Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer

Abstract

Objective: A phase II trial was performed to evaluate the efficacy and safety of the tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, lapatinib, and to explore EGFR, HER2 (EGFR2), phosphorylated ERK MAP kinase (pERK), and Ki67 expression, as well as EGFR mutations in persistent/recurrent endometrial cancer (EC).

Methods: Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 1500 mg oral lapatinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with 6 month PFS as the primary endpoint. The trial had a 10% type I error rate with 90% power. EGFR, HER2, pERK, and Ki67 were evaluated by immunohistochemistry (IHC) from hysterectomy specimens, pre-treatment biopsies, and post-treatment biopsies (when available). Exons 18-21 of EGFR were sequenced.

Results: Three patients of 30 evaluable had PFS ≥6 months, one had a partial response, seven had stable disease, 21 had progressive disease and one was indeterminate. Three mutations in EGFR were identified. Two of these, L688F and K754E, were not associated with response or PFS. However, a newly identified mutation in exon 18, E690K, occurred in the patient with a partial response and progression-free survival extending past six months.

Conclusion: While lapatinib has limited activity in unselected cases, the identification of a previously unreported mutation in EGFR (E690K) with a response suggests that lapatinib may be beneficial in some cases of EC.

Figure 1

Kaplan-Meier Curve for patients in GOG 229D. The solid line represents cases with progression-free survival, and the dashed line represents surviving cases.

Figure 2

pERK immunostaining controls. Note the presence of pERK in both the nuclear and cytoplasmic cellular compartments in the positive control.

Figure 3

Epidermal Growth Factor Receptor Structure and Identified Mutations. The mutations identified in this study are shown within the tyrosine kinase domain. One mutation, E690K, was found in the patient who experienced a partial response and prolonged progression-free survival.