Dr. Lenz on Optimal Sequencing Strategies in CRC

Heinz-Josef Lenz, MD, FACP, professor of medicine; J. Terrence Lanni Chair in Gastrointestinal Cancer Research; and co-director of the University of Southern California (USC) Center for Molecular Pathway and Drug Discovery, at the USC Norris Comprehensive Cancer Center, discusses optimal sequencing strategies for the treatment of patients with colorectal cancer (CRC).

With all of the different agents that are available in the metastatic CRC paradigm, sequencing has become somewhat of a challenge, says Lenz. The first-line approach is straight forward in that a chemotherapy backbone with targeted agents is typically used, depending on the molecular testing of the tumor. If a patient does not have RAS or BRAF mutations, then EGFR inhibitors are a viable option. If a patient has mutations, anti-VEGF treatments such as bevacizumab (Avastin) can be used and that will then inform second-line treatment decisions, adds Lenz. In the United States, oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX) and bevacizumab are typically used first. Even in the wild-type setting, they will continue to irinotecan, leucovorin, and 5-fluorouracil (FOLFIRI) plus bevacizumab, which will then determine the choice for third-line therapy.

If chemotherapy in the first- and second-line settings is not effective anymore, third-line options can include, standard-of-care agents such as regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102; Lonsurf). New developments have also been made, including reuse of chemotherapy and targeted agents, such as EGFR inhibitors, explains Lenz. Many clinical trials have suggested that when an EGFR inhibitor is used in the first-line setting, and these treatments showed some effect measured by response or progression-free survival, when switched to an alternative regimen like bevacizumab-based chemotherapy, there is a possibility that the mechanism of resistance gained under EGFR pressure will be lost. If this is the case, data show that re-challenging with EGFR inhibitors show a response rate between 20% and 30%, Lenz adds. The efficacy goes up if it can be determined with a liquid biopsy that the mechanism of resistance is not present, such as wild-type RAS and wild-type BRAF mutations, which in most cases are the most frequent mechanisms of resistance, concludes Lenz.