A phase I safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients (pts) with advanced solid tumors.

Abstract

3070 Background: The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mechanism of resistance to EGFR inhibitors. In preclinical xenograft models, the oral, selective Class I PI3K inhibitor XL147 augments the anti-tumor efficacy of EGFR inhibitors including erlotinib (E). Methods: A standard 3 + 3 design was used with a maximum tolerated dose (MTD) cohort expansion in NSCLC pts. E is dosed qd, and XL147 is dosed qd on days 1-21 of each 28-day cycle. Dose limiting toxicities are determined using cycle 1 safety data. Tumor response is evaluated every 8 weeks. Results: 23 pts with diverse advanced solid tumors have been enrolled including 8 NSCLC and 5 CRC. Pts have been treated at 7 dose levels up to 600 mg XL147/150 mg E. The most frequently reported related AEs were rash (45%), nausea (30%), diarrhea, fatigue and vomiting (each 20%). One pt (status post pneumonectomy) treated with XL147 600 mg and E 150 mg had a treatment-related SAE of DRESS (drug rash with eosinophilia and systemic symptoms) syndrome and died from progressive disease and DRESS. No major PK interaction between XL147 and E was evident across cohorts based on comparison with single agent data. In tissue biopsies, robust inhibition of the PI3K and MAPK/EGFR signaling pathways was evident. For example, in serial tumor biopsies from a pt with an ethmoid tumor, maximum reductions in pAKT- T308 (61%), pERK (68%), and pEGFR (68%) were evident at day 43 post-dose, with a corresponding reduction in Ki67 (45%) and induction of apoptosis (2.6-fold). One EGFR inhibitor-naïve NSCLC pt had a confirmed PR (59% reduction in the sum of target lesions). One pt with adenoid cystic carcinoma had a decrease in FDG uptake by PET and a decrease in size of a lung nodule by CT. One pt with HNSCC (left maxillary alveolar ridge) had a decrease in FDG uptake by PET and a shrinkage of the primary tumor bulk by CT. Eight pts continued on treatment ≥ 16 weeks, including 5 pts on treatment ≥ 24 weeks. Conclusions: The combination of XL147 and E is generally well tolerated at doses up to 400 mg XL147/150 mg E with no major PK interaction and results in clinical activity and robust simultaneous inhibition of PI3K and EGFR signaling. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Exelixis Exelixis Exelixis Exelixis