Atezolizumab boosts colon cancer disease-free survival, study finds

Adding the immunotherapy drug atezolizumab to standard chemotherapy after surgery significantly improved the time patients lived without their cancer returning in people with stage III colon cancer that has mismatch repair deficiency, according to a phase 3 study published in the New England Journal of Medicine.

At 3 years, 86% of patients treated with the immune checkpoint inhibitor atezolizumab plus modified FOLFOX6 (fluorouracil, oxaliplatin, and leucovorin) were alive without recurrence versus 76% of those receiving chemotherapy alone, translating to about half the risk of recurrence or death with the combination approach.

For the randomized ATOMIC trial, first author Frank A. Sinicrope, MD, of the Department of Oncology at the Mayo Clinic, Rochester, Minn., and colleagues at 312 sites in the US and Germany enrolled 712 patients with resected stage III colon cancer with deficient DNA mismatch repair (dMMR), assigning them 1:1 to atezolizumab plus mFOLFOX6 or mFOLFOX6 alone. Atezolizumab was given concurrently with chemotherapy for 6 months and then continued as monotherapy to complete 12 months of immunotherapy. The primary end point was disease-free survival.

After a median follow-up of nearly 41 months, disease recurrence or death occurred in 46 patients in the atezolizumab group vs 81 in the chemotherapy-alone group. This corresponded to a 50% lower likelihood of recurrence or death with the addition of immunotherapy.

Baseline characteristics were balanced between groups, with a median age of 64 years and more than half of patients classified as high risk based on T stage (local tumor extent) and nodal stage. More than 80% had proximal tumors, and about one-fifth had Lynch syndrome.

Subgroup analyses showed consistent benefit across most clinical categories, including T stage, nodal status, and risk group. However, data suggest that treatment effect may depend on chemotherapy exposure. Patients who received more than six cycles (three months) of mFOLFOX6 had a greater benefit from the addition of atezolizumab, while the benefit appeared less pronounced among those who received six cycles or fewer.

The overall survival results are still early. After a median follow-up of about 46 months, there was no meaningful difference between the groups. About 90% of patients in the atezolizumab group and 88% in the chemotherapy group were alive at five years.

Safety findings were consistent with known profiles of chemotherapy and immune checkpoint inhibition. Grade 3 or 4 adverse events occurred in 84% of patients receiving atezolizumab plus chemotherapy vs 72% with chemotherapy alone. Higher rates of fatigue, neutropenia, and gastrointestinal toxic effects were observed with the combination. Immune-related events, including hypothyroidism, hyperglycemia, colitis, and rash, were more common with atezolizumab, although severe immune-related events were uncommon and similar between groups.

More patients stopped treatment in the atezolizumab-containing group, often due to side effects or other reasons.

The investigators pointed out a few limitations. The overall survival results are still early, and many patients in both groups subsequently received immunotherapy after their cancer returned or metastasized, which may make survival differences harder to see. The study also was not designed to test atezolizumab on its own, and the results about how long chemotherapy should be given are exploratory.

For gastroenterologists, the results reinforce the importance of universal mismatch repair testing in colon cancer to identify patients eligible for immunotherapy-based adjuvant strategies, in addition to enabling the detection of Lynch syndrome. The magnitude of disease-free survival benefit observed in the trial suggests a new standard option for patients with stage III dMMR colon cancers, particularly those able to complete full-course chemotherapy.

“The addition of atezolizumab to mFOLFOX6 therapy resulted in a significantly lower risk of recurrence or death, which indicates that it is an effective adjuvant treatment in patients with resected dMMR stage III colon cancer,” the authors concluded.

The study was funded by the National Cancer Institute and Genentech. Many study authors reported relationships with industry, detailed in the publication.

Q & A with Dr. Sinicrope

GI & Hepatology News invited Dr.  Sinicrope to provide further insight into the study’s findings.

Why does this study matter?

Dr. Sinicrope: Evidence indicates that colon cancers with defective DNA mismatch repair (dMMR) do not respond as well to chemotherapy compared to the more common type with proficient or intact mismatch repair. Until a short time ago, however, all patients with stage III or node positive colon cancer, regardless of their mismatch repair status, were recommended to receive combination chemotherapy after surgical resection with curative intent.

The ATOMIC trial addressed the question of whether adding an immune checkpoint inhibitor to standard adjuvant chemotherapy can improve patient survival. ATOMIC demonstrates that the addition of atezolizumab, an immune checkpoint inhibitor, to standard FOLFOX chemotherapy in patients with dMMR stage III colon cancer can significantly improve patient disease-free survival with an approximately 50% reduction in recurrence or death compared to FOLFOX alone. These findings are practice-changing and have been added to the NCCN guidelines.

When you had all the data in front of you, was there a finding, or perhaps more than one, that surprised you?

Dr. Sinicrope: In oncology, what works in metastatic disease is typically studied subsequently in earlier stage disease. However, this strategy failed for anti-EGFR and anti-VEGF antibodies which, well standard treatment in metastatic disease, did not improve outcomes in earlier stage CRC where micrometastases are believed responsible for recurrence. While the biology behind immune checkpoint inhibitors is very different, there was concern about efficacy of immunotherapy in non-metastatic disease. Also, the study evaluated an anti-PD-L1 antibody whereas most of the data in metastatic CRC had been obtained using anti-PD-1 antibodies, and no direct comparative data between these two are available.

How might the findings influence clinical practice for gastroenterologists?

Dr. Sinicrope: Until recently, only patients with metastatic dMMR cancers were recommended to receive initial treatment with immunotherapy. Our data extends the use of immunotherapy to earlier stage colon cancers, and gastroenterologists commonly see these patients and find their cancers at colonoscopy. While all patients with newly diagnosed CRC are recommended to undergo tumor testing for DNA mismatch repair status, the intent has been primarily to identify patients with Lynch syndrome which is the most common hereditary CRC syndrome. Importantly, such testing serves the dual purpose of identifying CRC patients with deficient mismatch repair who are candidates for immunotherapy.

Is there anything else you'd like to say about this work?

Dr. Sinicrope: In metastatic CRC with deficient mismatch repair, initial treatment is with only an immune checkpoint inhibitor(s) without chemotherapy. A common question is whether immunotherapy alone is sufficient in stage III patients. ATOMIC was not designed to look only at immunotherapy alone since at the time it was designed, chemotherapy was standard of care, and it was considered unethical not to give it. So, we cannot formally answer this question. However, a prespecified analysis was done looking at chemotherapy duration and patient disease-free survival and there is a suggestion that the chemotherapy duration (combined with immunotherapy) impacts patient survival. We will be doing a deep dive into these data which will be submitted for an upcoming oncology meeting.