A new prospective phase II trial, ENGIC 01 – PRODIGE 107 – FFCD 2306 – COLOSOTO, is evaluating the combination of sotorasib, panitumumab, and 5-fluorouracil (5-FU) as first-line treatment in frail and/or elderly patients with unresectable KRAS G12C–mutated colorectal cancer (CRC) who are unfit for doublet or triplet chemotherapy.
The trial protocol was published in Digestive and Liver Disease (May 1, 2026).
Why This Trial Matters
Approximately one-fifth of individuals presenting with unresectable metastatic colorectal cancer (mCRC) are either advanced in age or medically frail, often carrying a WHO performance status of 2 or above, and cannot safely receive aggressive chemotherapy. In this subgroup, head-to-head randomized studies have not shown that adding a second cytotoxic agent extends survival compared with single-drug therapy. For that reason, treatment with a fluoropyrimidine — either 5-FU or capecitabine — sometimes paired with a biologic agent, has remained the accepted upfront option. Findings from earlier studies such as AVEX and PANDA reinforce this approach, and ESMO’s current recommendations support pairing a fluoropyrimidine with a targeted therapy as a sensible first choice in this setting.
KRAS G12C, a mutation identified in roughly 3 to 4 percent of mCRC tumors, was for many years considered untreatable at the molecular level. That assumption has been overturned in recent years. Data from the phase III CodeBreaK 300 study showed that combining sotorasib with panitumumab extended progression-free survival (PFS) when measured against conventional third-line therapies, with PFS reaching 5.6 months versus 2.0 months (HR=0.48; p=0.005) — a result that prompted FDA approval. The follow-on phase Ib CodeBreaK 101 trial layered FOLFIRI onto this doublet and recorded a 78% objective response rate among previously untreated patients, opening the door to the currently enrolling phase III CodeBreaK 301 study.
What has yet to be answered is whether targeting KRAS G12C alongside EGFR blockade can work effectively when partnered with a less demanding chemotherapy backbone in patients who can’t manage a full doublet. COLOSOTO is the first prospective investigation specifically designed to tackle this question.
Read more about CodeBreaK 101 trial at ASCO 2025 on OncoDaily.
Trial Design and Treatment
COLOSOTO is being run as an open-label, single-arm phase II study across multiple European centers, with sponsorship from the Fédération Francophone de Cancérologie Digestive (FFCD) and backing from the PRODIGE and ENGIC intergroups. A total of 21 investigative sites are participating across France, Germany, Italy, and Spain. The first participant entered the trial on October 3, 2025, and by December 22, 2025, three patients had been enrolled. Enrollment is projected to close in September 2028, with the final analysis planned for September 2030.
Patients meeting eligibility criteria receive an LV5FU2 backbone — bolus 5-FU at 400 mg/m² intravenously on Day 1, given alongside folinic acid at 400 mg/m² (or 200 mg/m² in its levorotatory form), then a 46-hour continuous 5-FU infusion at 2400 mg/m² — together with intravenous panitumumab dosed at 6 mg/kg on Day 1 and oral sotorasib taken once daily at 960 mg. Each cycle lasts two weeks, with treatment continuing until tumor progression, prohibitive toxicity, or patient withdrawal.
Expert Highlight
Sharing an update from the trial, Prof. David Tougeron, Professor at Poitiers University Hospital and one of the trial’s principal investigators, wrote on LinkedIn:
“We are happy to share the TIP of COLOSOTO trial in KRAS G12C frail patients. Enrollment goes two times faster than planned! More than half of inclusions are done in 6 months! European academic digestive cancer groups are stronger together thanks to ENGIC group.”
This faster-than-expected enrollment underscores both the unmet clinical need in this patient population and the strength of pan-European academic collaboration through the ENGIC network.
Eligibility
To qualify, patients must have histologically confirmed unresectable, MSS/pMMR KRAS G12C–mutated CRC, with no prior treatment for metastatic disease (prior adjuvant chemotherapy is allowed). They must also be considered unfit for doublet or triplet chemotherapy, defined as having a WHO PS of 2, being 70–75 years old with PS 1–2, or being aged 75 years or older with PS 0–2. Measurable disease per RECIST 1.1 and a life expectancy of more than six months are also required.
Endpoints and Statistical Design
The principal endpoint is the proportion of patients who remain alive and progression-free at 8 months. The study is designed around an expected 8-month progression-free survival rate of 70%, compared with a null hypothesis threshold of 50% or less. Additional outcomes being tracked include median PFS, overall survival, best objective response rate, disease control rate, time to progression, duration of response, treatment-related toxicity, patient-reported quality of life through the EORTC QLQ-C30 and FACIT-GP5 instruments, and geriatric profiling using the G8 screening tool and the Geriatric Core Data Set (G-CODE).
The statistical framework relies on Simon’s two-stage approach, calling for 37 enrolled patients (35 evaluable). After the initial 21 enrollees, the study will be halted for futility if 10 or fewer remain progression-free at 8 months. To declare the regimen worth further development, at least 22 of the 35 evaluable participants will need to meet that survival benchmark. A safety check by an Independent Data Monitoring Committee is scheduled once the first 10 patients have received at least two months of therapy.
Translational Research
Each enrolled patient contributes mandatory tumor tissue and serial blood draws — including circulating tumor DNA (ctDNA) sampling at baseline, before the third cycle, and upon disease progression. These specimens are processed at the Centre de Ressource Biologique EPIGENETEC in Paris under the leadership of Professor Pierre Laurent-Puig, with the goal of pinpointing molecular markers that predict who will benefit from the regimen and who will develop resistance.
Looking Ahead
COLOSOTO is the inaugural prospective trial to test a chemotherapy-light, KRAS G12C–directed combination as initial treatment in elderly and frail patients with mCRC. Since a substantial portion of these individuals never advance to third-line treatment, delivering this targeted strategy at the front end of care could help fill a real gap. While the absence of a comparator arm and the limited cohort size will prevent direct comparisons with current standard regimens, favorable results would support expanding the role of KRAS G12C inhibition into earlier lines of therapy for this underserved patient group.
Read the full publication about COLOSOTO Trial in Digestive and Liver Disease.
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