Clinical Summary: 

• Design/Population: This post hoc analysis of the phase 3 CodeBreaK 300 trial evaluated ctDNA dynamics in patients with KRAS G12C-mutated metastatic colorectal cancer treated with sotorasib plus panitumumab or investigator’s choice therapy.
• Key Outcomes: Early ctDNA clearance was strongly associated with radiographic response, progression-free survival, and overall survival, with substantially higher clearance rates observed in patients receiving sotorasib plus panitumumab.
• Clinical Relevance: These findings support ctDNA as a promising early biomarker of treatment response and prognosis in KRAS G12C-mutated metastatic colorectal cancer.

Filippo Pietrantonio, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, discusses results from a post hoc analysis of the phase 3 CodeBreaK 300 trial evaluating circulating tumor DNA (ctDNA) as an early biomarker in patients with KRAS G12C–mutated metastatic colorectal cancer (mCRC). 

The analysis showed that early ctDNA clearance correlated with tumor shrinkage and improved progression-free and overall survival, with patients receiving sotorasib plus panitumumab achieving higher clearance rates than those receiving standard therapies. 

Dr Pietrantonio presented these findings at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 

Transcript: 

Hello, my name is Filippo Pietrantonio, I’m a GI medical oncologist at the National Cancer Institute of Milan in Italy. We are here at ASCO 2026, where we have heard groundbreaking and practice-changing results in GI oncology. Today, I presented the results of a post hoc analysis of the phase 3 CodeBreaK 300 study.

As you know, this study demonstrated superior progression-free survival and other end points, such as overall response rate and quality of life, with the use of sotorasib plus panitumumab compared with investigator’s choice therapy in the later-line treatment of patients with KRAS G12C-mutated metastatic colorectal cancer. This exploratory retrospective analysis evaluated the role of circulating tumor DNA (ctDNA) as an early biomarker of response and prognosis in this patient population.

Basically, ctDNA clearance was assessed by measuring KRAS G12C variant allele frequency and also methylation-based circulating tumor fraction. The key results of this study showed that declines in KRAS G12C variant allele frequency were strongly associated with radiographic tumor shrinkage, and patients with RECIST responses also had 80% or greater ctDNA clearance. 

More importantly, when comparing the 2 experimental arms of the study, sotorasib at the standard dose plus panitumumab, or sotorasib at a lower dose of 240 mg daily plus panitumumab, the ctDNA clearance rates were markedly higher than in the control arm. This is very important because it is aligned with the other endpoints of the study, including response and survival. ctDNA clearance was consistent with the higher efficacy observed with targeted therapy compared with the previous standard of care.

Another important point is the prognostic impact of early ctDNA clearance in terms of progression-free survival and overall survival. In this study population, patients who achieved ctDNA clearance, regardless of treatment arm, had longer progression-free survival and overall survival compared with patients who did not achieve early ctDNA clearance. Importantly, this was a very early readout because we analyzed plasma samples collected at baseline and again at cycle 2, day 1, approximately four weeks after treatment initiation.

In summary, this early readout can help stratify patients, and liquid biopsy can be very useful in this setting to provide prognostic information. We could potentially use liquid biopsy together with clinical factors, radiographic response, and, of course, patient symptoms to help guide treatment decision-making. 

This is really just the beginning, liquid biopsy is increasingly being used in different settings and with different treatments in patients with metastatic colorectal cancer, with the aim of assessing tumor burden, monitoring treatment response and resistance, and detecting resistance mechanisms that may be targeted with subsequent therapies. I was very happy to present this data. This is the last day of ASCO 2026, so we’ll see you next year. We’re ready to go home, and it has been a very interesting and very exciting conference. Thank you very much.

Source: 

Pietrantonio F, Mukundan L, Anderson A, et al. Circulating tumor DNA (ctDNA) clearance as an early indicator of sotorasib + panitumumab efficacy and prognosis in KRAS G12C–mutated colorectal cancer (mCRC): Results from phase 3 CodeBreaK 300. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 3511.