3512 Background: XL228 is a protein kinase inhibitor targeting IGF1R, the AURORA kinases, FGFR1–3, ABL and SRC family kinases. It is being evaluated in a phase 1 trial in patients (pts) with advanced malignancies. Methods: XL228 is administered as weekly 1-hour IV infusions. Cohorts of pts with refractory solid tumors or lymphoma are evaluated for determination of the maximum tolerated dose, pharmacokinetics, and pharmacodynamic effects using FDG-PET, signal pathway analysis in tumor and normal tissue biopsies, and plasma marker analysis. MTD expansion cohorts will include pts with multiple myeloma and colorectal cancer. Results: Thirty-six pts have been treated at doses ranging from 0.45 to 8.0mg/kg. The maximum administered dose was defined as 8.0mg/kg as a result of the dose limiting toxicities of Grade (Gr) 4 neutropenia, and Gr 3 neutropenia requiring dose skipping. XL228 is generally well tolerated; one serious adverse event of drug-related Gr 3 vomiting has been observed. Common drug-related adverse events include Gr 1 nausea, fatigue, decreased appetite, and flushing, and Grade 1–2 hyperglycemia (fasting) lasting up to 4 hours post- infusion. XL228 exposure was approximately dose-proportional; the mean terminal half-life (t1/2, z) ranged from 27 to 54 hours. Low accumulation was observed after weekly administration. Protein phosphorylation measurements in skin, hair, and blood samples demonstrate inhibition of IGF1R, SRC and FGFR1 signaling by XL228, including reductions in hair follicle phospho-IGF1R and phospho-FAK1 of 39% and 42%, respectively, in a pt dosed at 5.4mg/kg. Evidence of clinical activity includes one non-small cell lung cancer pt with an unconfirmed partial response (confirmation pending) and 9 additional pts (of 30 evaluable) with stable disease (SD) lasting >3 months, including a small cell lung cancer pt on study for 13.3+ months after failing carboplatin/etoposide. For pts with SD, the median time on study is currently 5.9 months (range 3.3+ to 13.3+). Conclusions: XL228 is generally well tolerated and has shown encouraging preliminary clinical and pharmacodynamic activity. [Table: see text]
First-in-human phase 1 study of the anti–TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non–small cell lung cancer