Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer

In managing patients with rat sarcoma virus (RAS) wild-type (WT) metastatic colorectal cancer (mCRC), monoclonal antibodies against the epidermal growth factor receptor (EGFR) represent a key therapeutic strategy. However, their limited ongoing effectiveness in this setting underscores the importance of elucidating other factors that affect response, including underlying immunological and metabolic repertoires. An emerging therapeutic target, glutamine metabolism is crucial for cancer cell growth; symbiotically, tumor glutamine demand relative to the microenvironment disadvantages potential anti-tumor immunity. We conducted a phase I/II clinical trial in patients with RAS WT mCRC combining panitumumab, an EGFR inhibitor, and CB-839, a glutaminase inhibitor, hypothesizing that antagonizing glutamine-centric tri-carboxylic acid (TCA) cycle metabolism and mitogen-activated pathway kinase (MAPK)-mediated growth would favor response in well-selected patients. Here, we demonstrate that a novel B cell activation signature, ‘Bscore’ was associated with clinical benefit from combined therapy in patients who previously progressed on anti-EGFR therapy. Patient ‘Bscore’ was positively associated with treatment-induced change in lesion size. Furthermore, patients with lower ‘Bscore’ tended to exhibit greater tumor avidity of glutamine by non-invasive positron emission tomography (PET), suggesting the sensitivity of B cell activation to a glutamine-depleted microenvironment and highlighting future opportunities to enhance immune response in the treatment of mCRC and potentially other glutaminolysis-dependent solid tumors.