Dr Bekaii-Saab on Evolving Sequencing Approaches in CRC

"[The expansion of treatment options in] CRC is becoming very exciting. It’s not a question anymore of bevacizumab vs cetuximab or panitumumab; it’s more a question of how to place all these different subgroups of patients."

Tanios S. Bekaii-Saab, MD, leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center; as well as medical director of the Cancer Clinical Research Office and vice chair and section chief for Medical Oncology in the Department of Internal Medicine at Mayo Clinic, discussed the evolving approach to sequencing decisions across molecular subgroups of patients with colorectal cancer (CRC), along with significant unmet needs in the field.

Bekaii-Saab noted that numerous targeted therapies that were once approved for later-line use are now moving into the first-line setting. He added that these agents are either already approved or progressing through clinical trials, noting that this shift signals an exciting time for the field. 
In light of these developments, treatment decision-making is moving beyond a straightforward choice between agents such as bevacizumab (Avastin), cetuximab (Erbitux), or panitumumab (Vectibix), Bekaii-Saab continued. Instead, the critical challenge is determining the optimal placement of various patient subgroups within complex treatment algorithms and considering whether to initiate with a biologic plus chemotherapy or a targeted therapy first, he explained.

Despite these advances, significant unmet needs persist for most patients, particularly those lacking identifiable molecular targets, Bekaii-Saab stated. This includes individuals with 

 alterations, or tumors that are not microsatellite instability–high (MSI-H). For those with

-mutated tumors, progress is evident with the emergence of pan-RAS inhibitors, plus KRAS G12D and G12C inhibitors, which are beginning to fill a crucial therapeutic gap, he said. However, the arsenal for patients with

 wild-type disease remains largely limited to EGFR inhibitors, unless a

 mutation or an MSI-H tumor is present, Bekaii-Saab concluded.

Tanios S. Bekaii-Saab, MD, is the leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center; as well as medical director of the Cancer Clinical Research Office and vice chair and section chief for Medical Oncology in the Department of Internal Medicine at Mayo Clinic

Dr Bekaii-Saab on the Expanding Targeted Therapy Paradigm for Biliary Tract Cancers

 G12C mutation, for which the KRAS G12C inhibitor adagrasib (Krazati) has been incorporated into National Comprehensive Cancer Network guidelines, according to Bekaii-Saab. 

 V600E mutations, found in approximately 5% to 10% of biliary tract cancers, are responsive to combined BRAF/MEK inhibition using agents like dabrafenib (Tafinlar) plus trametinib (Mekinist), he noted. 

 mutations, present in approximately 20% of intrahepatic cholangiocarcinomas, can be targeted with ivosidenib (Tibsovo), which has demonstrated progression-free survival benefit and a modest overall survival advantage, although ORRs have been limited, he stated.

Furthermore, an expanding list of rare oncogenic fusions is being identified and matched with corresponding targeted therapies, contributing to the growing paradigm of precision oncology in biliary tract cancers, Bekaii-Saab emphasized. Overall, despite the relative rarity of biliary tract malignancies, approximately 30% to 40% of patients may benefit from biomarker-driven therapies beyond conventional chemotherapy and immunotherapy, many of which elicit ORRs in the 30% to 40% range, with the notable exception of ivosidenib, he concluded.

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Tanios S. Bekaii-Saab, MD, discusses sequencing decisions according to molecular subgroups in colorectal cancer.