ASCO 2025 | CodeBreaK 101: sotorasib, panitumumab, and FOLFIRI in KRAS G12C mCRC

In the clinic, we have FDA approved the combination of the KRAS G12C inhibitor sotorasib with the anti-EGFR antibody panitumumab. Although this chemotherapy-free regimen is generally well-tolerated and active, what we’ve noticed is that there’s molecular outgrowth of resistant subclones, and that probably drives resistance. So the thinking is that perhaps if we could build a strategy to attack those subclones that we may be able to do better, have more responders, have longer duration of response. So one of the advantages of the sotorasib-panitumumab combination is that it does not have overlapping toxicity with standard chemotherapy regimens like, for example, FOLFIRI. And the thinking is if you add a cytotoxic chemotherapy strategy, it will be well tolerated and at the same time will prevent that outgrowth of those resistant subclones, thereby driving longer responses and more durable benefit for patients. So this study originated out of the Phase 1b Code Break 101 protocol, which is looking at various combinations of different therapies together with the KRAS G12C inhibitor, sotorasib. And specifically, what we examined was the activity of the sotorasib-panitumumab-FOLFIRI combination in patients with KRAS-G12C-mutated metastatic colon cancer that had progressed on at least one line of therapy. So in terms of eligibility for this, as mentioned, it was a fairly heavily pretreated patient population. It was a fairly heterogeneous patient population. It took patients with KRAS-G12C-mutated disease, and that was determined by local testing. All the patients had received prior 5-FU and oxaliplatin. A majority of the patients had actually received prior irinotecan, and half of the patients had progressed on prior irinotecan at the time at which they enrolled. Patients were, we first did a safety cohort to evaluate the safety of the combination, and then rapidly moved into this expansion cohort, And that’s what I presented at ASCO at the meeting. So what we found was that the combination of sotorasib, panitumumab, and FOLFIRI was highly active. Response rate was 55%, which is well in excess of what we would get with standard of care therapies. Progression-free survival was over eight months, which is well in excess of what we would get with standard therapies. And overall survival was also favorable. I think what was most promising for us is that the safety and tolerability was as expected, and it was manageable for most patients. There were no patients that discontinued sotorasib due to toxicity. Only three patients, or 7% of the patients enrolled, needed to discontinue chemotherapy due to toxicity. So overall, fairly active regimen, fairly well tolerated, and importantly, also appeared to be quite active in patients who had progressed on prior irinotecan.

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