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3081 Background: Zotatifin (eFT226) is a first in class, potent and sequence selective inhibitor of RNA helicase eIF4A1 that promotes stable mRNA:eIF4A:drug ternary complex at specific polypurine motifs within the 5’-UTR, preventing ribosome docking and thus, efficient translation of select transcripts. In preclinical models zotatifin treatment simultaneously down-regulated translation of numerous oncogenes with complex 5’ mRNA structures, including ERBB2, FGFR1/2, EGFR, KRAS, and CCND1. Methods: Patients (pts) with select advanced solid tumors harboring mutations/amplification of ERBB2, FGFR1, FGFR2, EGFR, or KRAS or with pancreatic cancer were enrolled into 3+3 dose escalation portion of the protocol (Part 1), and indication specific expansions continue to enroll at recommended phase 2 dose (RP2D; Part 2). The primary endpoints of Part 1 include determination of safety, tolerability, and maximum tolerated dose (MTD)/RP2D; additional endpoints include characterization of pharmacokinetic, pharmacodynamic (including from blood-based assay during escalation and from pre- and on-treatment biopsy at/near MTD with reverse phase protein array (RPPA)), and initial efficacy. Results: As of cut-off date Jan 13, 2022, Dose escalation phase (Part 1) included 37 patients treated with zotatifin at dose levels: 0.005, 0.01, 0.02, 0.035 mg/Kg IV weekly, and 0.035, 0.05, 0.07, 0.1 mg/kg IV 2 weeks-on and 1 week-off. DLTs were observed in 3 patients: Gr 2 thrombocytopenia (0.035 mg/kg weekly), Gr 3 anemia (0.1 mg/kg) and Gr 3 gastrointestinal bleed resulting in anemia (0.1 mg/kg). MTD/RP2D is 0.07 mg/Kg IV 2 weeks-on and 1 week-off. The most common treatment emergent adverse events (TEAEs) in Part 1 include: fatigue, anemia, diarrhea and dyspnea. The most common AEs at RP2D (n = 16 pts; Part 1 and Part 2) include: anemia (25% all gr 1 or 2), fatigue (25% all gr 1 or 2) and dyspnea (19%; 13% Gr 3) diarrhea (13%, all Gr 1 or 2). Pharmacokinetics were generally linear and dose proportional and exposures at MTD/RP2D are consistent with target pharmacologic levels in preclinical models. Blood based biomarkers showed dose- and time- dependent evidence of target engagement. Pre- and on-treatment biopsy data in expansion patients showed decreased expression of target proteins. No patient in dose escalation experienced an objective tumor response; initial efficacy data from Part 2 and at RP2D will be presented. Conclusions: eIF4A inhibitor zotatifin achieves pharmacologically relevant exposures with on-target AEs that are manageable at the MTD, with evidence of target knockdown from on-treatment biopsies. Part 2 indication-specific expansions (including in ER+ FGFR-amplified MBC as single agent, ER+ MBC in combination with fulvestrant and abemaciclib, and KRAS NSCLC in combination with sotorasib) are on-going. Clinical trial information: NCT04092673.

Inheritance of a defective copy of the von Hippel-Lindau (VHL) gene leads to the most common cause of inherited renal cell carcinoma (RCC). In addition, most patients with sporadic RCC have aberrant VHL. In the absence of VHL, hypoxia-inducible factor α accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. We review here the biology of RCC and how a combination of proximal and distal block of VHL/hypoxia-inducible factor α pathway by novel targeted agents, including sunitinib, sorafenib, bevacizumab, everolimus, and temsirolimus, has led to significant improvements in progression-free survival.

3079Background: Stimulating effector T cells is an attractive anti-cancer therapeutic strategy. PF-8600 is a novel fully human IgG2 agonistic mAb specific for human OX40, a tumor necrosis factor re...