Tecentriq plus chemotherapy gains FDA approval for stage III dMMR colon cancer after a phase 3 trial showed improved disease-free survival.
The FDA has approved atezolizumab (Tecentriq) and its subcutaneous formulation with hyaluronidase-tqjs (Tecentriq Hybreza), each combined with a fluoropyrimidine and oxaliplatin, as adjuvant treatment for stage III colon cancer with deficient DNA mismatch repair (dMMR), Roche announced Oct. 9.1
The company counts the decision as the twelfth US indication for the programmed death-ligand 1 (PD-L1) inhibitor and, by its account, the first immunotherapy-based regimen in this setting.1
“This approval provides a new adjuvant treatment option for people with stage III dMMR colon cancer who face a high risk of disease recurrence,” said Levi Garraway, MD, PhD, Roche’s Chief Medical Officer and Head of Global Product Development.1
The approval covers intravenous atezolizumab and the subcutaneous co-formulation, both paired with chemotherapy.1 Roche said eligibility depends on mismatch repair status determined by an immunohistochemistry test, such as the Ventana MMR RxDx Panel.1
The agency accepted the supplemental biologics license application in June under priority review, with an Oct. 9 target action date, so the decision arrived on schedule.2 One scope difference is worth noting: the June filing announcement described dMMR or microsatellite instability–high tumors, while the approval announcement refers only to dMMR disease.1,2 The final label language was not available for review.
The approval rests on ATOMIC (Alliance A021502; NCT02912559), a phase 3, randomized, open-label study of 712 patients with resected stage III dMMR colon cancer.1 Participants received modified FOLFOX6 (mFOLFOX6) chemotherapy plus atezolizumab for 12 cycles, followed by 13 cycles of atezolizumab alone, or mFOLFOX6 alone for 12 cycles.1
The primary endpoint was disease-free survival.3 The National Cancer Institute sponsored the study, the Alliance for Clinical Trials in Oncology led it, and Genentech, a Roche Group member, provided support through a cooperative research agreement.1
Roche reports that adding atezolizumab reduced the risk of recurrence or death by 50%, with 36-month disease-free survival of 86% versus 76% for chemotherapy alone.1 In the published results, grade 3 or 4 adverse events occurred in 84.1% of patients receiving the combination and 71.9% of those receiving mFOLFOX6 alone.3
Roche describes the safety profile as consistent with earlier studies of the two regimens.1 Overall survival, a secondary endpoint, did not separate clearly. Five-year rates were 89.7% and 87.9% (hazard ratio, 0.90; 95% confidence interval, 0.55-1.47), and two deaths in the combination arm were considered treatment related, according to a summary of the published paper.4
Roche cites more than 1 million colon cancer diagnoses worldwide each year, with nearly 25% found at stage III. Nearly 30% of stage III patients experience recurrence within five years despite surgery and chemotherapy, the company said.1
Roughly 15% of colon cancers have dMMR or microsatellite instability–high features, which indicate higher mutation rates and potential responsiveness to immunotherapy.1
“Until now, the adjuvant standard of care for stage III colon cancer has not differed based on mismatch repair status,” said Frank A. Sinicrope, MD, Professor of Oncology at the Mayo Clinic and US principal investigator for ATOMIC.1 Sinicrope led the trial globally and is the corresponding author of its publication, so the assessment comes from an investigator close to the data.1,4
Atezolizumab is a monoclonal antibody that binds PD-L1 on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both the programmed death-1 and B7.1 receptors. Roche says this may re-activate T cells.1
The company also states that Tecentriq is the first immunotherapy targeting the programmed death-1 or PD-L1 pathway available in both subcutaneous and intravenous formulations.1 The announcement does not detail clinical data specific to the subcutaneous formulation in this setting.
The evidence base is a single open-label phase 3 trial in a molecularly defined subgroup. Approval is grounded in disease-free survival, and the wide confidence interval around the five-year overall survival estimate leaves the long-term survival effect an open question.4
Grade 3 or 4 adverse events were more frequent with the combination.3 Whether guidelines will adopt the regimen as a standard was not addressed in the materials reviewed.
Roche is pursuing further regulatory filings, including with the European Medicines Agency.1 How regulators outside the US weigh the same data, and how mismatch repair testing is applied to eligible patients, remain to be seen.
