Keith T. Flaherty, MD, Associate Professor of Medicine, Harvard Medical School, and Director of the Termeer Center for Targeted Therapy, Boston, was interviewed by The ASCO Post for his thoughts on the findings from Atreya and colleagues.
He believes the study’s outcomes are sufficient for pursuing a “definitive trial” of this triplet in BRAF-mutated colorectal cancer. His likely comparator would be anti-EGFR therapy, which remains a standard, though imperfect, treatment for these tumors. Outcomes with triple inhibition may be much better, he suggested.
“BRAF-mutated colon cancer is one of the most aggressive forms of colon cancer,” said Dr. Flaherty. “The data from this early-phase study are swimming up against a pretty strong current.”
‘Lineage-Specific Biology’
Asked how the triplet might be effectively tackling BRAF-mutated colorectal cancer, Dr. Flaherty explained, “What was quickly discovered in the lab is that when BRAF-mutated colorectal cancer cell lines are treated with a BRAF inhibitor, signaling through EGFR would almost immediately engage and rescue the cells, both by restoring MAP kinase pathway signaling, which is where BRAF sits, but also by activating other pathways. Intriguingly, this rescue loop is available to colorectal cancer but not melanoma or other BRAF-mutated cancers,” he said.
Such observations have made clear to Dr. Flaherty that “It is not only genetic information—ie, forget about site of origin—or only site of origin that matters. It’s a mix of the two.” He refers to this as “lineage-specific biology.” He adds, “When you open the door with a single drug targeting a single vulnerability, the tumor system will tell you what is its next most important feature.”
The BRAF-mutated colorectal cancer story is a perfect example of this approach, where “we promulgate all the single-agent opportunities but then quickly try to cycle to the combinations…. We pick the genetic low-hanging fruit, but then engage the lineage-specific biology.” ■
Disclosure: Dr. Flaherty is a consultant for Roche, Novartis, and Array BioPharma.
