Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Targeted therapies such as epidermal growth factor receptor (EGFR) neutralizing monoclonal antibodies (ie. cetuximab and panitumumab) are approved for patients with advanced wild-type (WT) RAS CRC with a reported response rate of 10-23%. However, drug resistance is common and limits treatment options. Alterations in glutamine (Gln) metabolism have been shown to play a critical role in cancer cell growth and survival. Recently, drugs targeting glutaminolysis have been developed for the treatment of a variety of cancers. Preclinically, we have demonstrated that combination of EGFR inhibition and blockade of Gln metabolism results in improved cytoreduction of CRC cells in vitro and in vivo. This data formed the basis of the therapeutic combination used in the current clinical trial. However, there are no definitive methods for identifying responders and no existing diagnostic tools of early response. Imaging Gln metabolism using a non-invasive approach would allow early monitoring for detection of disease progression or response. We hypothesize that Gln-based molecular imaging by positron emission tomography (PET) can serve as a novel diagnostic tool to provide early evidence of predictive and prognostic therapeutic response for drugs that target glutaminolysis. Objectives: The purpose of this phase I/II clinical trial (NCT03263429) is to evaluate the combinatorial activity of an EGFR-targeting antibody (panitumumab) and an oral glutaminase inhibitor (CB-839) for treatment of WT RAS metastatic CRC. Two PET tracers that target different aspects of Gln metabolism, Gln influx (¹¹C-Gln) and glutamate efflux (¹⁸F-FSPG), are being evaluated pre- and post-treatment. Imaging will be correlated with clinical outcomes and biological correlates (gene expression and immunohistochemistry). This is the first-in-human trial to utilize ¹¹C-Gln, so we will also determine the safety and biodistribution for this novel imaging tracer.

We are conducting a phase I/II clinical study combining panitumumab and CB-839 in anti-EGFR therapy pretreated WT RAS metastatic CRC patients. Patients undergo a pre-treatment biopsy (for correlative analyses) prior to treatment with panitumumab and CB-839 in 28-day treatment cycles. PET imaging with ¹¹C-Gln and ¹⁸F-FSPG is performed at baseline and day 28. The imaging study is carried out in accordance with the VUMC RDRC and FDA IND 124202. Tumor response is assessed with CT scans every 2 cycles of therapy.

We have performed the first-in-human PET scans using ¹¹C-Gln, with no signs of toxicity or observed adverse events. To date, we have collected pre- and post-therapy PET images with ¹¹C-Gln and ¹⁸F-FSPG in 4 patients. One patient demonstrated a partial response. In this patient, ¹¹C-Gln uptake at baseline was highest in the lesion with the largest decrease in tumor size and ¹⁸F-FSPG uptake was reduced in all lesions, which corresponded to decreases in tumor size. Two patients have come off study due to disease progression. Changes in ¹¹C-Gln uptake in their lesions were variable which could reflect individual lesion heterogeneity; ¹⁸F-FSPG uptake decreased for most lesions as was expected based on CB-839’s mechanism of action. This study is ongoing and additional data will be presented.

We have identified two PET imaging biomarkers for detection of response in patients treated with combined EGFR/glutamine metabolism-targeting therapy. These biomarkers could serve as an innovative imaging approach to help guide precision medicine by …