esophageal, bladder, ovarian, or uterine tumors.
Purpose of the Study:
- To evaluate the response rate and progression-free survival of lapatinib in patients with HER2-amplified tumors.
- To determine the incidence of HER2 amplification in various non-breast tumor types.
Main Methods:
- A double-blinded randomized discontinuation study of lapatinib (1,500 mg PO daily) was conducted.
- Patients with HER2-amplified tumors were enrolled; those with stable disease at week 12 were randomized to lapatinib or placebo.
Main Results:
- Only 32 patients with HER2-amplified tumors were enrolled out of 141 screened.
- A low response rate (3% complete response, 28% stable disease) was observed at week 12.
- Slow enrollment and low response led to early study closure with only 7 patients randomized.
Conclusions:
- Target-based trial eligibility is challenging; HER2 amplification is prevalent in select non-breast tumors.
- Lapatinib monotherapy demonstrated modest activity in this patient population.
- The histology-independent randomized discontinuation design may be valuable for other "oncogene addiction" targets.
