Peter Schmid, MD
As reported in The Lancet Oncology by Peter Schmid, MD, and colleagues, the prespecified second interim analysis of overall survival in the phase III IMpassion130 trial has shown no overall survival benefit with the addition of atezolizumab to nab-paclitaxel as first-line treatment of unresectable, locally advanced or metastatic triple-negative breast cancer. A potential benefit was observed among patients with programmed cell death ligand 1 (PD-L1)-stained tumor-infiltrating immune cells covering ≥ 1% of the tumor area (PD-L1–positive population).
Results of the final progression-free survival analysis—conducted at the time of first interim analysis of overall survival—showed significant benefit of adding atezolizumab to nab-paclitaxel in the PD-L1–positive population and supported the March 2019 accelerated approval of atezolizumab in combination with nab-paclitaxel in this setting.
In the double-blind trial, 902 patients were randomly assigned to receive atezolizumab plus nab-paclitaxel (n = 451) or placebo plus nab-paclitaxel (n = 451). Patients received 840 mg of atezolizumab or placebo intravenously on days 1 and 15 of 28-day cycles and 100 mg/m2 of nab-paclitaxel intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. The co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat population and in the PD-L1–positive population. Prespecified statistical hierarchical testing permitted formal testing for overall survival in the PD-L1–positive population only if results were significant in the intention-to-treat population.
At first interim analysis of overall survival, with a median follow up of 12.9 months, the hazard ratio (HR) favoring atezolizumab plus nab-paclitaxel was 0.84 (95% confidence interval [CI] = 0.69–1.02, P = .08) in the intention-to-treat population, which did not cross the prespecified significance boundary (α = .0065). In the PD-L1–positive population, median overall survival was 25.0 vs 15.5 months (HR = 0.62, 95% CI = 0.45–0.86).
The findings in the second interim analysis of overall survival in the current report are consistent with those in the first interim analysis. At second interim analysis, median follow-up was 18.5 months in the atezolizumab group and 17.5 months in the placebo group. Median overall survival was 21.0 months vs 18.7 months in the intention-to-treat population (stratified HR = 0.86, 95% CI = 0.72–1.02, P = .078). In an exploratory analysis of 185 vs 184 patients with PD-L1–positive tumors, median overall survival was 25.0 months vs 18.0 months (stratified HR = 0.71, 95% CI = 0.54–0.94).
Updated Safety Data
Updated safety data indicate that the most common grade 3 or 4 adverse events were neutropenia (8% of the atezolizu-mab group vs 8% of the placebo group), peripheral neuropathy (6% vs 3%), decreased neutrophil count (5% vs 4%), and fatigue (4% vs 3%). Treatment-related deaths occurred in two patients in the atezolizumab group (due to autoimmune hepatitis and septic shock, respectively) and one patient in the placebo group -(hepatic failure).
The investigators concluded, “Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population, but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell–positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell–positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need.” ■