Preclinical and phase 1/2 data of the CHK1 inhibitor BBI-355 in development for esophageal and gastric cancers (EGC) with
EGFR
or
FGFR2
amplifications.
Authors: Maron Steven Brad , Sharma Manish R , Spira Alexander I. , Rodriguez Rivera Ildefonso I , Chawla Sant P. , Philipovskiy Alexander , Johnson Melissa Lynne , Falchook Gerald Steven , Wainberg Zev A. , Hansen Ryan , Weymer Sara , Wagner Klaus , Yap Timothy A. 
Published: January 2025

TPS517

Background:
High-copy number amplifications of oncogenes (e.g.,
EGFR
,
FGFR2
) frequently occur on extrachromosomal DNA (ecDNA), highly transcribed units of circular non-chromosomal DNA. While targeted therapies have improved survival for patients with oncogene mutations, they have limited activity in oncogene amplified cancers. In Barrett’s esophagus-associated esophageal adenocarcinoma (EAC) ecDNA can be found early in the transition from high-grade dysplasia to EAC. In EAC and gastric cancer (EGC), ~7% and ~3% have
EGFR
and
FGFR2
amplifications, respectively, with possibly >50% occurring on ecDNA. Tumor cells with oncogene amplifications, particularly on ecDNA, have increased DNA replication stress and are sensitive to inactivation of checkpoint kinase 1 (CHK1). We developed BBI-355, an oral, potent, and selective small molecule inhibitor of CHK1, which is in Phase 1/2 clinical development.
Methods:
BBI-355-101 is a first-in-human Phase 1/2 study of BBI-355 alone or in combination with targeted therapies for advanced or metastatic solid tumors with oncogene amplification (NCT05827614). Part 1 is dose escalation of BBI-355 (PO Q2D). In Parts 2 and 3, patients with
EGFR
or
FGFR
1-3 amplifications are treated with BBI-355 in combination with the EGFR inhibitor erlotinib (150 mg PO QD) or the FGFR inhibitor futibatinib (20 mg PO QD). While this study is enrolling all tumor types, EGC are some of the most likely to harbor ecDNA amplifications. Amplification-driven cancers rarely contain driver oncogene mutations or fusions, and so are excluded.
Results:
Preclinical:
Tumors that harbor oncogene amplifications on ecDNA can evade targeted therapeutic pressure via ecDNA-based resistance mechanisms. BBI-355 in combination with agents targeting the amplified oncogenes (
FGFR2
or
EGFR
) prevented resistance to targeted therapies in multiple ecDNA+ gastric cancer CDX and PDX models.
Clinical:
Safety and PK data of BBI-355 alone and in combination with erlotinib or futibatinib will be presented. The most common drug-related TEAEs, SAEs, and DLTs were hematologic (i.e., leukopenia, neutropenia, lymphopenia and thrombocytopenia) which are on target for CHK1 inhibition and generally well managed. Dose escalation is ongoing and the RP2D/MTD has not been determined. PK showed dose-dependent increase in exposure of BBI-355. Target engagement as determined by pCHK1 IHC as a PD biomarker was observed at all dose levels of BBI-355.
Conclusions:
The first ecDNA directed therapy, BBI-355, demonstrated significant synergistic anti-tumor activity in combination with targeted therapies in multiple ecDNA+ oncogene amplified EGC models. BBI-355 alone and in combination with erlotinib/futibatinib was well tolerated. Clinical testing in patients with
EGFR
and
FGFR2
oncogene amplifications is ongoing with a strong rational for EGC.
Clinical trial information: NCT05827614
.