Liquid Biopsy May Guide EGFR Inhibitor Treatment

A liquid biopsy may select patients with metastatic colorectal cancer who are good candidates for additional anti-EGFR therapy after developing resistance to it earlier in their treatment. In a phase II trial, patients without resistance mutations in circulating tumor DNA (ctDNA) who received panitumumab (Vectibix; Amgen) had a 30% response rate to the anti-EGFR agent. Results were presented by Andrea Sartore-Bianchi, MD, of Grande Ospedale Metropolitano Niguarda in Milan, Italy, at the American Society of Clinical Oncology 2021 Annual Meeting, June 4–8.

In recent years, targeted therapies have emerged for patients with metastatic colorectal cancer—the most prevalent of which is anti-EGFR therapy for patients who lack RAS or BRAF alterations. “However, even with this molecular selection, all anti-EGFR–treated patients eventually develop resistance” due to the expansion of mutant RAS and EGFR clones, Sartore-Bianchi said. Yet once patients stop treatment with an EGFR inhibitor, these clones may decay, causing tumors to regain sensitivity to the therapy.

Models based on the half-life of RAS and EGFR clones suggest that sensitivity to anti-EGFR therapy may return around 4 to 8 months after a patient develops resistance. Thus, oncologists have developed clinical criteria for a “rechallenge” strategy: After an initial response to an EGFR inhibitor followed by progression, the patient must stop anti-EGFR therapy for at least 4 months before restarting it. The strategy has shown some success: In the CRICKET trial, patients rechallenged with the EGFR inhibitor cetuximab (Erbitux; Eli Lilly) had a response rate of 21% and a median progression-free survival (PFS) of 3.4 months (JAMA Oncol 2019;5:343–50).

However, “no data are available regarding an actual interventional use of ctDNA information to drive treatment” with additional anti-EGFR therapy, Sartore-Bianchi said. The CHRONOS trial included patients with metastatic colorectal cancer who had previously responded to an anti-EGFR agent, progressed on that therapy, and then received at least one non-EGFR inhibitor.

Fifty-two patients eligible for anti-EGFR rechallenge based on clinical criteria had ctDNA testing, and 16 were excluded based on the presence of RAS, BRAF, or EGFR mutations. “These results suggest that liquid biopsy can spare about 30% of patients from a potentially ineffective new anti-EGFR exposure,” Sartore-Bianchi said. Of 27 patients ultimately treated with panitumumab, eight had partial responses and 11 experienced stable disease; median PFS was 4.1 months. Patients without resistance mutations had stopped anti-EGFR therapy as recently as 4 months earlier, suggesting that they lost these mutations within 4 months. Conversely, patients excluded from the trial due to resistance mutations had stopped anti-EGFR therapy up to 33 months earlier, revealing a much longer period of resistance. “[This indicates] that actual molecular data can better guide the optimal timing for rechallenging patients than theoretical estimation,” Sartore-Bianchi said.

The response rate to the ctDNA-guided rechallenge appears higher than observed in trials using clinical criteria, Sartore-Bianchi noted, and compares favorably to standard treatment response rates in patients who have received two or more therapies. “The trial … demonstrates that genotyping tumor DNA in the blood to direct therapy can effectively be incorporated into the management of advanced and metastatic colorectal cancer,” Sartore-Bianchi concluded.

“The CHRONOS trial data support the use of circulating tumor DNA to decide anti-EGFR rechallenge,” said Guillem Argilés, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who provided outside commentary. The trial is the first to prospectively test a liquid biopsy strategy, he added, although randomized data are needed. Furthermore, the lack of standardized ctDNA panels, variable access to ctDNA testing, and long turnaround times need to be resolved before implementing the strategy. –Catherine Caruso