The primary goal of this trial is to answer this question:
Does adding immunotherapy (cemiplimab (Libtayo®), an anti-PD-1 therapy) to standard of care (adagrasib (Krazati®), a KRAS G12C inhibitor, and cetuximab (Erbitux®), an anti-EGFR therapy) for patients with KRAS G12C mutated metastatic CRC (mCRC) significantly improve response rate? The secondary objective is to estimate the duration of response, progression-free survival, and overall survival. The study also aims to estimate the safety and tolerability of the combination.

According to Dr. Parseghian, KRAS G12C mutations occur in approximately 4% of all patients with metastatic colorectal cancer (mCRC) and are associated with poor survival. Dr. Parseghian points to three main observations that led to the development of the treatment strategy used in this trial.

1. Analysis of 94 previously treated KRAS G12C mCRC patients who received adagrasib and cetuximab in the KRYSTAL-1 trial revealed an overall response rate of 34% and a disease control rate of 85% at 12 months. However, the median duration of response was only 7 months, and median survival was 16 months. These results led to the Food and Drug Administration (FDA) granting accelerated approval (June 2024) to adagrasib (KRAS G12C inhibitor) plus cetuximab (anti-EGFR therapy) for adults with KRAS G12C-mutated locally advanced or mCRC who have received previous treatment with chemotherapy. The adagrasib and cetuximab combination is the current standard of care. However, the fact that most patients with KRAS G12C mCRC developed early progression highlights the ongoing unmet need for this population.
2. Preclinical studies in mutant KRAS G12C tumor models show that adagrasib enhances the potential for tumor cells to present antigens and reconditions the tumor microenvironment through changes in the proportions of key cell populations, both of which are predicted to increase susceptibility to immune checkpoint inhibition.
3. In the phase I SWOG 2107 trial, a significant improvement in overall response rate and durability was seen with a similar strategy using combined immunotherapy (anti-PD-1 therapy) plus encorafenib (BRAF inhibitor) and cetuximab (anti-EGFR therapy) in patients with BRAF V600E mutations.

These observations suggest the combination of adagrasib plus cetuximab (currently the standard of care) with a PD-1/PD-L1 inhibitor may improve response rates and duration of response compared to the current standard of care alone.

• Patients must have mCRC.
• The cancer must have a KRAS G12C mutation. Other KRAS mutations are unfortunately not eligible.
• Patients must have received at least 1 prior treatment. Patients must not have received previous targeted treatment against KRAS or EGFR (such as standard-of-care adagrasib and cetuximab or sotorasib and panitumumab), or any kind of immunotherapy before starting the trial.
• Because the trial uses immunotherapy, patients cannot have a severe autoimmune condition. However, patients are encouraged to reach out to inquire whether their specific condition is disqualifying.

Prior to starting therapy, patients will undergo a screening process including a clinic visit, blood work, an electrocardiogram (ECG), and imaging to ensure they are eligible for the trial.

If eligible, patients will then start on the treatment as soon as possible. This trial is a single arm study where all patients receive the same 3 medicines. One medicine, adagrasib, is a pill that will be taken twice a day, every day. The other two medicines are IV infusions and will be given in the infusion center. The cetuximab will be given every 2 weeks while the cemiplimab will be given every 3 weeks. This results in a 6-week cycle. IV infusion will occur on weeks 1, 3, 4, and 5, while weeks 2 and 6 are a break from IV treatment.

In addition, patients will be asked to undergo a biopsy before starting treatment and another biopsy 2 weeks into treatment, if safe to do so.

We asked Drs. Parseghian and Caughey what else interested patients should know about this trial. Here are their thoughts:

Dr. Parseghian: “I would encourage patients with metastatic CRC to ensure molecular testing for KRAS G12C is completed early in their disease assessment, and to present to MD Anderson or MGH as soon as a KRAS G12C mutation is identified. Patients will need to have had at least one prior line of therapy for metastatic CRC; however, if they have received prior KRAS G12C directed therapy, they would be ineligible for this trial.”

Dr. Caughey: “This trial takes a good, standard therapy for KRAS G12C and adds immune therapy to it. That means that this trial is giving a treatment a KRAS G12C patient would get anyway, plus something extra that may make it work better and for longer.”

Special thanks to Drs. Christine Parseghian and Bennett Caughey for their contributions to this blog and to colorectal cancer research.

Dr. Bennett Caughey is a GI medical oncologist at Mass General Brigham Cancer Center. He is a clinical investigator with a focus on colorectal and anal cancers. Dr. Caughey has a particular interest in the applications of molecular testing (e.g., DNA sequencing), such as which tests to use in each situation and how to interpret ambiguous results. He aims to open clinical trials using targeted therapies based on the specific changes in the DNA of a cancer.

Dr. Christine Parseghian is a GI Medical Oncologist at MD Anderson Cancer Center. She is a clinical scientist with a focus in colorectal cancer, particularly KRAS G12C mutated colorectal cancer, and mechanisms of acquired resistance to anti-EGFR directed therapy. Dr. Parseghian runs several clinical trials in this setting and is actively involved in translational research in this space.

Once a month, Maia Walker and Manju George spend time unpacking important research trials, tips, and advice for our community. Be sure to subscribe to sign up with Fight CRC and join COLONTOWN’s online community to continue receiving the most relevant updates in the CRC world! You can also follow Maia (@sassycell) and Manju (@manjuggm) to stay updated on research and trials and visit ClinicalTrials.gov or Fight CRC’s Clinical Trial Finder for more information on trials.