Dr. Fountzilas on Molecular Characterization in mCRC

Christos Fountzilas, MD, FACP, associate professor, oncology, Department of Medicine, co-leader, Gastrointestinal Clinical Disease Team, associate director for solid tumors, Early Phase Clinical Trials Program, Roswell Park Comprehensive Cancer Center, discusses findings from a study of molecular characterization in patients with colorectal cancer (CRC) treated with cetuximab (Erbitux), an EGFR inhibitor, and pembrolizumab (Keytruda), a PD-1 inhibitor.

A phase 1b/2 trial (NCT02713373) investigated the safety and efficacy of cetuximab plus pembrolizumab in patients with advanced, RAS wild-type CRC. Although this trial did not show activity with this combination, the investigators conducted a comprehensive molecular characterization of the patients whose tumors could be analyzed through DNA and RNA sequencing.

This subsequent study sequenced tumor tissue from 18 patients enrolled in the phase 1b/2 trial. Many patients had at least 1 mutation that made their disease resistant to EGFR inhibitors, even though most of these patients did not have prior EGFR inhibitor exposure, Fountzilas says. Common mutations in the sequenced population included TP53 in 14 patients and CDKN2A and APC in 6 patients each. The investigators also found a high frequency of ERBB4 mutations, which appeared in 5 patients, Fountzilas explains.

This study also used whole transcriptome sequencing to determine whether any patients had gene signatures that were associated with treatment response or resistance, Fountzilas notes. Although the investigators found no statistically significant differences in progression-free survival in patients based on the presence or absence of resistance mutations, they did notice pathways that were upregulated or downregulated by the mutations, including the metabolism of lipids and retinoic acids, Fountzilas emphasizes.

Ongoing analyses of these patients using flow cytometry and proteomics may complement the currently available genetic and genomic data, Fountzilas says. Although these findings are pending, they may further inform therapeutic strategies that combine EGFR inhibitors and PD-1 inhibitors as a backbone regimen in patients with CRC, Fountzilas concludes.