Abstract CT020: Safety and tolerability of the dual PI3K/mTOR inhibitor LY3023414 in treatment of patients with advanced mesothelioma
Authors: Zauderer Marjorie G. , Hyman David M. , Alley Evan W. , Bendell Johanna C. , Novello Silvia , Bauer Todd M. , Hanauske Axel-Rainer , Szpurka Anna M. , Kang Suhyun , Chatterjee Anindya , Wacheck Volker , Brueck Patrick , Varghese Anna M. 
Published: August 2018

Abstract
Background: The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is aberrantly activated in malignant mesothelioma. LY3023414 (LY) is a potent oral ATP- competitive inhibitor that selectively and potently inhibits class I PI3K isoforms, mTOR, and DNA-PK. The recommended phase 2 dose (RP2D) of LY monotherapy was previously established to be 200 mg twice daily (BID). Here we report safety and clinical activity of LY monotherapy in advanced mesothelioma patients (pts) as part of a multi-cohort Phase 1 study (NCT01655225).
Methods: In this cohort, 42 pts with malignant pleural or peritoneal mesothelioma with measurable disease as per RECIST v1.1, ECOG PS 0-1 and refractory or ineligible to standard therapies were enrolled to receive LY 200 mg BID. Primary objective was to explore single agent activity of LY. Other objectives included assessment of pharmacokinetics (PK), antitumor activity, and biomarker analysis.
Results: 41 pts received treatment. Common treatment-related adverse events (TRAEs) included fatigue (44%), nausea (37%), vomiting (34%), decreased appetite (29%), diarrhea (22%) and maculo-papular rash (15%). Grade(G) 3/4 TRAEs reported were G3 fatigue (10%), G3 maculo-papular rash (7%), G3 pruritus (5%), G3 constipation (2%), G3 hyperglycemia (2%), G3 hyponatraemia (2%), G3 dyspnoea exertional (2%), G3 hypoxia (2%) and G4 hyperglycemia (2%). Serious adverse events related to study treatment were reported in 7(17%) pts. There were no deaths related to study treatment. Median duration of treatment was 12 weeks (range 3-48). In the 41 pts evaluable for tumor response, 2 pts (5%) had durable partial response (PR) and 17 pts (42%) had stable disease (SD) according to RECIST for an ORR of 5% and DCR of 46%. Overall, 29% of pts had a decrease in tumor lesions from baseline. The median progression-free survival for this cohort is 2.8 months (90% CI 2.5, 3.9). Alterations in the BAP1 gene, a potent tumor suppressor implicated in PI3K signaling pathway and in the pathogenesis of malignant mesothelioma, was identified in one pt with PR and in 4 of 17 pts (24%) with SD. Further biomarker analysis is ongoing.
Conclusions: LY monotherapy at the RP2D of 200 mg BID demonstrated an acceptable and manageable safety profile. Single agent LY activity is limited in pts with advanced mesothelioma and more work is needed to identify the characteristics of benefitting patients.
Citation Format: Marjorie G. Zauderer, David M. Hyman, Evan W. Alley, Johanna C. Bendell, Silvia Novello, Todd M. Bauer, Axel-Rainer Hanauske, Anna M. Szpurka, Suhyun Kang, Anindya Chatterjee, Volker Wacheck, Patrick Brueck, Anna M. Varghese. Safety and tolerability of the dual PI3K/mTOR inhibitor LY3023414 in treatment of patients with advanced mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT020.