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The results of the phase III ATOMIC trial fired another volley in the ongoing debate over adjuvant vs neoadjuvant immunotherapy for patients with locally advanced colon cancer. But experts are divided about which treatment plan is best.

Adjuvant immunotherapy plus chemotherapy has yet to square off against neoadjuvant immunotherapy in a head-to-head trial. Even if that trial doesn’t happen, post hoc analyses of ATOMIC and the neoadjuvant NICHE-2 studies may clarify whether a one-size-fits-all approach is appropriate and help determine which patients benefit more from one approach over the other, according to Christopher Lieu, MD, an investigator in the ATOMIC study.

The ATOMIC study showed that adding adjuvant immunotherapy to standard-of-care chemotherapy following resection reduced the risk for disease recurrence or death by 50% compared with chemotherapy alone in the 355 patients with stage III colon cancer with mismatch repair deficiency (dMMR), who received adjuvant atezolizumab along with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy, providing those in the pro-adjuvant camp with important data. In addition, 3-year disease-free survival (DFS) was 86.4% with the combination compared with 76.6% with chemotherapy alone. The results of this trial were presented at the American Society of Clinical Oncology (ASCO) 2025.

“These data established this combination as a new standard treatment for patients with stage III colon cancer and deficient mismatch repair,” said study author Frank A. Sinicrope, MD, during a press conference at the meeting. “We regard this as a highly impactful study that will change clinical practice, and it actually represents the first immunotherapy adjuvant study in colon cancer.”

In NICHE-2, patients were given neoadjuvant ipilimumab or nivolumab followed by surgical resection. At 3 years, 100% of all 111 patients treated with ipilimumab and nivolumab prior to surgery were recurrence-free, according to a presentation at last year’s annual meeting of the European Society for Medical Oncology (ESMO). The DFS beat the prespecified success threshold of 93%.

Adding Immunotherapy

The standard treatment for stage III colon cancer, regardless of dMMR status, is surgical resection followed by FOLFOX chemotherapy. However, about 15% of patients with stage III colon cancer have dMMR and display resistance to chemotherapy, providing a rationale for adding immunotherapies to standard treatment.

“These tumors are unable to repair their DNA and therefore accumulate mutations that trigger an immune response that is ineffective due to immune checkpoint proteins. Therefore, the use of immune checkpoint inhibitors is very attractive in this setting,” Sinicrope said during the press briefing. Sinicrope is professor of medicine and oncology, and coleader of the Gastrointestinal Cancer Program at Mayo Clinic in Rochester, Minnesota.

Adjuvant Immunotherapy

The ATOMIC trial is significant because it demonstrates improved DFS with the addition of immunotherapy to standard chemotherapy treatment, improving outcomes for patients with this type of locally advanced cancer over standard care. There are several rationales for adding immunotherapy following surgical resection. For example, staging relies on tumor appearance on CT scan, said Lieu, who is the codirector of Gastrointestinal Medical Oncology at the University of Colorado Cancer Center in Aurora, Colorado.

There are patients with dMMR or microsatellite instability-high (MSI-H) colon cancer that appear to have stage I or II disease on their CT scan. “In those patients, starting with immunotherapy first may not be the best idea because after a stage I or II colon cancer is resected, they don’t require any further therapy because of the low risk of recurrence,” he said.

“If you think it is an early-stage cancer based of radiographic findings, you could cut out the cancer and then only offer chemotherapy and immunotherapy if it is unexpectedly stage III. I think that there's certainly rationale for that,” he continued.

Other arguments for adjuvant immune checkpoint inhibitors, like atezolizumab, with chemotherapy include synergy between cytotoxic and immune mechanisms and systemic insurance against micrometastatic spread. It also avoids the potential for rare immune complications from upfront immunotherapy that could delay surgery.

“I don’t think that [giving all patients neoadjuvant treatment] is the answer. If you think that they have stage I or stage II colon cancer at the beginning, then you might end up hurting them with upfront immunotherapy,” said Lieu.

Neoadjuvant Immunotherapy

The standard treatment for stage III colon cancer, regardless of dMMR status, is surgical resection followed by chemotherapy, FOLFOX and capecitabine and oxaliplatin (CAPOX) are two of the most common regimens. However, chemotherapy can be hard on patients, making neoadjuvant immunotherapy that can reduce or eliminate the need for post-surgical chemotherapy very attractive.

The data from the NICHE-2 trial support the efficacy of neoadjuvant immunotherapy.

“The data strongly suggest that neoadjuvant immunotherapy is better than adjuvant immunotherapy and that chemotherapy for dMMR colorectal cancer has limited activity,” said Michael J. Overman, MD, Associate Vice President of Research for the MD Anderson Cancer Network in Houston, in an interview. “Thus, I am a believer that neoadjuvant is the preferred approach for dMMR localized cancers.”

Lieu said neoadjuvant immunotherapy might be more appropriate for more aggressive disease.

“What we discuss in our multidisciplinary clinic is that if these patients are diagnosed prior to surgery and particularly if they have aggressive features…those are some of the patients that I really would consider for neoadjuvant therapy,” he said. “While it’s high-risk disease, there could be some benefit to down-staging the patient, so that there isn’t a positive margin. If there’s pathologic complete response…and you don’t have to give adjuvant chemotherapy, most people would consider that to be a win.”

Overman noted that “a big open area relates to whether the goal of neoadjuvant therapy should be operation or no operation. Likely both approaches can be done and that would be up to patient and physician.” However, “with a nonoperative approach, we still have unknowns regarding disease assessment and surveillance for neoadjuvant therapy.”

Patient-Specific Care

In the absence of data from a head-to-head trial of the two approaches, a patient-specific approach may be the appropriate strategy, Lieu suggested.

“If I had a take home message, it’s just that it’s clear that these patients really require multidisciplinary discussion before an operation,” he said.

Molecular testing has an important role to play as well, said Lieu. “It speaks to the importance of doing biomarker testing for MMR, MSI, or both. Alarm bells should be ringing as soon as [either or both come] back positive; it should make everyone think for a second and make sure we have the right plan for the right patients.”

Sinicrope reported several relationships, including with Eli Lilly, Guardant Health, Roche Holdings AG, Ventana Medical Systems, and Woven Health Collective.

Lieu reported relationships with Amgen and Genentech.

Overman reported relationships with Jansen, Bristol-Myers Squibb, Merck, AbbVie, Medimmune, Takeda, Eli Lilly, Nouscom, Medimmune, and Genentech/Roche.