FDA Approves Atezolizumab With Chemotherapy as Adjuvant Therapy for Stage III dMMR Colon Cancer
The Food and Drug Administration approved atezolizumab with a fluoropyrimidine and oxaliplatin on Oct. 8 for resected stage III dMMR colon cancer. In ATOMIC, the disease-free survival hazard ratio was 0.50, but overall survival data are still immature.
On Oct. 8, the Food and Drug Administration approved atezolizumab (Tecentriq, Genentech) with a fluoropyrimidine and oxaliplatin for the adjuvant treatment of stage III colon cancer that is mismatch repair deficient (dMMR). The agency also approved subcutaneous atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza) for the same use.
The Alliance for Clinical Trials in Oncology, which led the supporting trial, said in an Oct. 9 statement that the results "represent the first demonstrated benefit of adjuvant immunotherapy in early-stage dMMR colon cancer."
What the label covers
The FDA notice names dMMR disease and does not use the term MSI-H, although some trade headlines add it. It names no companion diagnostic. The age wording differs by product: intravenous atezolizumab is approved for adults and pediatric patients 2 years and older, while the subcutaneous product is approved for patients 12 and older who weigh at least 40 kg.
In adults, the intravenous dose is 840 mg every two weeks, 1,200 mg every three weeks or 1,680 mg every four weeks with chemotherapy for six months. Atezolizumab then continues alone for six months or until recurrence or unacceptable toxicity. The subcutaneous dose is one 15 mL injection every three weeks, containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase, on the same schedule.
What ATOMIC showed
The approval rests on ATOMIC (Alliance A021502; NCT02912559), a randomized, open-label, active-controlled phase 3 trial that enrolled 712 patients from September 2017 through January 2023. The New England Journal of Medicine report assigned 355 to atezolizumab plus modified FOLFOX6 (mFOLFOX6) and 357 to mFOLFOX6 alone. The FDA counts 711 adults and one pediatric patient, so the pediatric indication rests on very little direct trial data.
The primary endpoint was investigator-assessed disease-free survival. The FDA reported a hazard ratio of 0.50 (95% CI, 0.35 to 0.73; p=0.0001), with median disease-free survival not reached in either arm. At a median follow-up of 40.9 months, 3-year disease-free survival was 86.3 percent (95% CI, 81.8 to 89.8) with the combination and 76.2 percent (95% CI, 70.9 to 80.6) with chemotherapy alone, the trial report said.
The disease-free survival gain is clear. Whether it becomes an overall survival gain is not yet known.
What the data cannot yet say
Overall survival was a secondary endpoint. At a median follow-up of 45.8 months, the full trial report counted 31 deaths in the atezolizumab arm and 33 in the control arm. Five-year overall survival was 89.7 percent with atezolizumab and 87.9 percent with chemotherapy alone (hazard ratio, 0.90; 95% CI, 0.55 to 1.47; p=0.68). With so few events, the interval is wide and the survival question is open.
The comparator was six months of mFOLFOX6, a standard regimen, but the experimental arm received 12 months of therapy in total. The design does not isolate the contribution of the monotherapy phase. In an analysis by chemotherapy duration, the hazard ratio was 0.41 for patients who received more than six cycles of mFOLFOX6 and 0.97 for those who received six or fewer. That is hypothesis-generating at best.
Some oncologists have gone further. Bishal Gyawali of Queen’s University and colleagues argued in Nature Reviews Clinical Oncology that ATOMIC "should not change clinical practice but rather form the basis for future trials that test de-escalation strategies."
Safety
Grade 3 or 4 adverse events occurred in 84.1 percent of patients given the combination and 71.9 percent of those given chemotherapy alone. Grade 5 events occurred in six patients in the combination arm and two in the control arm, and investigators judged two combination-arm deaths (one sudden death, one sepsis) treatment related. All-grade colitis was 6.6 percent versus 0.6 percent, and hypothyroidism 19.9 percent versus 3.9 percent, according to the trial report. The label carries warnings for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem-cell transplantation and embryo-fetal toxicity.
What it means in clinic
Eligibility turns on dMMR status, so the result has to be on the chart before the adjuvant plan is set. ATOMIC accepted dMMR by local immunohistochemistry or a reference laboratory, with central confirmation done retrospectively, and it allowed one cycle of mFOLFOX6 before enrollment while results were pending. Patients known to have Lynch syndrome were eligible.
Practices can check two things this week: whether mismatch repair testing is ordered on every resected stage III specimen, and how long the result takes to come back. Patients will also need a plain account of what a disease-free survival benefit does and does not promise, and the usual rules for communicating risk apply. Confirm payer coverage for both formulations, since the approval is new.
Reported, fact-checked and edited by The Script Pad's editorial staff.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
