SUN-442 EGFR/ErbB2 Targeted Therapy for Aggressive Prolactinomas

Introduction: Prolactinomas are usually benign and respond well to dopamine agonist therapy. However, approximately 20% are resistant, and 10% behave aggressively and persist or recur. Treatment resistance has been associated with ErbB receptor expression, prompting us to conduct a trial of ErbB targeted therapy in patients with aggressive prolactinomas. Objective: To evaluate efficacy of the EGFR/ErbB2 tyrosine kinase inhibitor lapatinib in patients with aggressive prolactinomas. Study design: We conducted a prospective 6-month phase IIa multicenter trial of oral lapatinib 1250 mg/d in adult patients with continued tumor growth on maximally tolerated dopamine agonist therapy. Pregnant women and patients with unstable visual fields were excluded. MRI was performed every 3 months. Primary endpoint was 40% reduction in tumor size; secondary endpoints were 50% PRL reduction, PRL normalization, % PRL reduction, % tumor size reduction, and immunohistochemical correlation of clinical response with ErbB receptor expression. A target sample size of 24 subjects was estimated to achieve power >80%, using one tailed hypothesis, an alpha of 0.10, and an effect size of 0.20. Numerical variables were summarized as median (range). Results: Due to rigorous inclusion criteria, 6 subjects were enrolled. Four were female; median age was 29 years (19-70) and median disease duration 8 years (1-30). Median tumor size was 40 mm (16-60) at diagnosis. Three subjects underwent 1 surgery and 3 had 2 surgeries; 1 had radiation therapy. At study start, median maximal tumor diameter was 25 mm (13-48) and baseline PRL was 379 ng/mL (114-11748). After 6 months on lapatinib, tumor size was stable in 3 subjects, decreased in 1 with 22% tumor volume reduction, and increased in 2. PRL decreased in 3 subjects, with a median decrease of 42% (-78% to -42%) and increased in 3 by 59% (28% to 103%). Median nadir PRL was 200 ng/mL (40-11753), for an overall 25% reduction (-87% to 25%). Final median PRL was 181 ng/mL (67-1726), with a median decrease of 7% (-79% to 103%). One subject with widely metastatic pituitary carcinoma initially experienced a 25% decrease in PRL but was withdrawn at 3 months when PRL increased and metastases progressed. Excluding this subject, overall median PRL decrease was 42% (-79% to 59%). EGFR and ErbB2 expression was not detectable in tumors derived from 3 subjects and did not correlate with treatment response. Lapatinib was well tolerated with reversible grade 1 transaminitis observed in 2 subjects, grade 2 rash in 4 subjects, and grade 1 asymptomatic bradycardia in 1 subject. Conclusions: Preliminary results suggest that lapatinib may be effective in controlling tumor growth in select patients with aggressive prolactinomas. Confirming the benefit of lapatinib in aggressive prolactinomas requires a larger cohort size.