EGFR/ErbB2-Targeting Lapatinib Therapy for Aggressive Prolactinomas

Abstract

Context: Approximately 10% to 20% of prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive prolactinoma behavior.

Objective: We evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive prolactinomas.

Design: A prospective, phase 2a multicenter trial was conducted.

Setting: This study took place at a tertiary referral pituitary center.

Patients: Study participants included adults with aggressive prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy.

Intervention: Intervention included oral lapatinib 1250 mg/day for 6 months.

Main outcome measures: The primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety.

Results: Owing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients.

Conclusions: An oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive prolactinoma.

Trial registration: ClinicalTrials.gov NCT00939523.

Keywords: ErbB; HER2; epidermal growth factor receptor; lapatinib; prolactinoma; tyrosine kinase inhibitor.