For the adjuvant treatment of stage III colon cancer with DNA mismatch repair–deficient (dMMR) tumors, the addition of the checkpoint inhibitor atezolizumab to standard chemotherapy significantly improved disease-free survival in the phase III ATOMIC trial. The results position this approach as a potential new standard of care for this patient subset, according to Frank A. Sinicrope, MD, of the Mayo Clinic, Rochester, Minnesota, who presented the findings during the Plenary Session of the 2025 ASCO Annual Meeting.1
“A very substantial disease-free survival benefit was achieved here [with the combination of atezolizumab and chemotherapy].”— Frank A. Sinicrope, MD
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Immunotherapy is standard therapy now for metastatic dMMR colon cancer, and ATOMIC is the first large trial to evaluate immunotherapy in the adjuvant setting, where about 10% to 15% of colon cancers have dMMR status. In the study, the 3-year disease-free survival rate was 86.4% with atezolizumab plus chemotherapy vs 76.6% with chemotherapy alone, corresponding to a 50% reduction in recurrence and death (hazard ratio [HR] = 0.5; P < .0001).
“A very substantial disease-free survival benefit was achieved here with chemoimmunotherapy,” Dr. Sinicrope said during a press briefing at the meeting. “These data establish this combination as a new standard treatment for patients with stage III dMMR colon cancer. We regard this as a very impactful study that will change clinical practice.”
About ATOMIC
Adjuvant chemotherapy with a fluoropyrimidine and oxaliplatin is considered the standard treatment of stage III tumors regardless of MMR status, but patients with dMMR tumors display resistance to fluoropyrimidines. Immune checkpoint inhibitors (without chemotherapy) are approved in the metastatic setting for dMMR cancers, but it has not been clear whether these agents can improve outcomes in earlier-stage disease following surgical resection (ie, as adjuvant therapy).
ATOMIC was conducted to determine whether adding the monoclonal antibody atezolizumab, which targets the ligand PD-L1 to restore antitumor T-cell activity, to fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) would be superior to mFOLFOX6 alone in patients with stage III dMMR tumors. The study enrolled 712 patients between 2017 and 2023, randomly assigning them to mFOLFOX6 plus atezolizumab (840 mg intravenously every 2 weeks) for 12 cycles (6 months) followed by atezolizumab monotherapy for 13 cycles (additional 6 months) or mFOLFOX6 alone for 12 cycles (6 months). The primary endpoint was disease-free survival, with the efficacy analysis being done in the intent-to-treat population. Patients’ disease-free survival was compared by arm. Baseline characteristics were well balanced between the arms. Among tumors, 83.8% were proximal, 46.1% were clinically low-risk, and 53.9% were high-risk based on T and N staging.
Full protocol treatment was completed by 46% of patients in the atezolizumab arm and 60% of those in the chemotherapy-alone arm. More patients discontinued treatment early in the atezolizumab arm, 54% vs 40%. Median treatment duration of FOLFOX was similar between the arms, about 5.5 months. Median number of atezolizumab cycles was 23. Median number of cycles and percent doses received for the chemotherapy components were similar between the arms; thus, there was no compromise in chemotherapy exposure with the addition of atezolizumab to FOLFOX, Dr. Sinicrope noted.
Key Findings
Dr. Sinicrope presented the findings from the second interim analysis, where median follow-up was 37.2 months and 75% of disease-free survival events had occurred. The 3-year disease-free survival rate was 86.4% in the atezolizumab arm and 76.6% in the mFOLFOX6 arm (HR = 0.50; P < .0001).
“Of note, the control arm performed slightly better than the 75% disease-free survival rate used for the study design, and the difference observed underscores the benefit for the addition of atezolizumab,” Dr. Sinicrope said. “A divergence in the survival curve occurs early, with a plateau effect seen for the atezolizumab-containing arm.”
Efficacy in the atezolizumab arm was consistent across all subgroups, including patients aged 65 and older and low- and high-risk groups alike. ATOMIC had dMMR status centrally confirmed, and by that analysis, the hazard ratio was maintained at 0.53, he noted.
Tolerability
Treatment-related grade 3 or 4 adverse events were reported in 72.3% of the atezolizumab arm and 59.2% of the mFOLFOX6 arm. Grade ≥ 3 adverse events that were more common with the addition of atezolizumab included fatigue and nausea. Grade 3 neutropenia occurred in 28.6% of the atezolizumab arm and 29.4% of the FOLFOX-alone arm, and these adverse events were grade 4 in 14.0% and 7.0%, respectively. No clinically significant differences in grade ≥ 3 immune-related adverse events were reported.
DISCLOSURE: Dr. Sinicrope reported having stock and other ownership interests in Eli Lilly; has served as a consultant or advisor to Guardant Health and Roche Holdings AG; has received institutional research funding from Ventana Medical Systems; and has an immediate family member who is employed by Woven Health Collective.
REFERENCE
1. Sinicrope FA, Ou FS, Arnold D, et al: Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair colon cancer (Alliance A021502; ATOMIC). 2025 ASCO Annual Meeting. Abstract LBA1. Presented June 1, 2025.
EXPERT POINT OF VIEW
The invited discussant of the phase III ATOMIC trial was Myriam Chalabi, MD, PhD, a gastrointestinal oncologist at the Netherlands Cancer Institute. “Adjuvant FOLFOX plus atezolizumab leads to a 10% absolute improvement in 3-year disease-free survival in stage III DNA mismatch repair–deficient [dMMR] colon cancers and is an option to consider for resected tumors,” she commented. “However, neoadjuvant immunotherapy is more effective and allows for de-escalation of chemotherapy and surgery” in early-stage dMMR tumors.
Myriam Chalabi, MD, PhD
The key questions that remain to be answered are which patients with dMMR colon cancer need adjuvant therapy, can immunotherapy cure them, and which is the preferred strategy—adjuvant or neoadjuvant therapy?
“The 10% improvement in 3-year disease-free survival is statistically significant and clinically meaningful,” said Dr. Chalabi, “but we also saw that 13% of patients recurred despite 6 months of FOLFOX and a full year of atezolizumab and that 77% of patients were disease-free at 3 years without atezolizumab [ie, in the control arm]. The big question is how many, and which, patients are cured with surgery alone, and what is the added benefit, if any, of chemotherapy in these patients?”
Addressing the safety profile of this approach, Dr. Chalabi deemed atezolizumab plus FOLFOX to be generally tolerable, although there were higher rates of grade 3 or 4 adverse events with the combination, including “unexpected increases” in grade 4 neutropenia. Six patients in the atezolizumab arm died, and two of the deaths were attributed to treatment.
“All of these data should be put together and balanced out against the 10% increase in disease-free survival, which brings us to a key question: How do the toxicity and efficacy of FOLFOX plus atezolizumab compare with immunotherapy alone?” she asked.
Neoadjuvant vs Adjuvant Therapy
Neoadjuvant therapy, which has a strong biologic rationale in dMMR tumors, has emerged as a promising approach in several early-stage malignancies, mostly notably melanoma, triple-negative breast cancer, and colorectal cancer. Dr. Chalabi led the landmark NICHE-2 trial in which, after two cycles of neoadjuvant nivolumab plus ipilimumab, 95% of patients with dMMR colon cancer achieved deep pathologic responses, and the 3-year disease-free survival was 100%.1 Neoadjuvant immunotherapy is typically more tolerable as well, she noted. How, then, do the ATOMIC findings fit in context with neoadjuvant immunotherapy?
It should be stated, however, that neoadjuvant data are nonrandomized and include relatively modest patient numbers. Also, pathologic response is not a surrogate for disease-free survival, and longer-term follow-up is needed to ensure that oncologic outcomes are not compromised by limited neoadjuvant treatment.
Dr. Chalabi continued: “Putting all the pieces together, we can state that chemotherapy has very limited efficacy in dMMR colon cancer. We don’t know the efficacy of atezolizumab alone, and that is the missing arm of ATOMIC. And could chemotherapy even be blunting the T-cell response? We’ve seen that neoadjuvant immunotherapy is extremely effective without chemotherapy and with very limited toxicity,” she said. The open-label phase III AZUR-2 study of perioperative dostarlimab monotherapy vs standard adjuvant chemotherapy in dMMR T4N0 or stage III colon cancer may help to answer some of these questions. However, this study will also include a full year of immunotherapy, which based on the current neoadjuvant data is likely not needed. Also, it will not be possible to discern the contribution of phases (ie, neoadjuvant vs adjuvant immunotherapy).
Meanwhile, Dr. Chalabi believes that for patients with dMMR colon cancer, adjuvant immunotherapy can be curable, chemotherapy is probably not needed, and a full year of atezolizumab is also probably not needed. She would recommend that clinically high-risk tumors be treated with neoadjuvant immunotherapy; then good responders should be followed, and poor responders should receive immunotherapy plus chemotherapy or a novel agent, ideally still in the neoadjuvant setting, so response can be monitored. The clinically low-risk group is more difficult to manage, she mentioned, as a proportion do recur, and they are impossible to identify upfront. Prognostic markers are needed to identify the benefits of neoadjuvant immunotherapy vs surgery alone in this group.
“Staging and risk assessment become less important when we’re aiming for organ preservation. This, in my opinion, should be the next step in many ongoing and future neoadjuvant immunotherapy trials,” Dr. Chalabi concluded.
DISCLOSURE: Dr. Chalabi has received travel funding from Bristol Myers Squibb.
REFERENCE
1. Chalabi M, Verschoor YL, Tan PB, et al: Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer. N Engl J Med 390:1949-1958, 2024.
