Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy

This study focuses on new therapies for a challenging disease in pituitary medicine, that of aggressive pituitary tumors which have limited therapeutic options beyond standard surgical, radiotherapy, and select medical therapies, each incurring significant morbidity and mortality, and each not optimally effective. To improve this gap in knowledge, we seek to translate findings from the laboratory into clinical practice and hone in on therapies directed at pituitary molecular targets, namely ErbB receptors. We have shown that human prolactinomas express nuclear EGFR and membranous ErbB2, ErbB3 and ErbB4, and expression correlates with tumor invasion. Pituitary tumor cell lines transfected with EGFR and ErbB2 translated to downstream effects on prolactin (PRL) gene expression and secretion,as well as cell proliferation. Animal models implanted with these cell lines developed larger tumors and PRL elevations. Treatment with ErbB tyrosine kinase inhibitors (TKIs) led to regression of tumors xenografted into these animals and attenuated PRL secretion. Primary culture of human prolactinomas confirmed expression of ErbB receptors and inhibitory effects of TKIs on PRL secretion and cell proliferation. Based on these exciting preliminary data, the objective of this new proposal is to conduct a Phase IIa clinical trial as a trenchant test of our translational hypothesis that tyrosine kinase inhibition constitutes highly effective targeted biologic therapy for these hitherto refractory pituitary adenomas. Specifically, our aims are to test the: 1) efficacy of TKI therapy with a clinical trial; 2) threshold level of tumor receptor expression to achieve TKI clinical response. Nineteen subjects will be treated with lapatinib for 6 months in combination with their current dopamine agonist therapy, with monthly measurements of PRL levels and MRI imaging every 3 months to evaluate the primary endpoints of achieving 40% reduction in tumor size and 50% reduction in PRL and secondary endpoints of radiologic stabilization and/or reduction and PRL normalization. Mean ErbB receptor protein expression will be compared between responders to lapatinib and non-responders by immunohistochemistry in pituitary tumor samples of these subjects collected from prior surgeries.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Patients with nonfunctioning adenomas who have undergone at least one prior surgical resection and have demonstrated recurrence on MRI
* Patients with prolactinomas who are resistant to dopamine agonist therapy
* Patients with malignant pituitary tumors
* Patients with visual field deficits and/or compression of the optic chiasm must be stable for at least 6 months

Exclusion Criteria:

* Patients with compromised visual fields and/or compression of the optic chiasm on MRI that has not been stable for last 6 months.
* Patients that have reduced left ventricular ejection fraction less than 50%
* Patients with moderate to severe hepatic impairment
* Patients that are pregnant or lactating
* Patients under the age of 18
* Active hepatitis
* Known previous HIV Positive
* Concurrent cancers
* Life expectancy less than one year

• DERIVEDDong W, Shi W, Liu Y, Li J, Zhang Y, Dong G, Dong X, Gao H. CHST7 Methylation Status Related to the Proliferation and Differentiation of Pituitary Adenomas. Cells. 2022 Aug 4;11(15):2400. doi: 10.3390/cells11152400. PMID 35954244
• DERIVEDCooper O, Bonert VS, Rudnick J, Pressman BD, Lo J, Salvatori R, Yuen KCJ, Fleseriu M, Melmed S. EGFR/ErbB2-Targeting Lapatinib Therapy for Aggressive Prolactinomas. J Clin Endocrinol Metab. 2021 Jan 23;106(2):e917-e925. doi: 10.1210/clinem/dgaa805. PMID 33150390