ATOMIC Trial – PD-L1 pulse FOLFOX as adjuvant in CRC

The **ATOMIC trial** evaluated the efficacy of combining the PD-L1 inhibitor **atezolizumab** with standard adjuvant chemotherapy (**FOLFOX**) in patients with **stage III colon cancer** that is **mismatch repair-deficient (dMMR)** or **microsatellite instability-high (MSI-high)**. Below is a detailed breakdown of the trial and its findings:

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### **Key Details of the ATOMIC Trial**

#### **Study Design**

• **Population:** 712 patients with **stage III colon cancer** that is **dMMR/MSI-high**.
• **Intervention Groups:**
• **Control arm:** FOLFOX alone for 6 months.
• **Experimental arm:** FOLFOX + atezolizumab for 6 months, followed by **atezolizumab alone** for an additional 6 months.
• **Primary Endpoint:** **Disease-Free Survival (DFS)** — the time patients remain free of cancer recurrence or progression.

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#### **Results**

• **DFS Rates:**
• Patients receiving **atezolizumab + FOLFOX** had a **DFS of 86.4%**.
• Patients receiving **FOLFOX alone** had a **DFS of 76.6%**.
• **Conclusion:** The addition of atezolizumab to FOLFOX significantly improved DFS, demonstrating a **strong survival benefit** for the immunotherapy combination.
• **Hazard Ratio (HR):** The trial showed a robust HR favoring the combination therapy, indicating reduced risk of recurrence or progression with atezolizumab.

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### **Implications**

1. **Potential New Standard of Care:**

• The findings suggest that **atezolizumab + FOLFOX** could become the **new adjuvant standard** for patients with **stage III dMMR/MSI-high colon cancer**.
• This is particularly relevant because **dMMR/MSI-high colon cancer** represents a subset (~10%) of all colon cancers.

2. **Practice-Changing Potential:**

• The trial highlights the importance of **immune checkpoint inhibitors** like atezolizumab in the adjuvant setting for colon cancer patients with dMMR/MSI-high tumors, a group that is highly responsive to immunotherapy due to their immunogenic nature.

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### **Remaining Questions**

While the ATOMIC trial provides compelling evidence for the combination therapy, several questions remain unanswered:

1. **Duration of Chemotherapy:**

• Is **6 months** of FOLFOX necessary, or could **3 months** (as increasingly common in practice) suffice?
• Shorter chemotherapy durations might reduce toxicity without compromising efficacy.

2. **Role of Atezolizumab Alone:**

• Could **atezolizumab alone** (without FOLFOX) be just as effective for these patients, given the strong immunogenicity of dMMR/MSI-high tumors?

3. **Optimal Duration of Atezolizumab:**

• Should atezolizumab be administered for **6 months**, **12 months**, or even **24 months**? Longer durations might improve outcomes but raise concerns about toxicity and cost.

4. **Toxicity and Cost:**

• What are the long-term side effects and financial implications of adding atezolizumab to standard chemotherapy?

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### **Significance**

Although only ~10% of colon cancers are **dMMR/MSI-high**, this trial has the potential to **change clinical practice** for this subgroup. The combination of immunotherapy with chemotherapy represents a promising strategy to improve outcomes in patients with this specific molecular profile.