A Phase II Open Label Trial of PF-00299804 Monotherapy in Patients With HER-2 Positive Advance Gastric Cancer After Failure of At Least One Prior Chemotherapy Regimen
The role of HER-2 during carcinogenesis and its prognostic role in breast cancer has been
already well established. Furthermore the value of HER-2 as a reasonable therapeutic target
in breast cancer has translated into the good clinical therapeutic result using HER-2
targeting agent, such as trastuzumab and lapatinib.
In case of gastric cancer, the incidence of HER-2 positivity (2+, 3+ on IHC and/or FISH (+))
is reported as similar as that of breast cancer, that is 22% of all cases. A recent ToGA
Trial, phase III trial comparing trastuzumab combined with chemotherapy
(fluoropyrimidine+cisplatin) versus chemotherapy alone in chemotherapy-naïve HER-2 (+)
gastric cancer shows the significant benefit of using trastuzumab in terms of overall
survival and progression-free survival. It provides the clinical evidence of HER-2 as a
reasonable and potential therapeutic target in gastric cancer.
Nowadays, lapatinib, HER-1 and HER-2 dual inhibitor, is also testing under the clinical
trial in gastric cancer.
PF-00299804 is an orally available, potent, and highly selective irreversible small molecule
inhibitor of the Human Epidermal Growth Factor Receptor (HER) family of tyrosine
kinases:HER-1 (EGFR), HER-2 and HER-4 (HER-3 does not possess kinase activity). PF-00299804
inhibits the tyrosine kinase activity of the HER family through binding at the ATP binding
site, which results in covalent modification of a cystine in the ATP binding pocket. The
unique irreversible and highly selective properties of PF-00299804 for the HER kinase family
results in sustained suppression of receptor tyrosine kinase activity. The long-lasting
inhibition of receptor phosphorylation reduces concern over potentially short plasma
half-lives. Furthermore, the low nanomolar potency and irreversible binding of the intended
targets reduce the need for high peak plasma levels, which in turn could minimize
In preclinical study, PF-00299804 is highly active in HER-2 amplified gastric cancer cell
lines.(SNU preclinical data)
Overall, the standard of care for advanced gastric cancer has been of modest benefit with
plateau in response rates using various combination chemotherapies. Therefore, development
of treatment options for these advanced gastric cancer patients, especially HER-2 (+)
gastric cancer patients, remains a target of active research.
So, the investigators plan this phase II trial of PF-00299804 monotherapy in patients with
HER-2 positive advance gastric cancer after failure of at least one chemotherapy regimen.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
progression-free survival at 4-months (PFS4mo)
PFS is defined as the interval from the date of enrollment to the date of disease progression or death due to any cause, whichever occurs first. PFS4m is defined as the proportion of patients alive and progression-free at 4 months relative to all enrolled patients.
Yung-Jue Bang, MD, PhD
Seoul National University Hospital
Republic of Korea: Food and Drug Administration