Results of the Phase I/II Study and Preliminary B-cell Gene Signature of Combined Inhibition of Glutamine Metabolism and EGFR in Colorectal Cancer

Authors

Kristen K Ciombor
Seong-Woo Bae
Jennifer G Whisenant
Gregory D Ayers
Quanhu Sheng
Todd E Peterson
Gary T Smith
Kangyu Lin
Saikat Chowdhury
Preeti Kanikarla Marie
Alexey Sorokin
Allison S Cohen
Laura W Goff
Dana B Cardin
John Paul Shen
Scott Kopetz
Cathy Eng
Yu Shyr
Jordan Berlin
H Charles Manning

Publication Date

4-14-2025

Journal

Clinical Cancer Research

DOI

10.1158/1078-0432.CCR-24-3133

PMID

39927885

PMCID

PMC11996605

PubMedCentral® Posted Date

10-14-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Purpose: EGFR-targeting mAbs are essential for managing rat sarcoma virus wild-type metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunologic and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.

Patients and methods: We conducted a phase I/II trial in patients with KRAS wild-type mCRC, combining panitumumab (6 mg/kg) and CB-839 (600 mg/kg or 800 mg/kg), hypothesizing that the dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B-cell activation signature "B-score" and glutamine PET as potential treatment response biomarkers.

Results: The combination of panitumumab and CB-839 was tolerable with manageable side effects, including grade 4 hypomagnesemia in four patients, a known panitumumab-related event. Two patients achieved partial response, and five had stable disease, with a 41% disease control rate. Median progression-free survival and overall survival were 1.84 and 8.87 months, respectively. A positive correlation between "B-score" and lesion size reduction suggested its association with clinical benefit (partial response and stable disease). Lower "B-score" correlated with greater tumor avidity for glutamine by PET, indicating B-cell activation sensitivity to glutamine depletion.

Conclusions: The combination of CB-839 and panitumumab showed safety and promising preliminary responses, but the study closed early due to CB-839 development termination. The B-cell activation signature "B-score" emerged as a potential biomarker for EGFR and glutaminase inhibition in mCRC, warranting further studies. These findings suggest opportunities to improve immune response and therapies in glutaminolysis-dependent tumors.

Keywords

Humans, Colorectal Neoplasms, ErbB Receptors, Glutamine, Male, Female, Panitumumab, Middle Aged, Aged, Antineoplastic Combined Chemotherapy Protocols, B-Lymphocytes, Benzeneacetamides, Proto-Oncogene Proteins p21(ras), Biomarkers, Tumor, Thiadiazoles

Published Open-Access

yes

Recommended Citation

Ciombor, Kristen K; Bae, Seong-Woo; Whisenant, Jennifer G; et al., "Results of the Phase I/II Study and Preliminary B-cell Gene Signature of Combined Inhibition of Glutamine Metabolism and EGFR in Colorectal Cancer" (2025). Faculty, Staff and Student Publications. 6007.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6007