Atezolizumab + Chemo Improves Colon Cancer Survival

The addition of postsurgical atezolizumab immunotherapy to standard-of-care chemotherapy in patients with stage III deficient DNA mismatch repair (dMMR) colon cancer significantly improved survival in the phase 3 ATOMIC trial.

“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 American Society of Clinical Oncology (ASCO) 2src25 annual 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.”

The standard treatment for stage III colon cancer, regardless of dMMR status, is surgical resection followed by fluoropyrimidine-oxaliplatin chemotherapy (FOLFOX), but about 15% of patients have dMMR and display resistance to chemotherapy, he explained during a press conference at the meeting.

“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,” noted Sinicrope, who is professor of medicine and oncology and co-leader of the GI Cancer Program at Mayo Clinic in Rochester, Minnesota.

While approved for dMMR metastatic cancers, it was unknown if an immune checkpoint inhibition would improve outcomes in stage III disease, he added.

Study Methods and Results

ATOMIC included 712 patients at least 12 years of age, who had resected stage III dMMR colon cancer without prior chemotherapy or radiation.

They were randomized within 1src weeks of surgery to FOLFOX chemotherapy alone for 6 months (n=357) or combined with atezolizumab, which was continued for an additional 6 months (n=355).

For the primary endpoint of disease-free survival, the 3-year rate was 86.4% vs 76.6% in the chemo-immunotherapy arm vs FOLFOX alone arm.

“This corresponds to a hazard ratio of src.5, which is a 5src% reduction in recurrence and death related to the treatment, so a very substantial survival benefit was achieved here,” Sinicrope said.

This benefit held up across all subgroup analysis, showing that “no matter what their age, their sex, their race, their tumor location, their T-stage, or N-stage, they are doing better with the addition of immunotherapy to chemotherapy,” he added.

The safety profile “was in line with the known safety profiles of each drug,” he noted, with an expected but manageable increase in nonfebrile neutropenia in the immunotherapy-containing arm (43% vs 36% for grade 3/4).

Regarding immune-related adverse events, there were no clinically significant differences between groups in grade 4 or greater events, but there were notable increases in grades 1 and 2 events in the immunotherapy arm, specifically, hyperglycemia (17.9% vs 9%), hypothyroidism (2src.5% vs 3.6%), and maculopapular rash (13.3% vs 6%), he reported.

Calling the results “dramatic,” Joel Saltzman, MD, a hematologist/oncologist and vice chair of Regional Oncology at Taussig Cancer Center, Cleveland Clinic, Cleveland, and an ASCO expert in gastrointestinal cancers, agreed that the study was practice-changing.

“The most important thing is that this is a real population that I’ll see this coming week in clinic. We have had patients for years that we’ve known immunotherapy would likely be helpful, but we just weren’t sure if we could integrate that into their care,” he said during the press conference.

Discussant Touts Benefits of Neoadjuvant Immunotherapy

The discussant for the study, Myriam Chalabi, MD, PhD, a medical oncologist at the Netherlands Cancer Institute in Amsterdam, the Netherlands, suggested that while the FOLFOX-atezolizumab combo “is an option to consider” for patients who undergo upfront surgery, neoadjuvant immunotherapy “is generally more effective and allows for de-escalation of chemotherapy, and of surgery, and also of the duration of immunotherapy.”

Additionally, “it would be important to investigate what the added benefit is of neoadjuvant immunotherapy in this patient population compared to surgery alone, and how that balances against the adverse events,” she suggested.

Is Chemotherapy Helpful?

In the adjuvant setting, Chalabi questioned whether chemotherapy might be abandoned altogether.

“What we haven’t talked about is whether chemotherapy could even be blunting the T-cell response,” she said, suggesting a third arm of the study might have evaluated atezolizumab alone.

Echoing Chalabi’s comments, Anwaar Saeed, MD, emphasized that ATOMIC’s results “should not be viewed as the endpoint, but a launchpad,” and agreed that a critical unanswered question is whether chemotherapy even remains necessary with immunotherapy in this setting.

“Does oxaliplatin-based chemotherapy meaningfully enhance survival when paired with immune checkpoint blockade, or could it be modified — or even omitted — without compromising outcomes? As the field moves forward, future trials must interrogate whether reduced-intensity or chemo-free regimens could offer comparable efficacy with fewer toxicities,” said the associate professor of medicine and the chief of the Gastrointestinal Medical Oncology Program at the University of Pittsburgh, University of Pittsburgh Medical Center (UPMC), and UPMC Hillman Cancer Center in Pittsburgh, in an interview with Medscape Medical News.

“This question is especially relevant in light of the accumulating data from early-phase neoadjuvant studies, many of which suggest that immunotherapy alone may induce profound pathological responses in resectable dMMR [colorectal cancer] CRC. How these findings in the neoadjuvant setting harmonize with ATOMIC’s adjuvant strategy remains to be seen, but the direction is clear: Immunotherapy should now be considered foundational in the treatment of resectable dMMR colon cancer,” Saeed said.

Saeed also expressed enthusiasm about the study, during the interview.

“The ATOMIC trial represents a watershed moment in the treatment of stage III dMMR colon cancer,” she said.

“This trial effectively redefines the standard of care for this patient population, with definitive phase 3 validation that immunotherapy has earned a place in the adjuvant treatment of dMMR colon cancer. But more importantly, it opens the door to deeper questions that must now guide the next generation of clinical investigation.”

The study was funded by the National Institutes of Health, the National Cancer Institute, Genentech, Inc., and the Alliance Foundation.

Sinicrope disclosed employment from MedVal, stock, and other ownership interests with Eli Lilly and Company; a consulting or advisory role with Guardant Health and Roche; and research funding from Ventana Medical Systems. He also disclosed patent royalties related to immune markers in colon cancer and a patent jointly held with Roche/Ventana Medical Systems.

Saltzman disclosed stock and other ownership interests with Eli Lilly and Company, GoodRx, and Sana Biotechnology.

Chalabi disclosed a consulting or advisory role with Bristol Myers Squibb/Celgene, MSD, and Roche/Genentech; research funding from Agenus, Bristol Myers Squibb, MSD, and Roche/Genentech; and travel, accommodations, and expenses from Bristol Myers Squibb.

Saeed disclosed a consulting or advisory rolewith Arcus Therapeutics, Astellas Pharma, AstraZeneca, Autem Therapeutics, Bristol Myers Squibb, Exelixis, Pfizer, Regeneron, Replimune, Taiho Pharmaceutical, and Xilio The