As reported in The New England Journal of Medicine by Roy S. Herbst, MD, PhD, and colleagues, the phase III IMpower110 trial has shown significantly prolonged overall survival with first-line atezolizumab vs platinum-based chemotherapy in patients with metastatic non–small cell lung cancer (NSCLC) with high PD-L1 expression.

The trial supported the May 2020 U.S. Food and Drug Administration approval of atezolizumab for the first-line treatment of patients with metastatic NSCLC with tumors that have high PD-L1 expression and no EGFR or ALK genomic tumor aberrations. High PD-L1 expression was defined as PD-L1 staining of ≥ 50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 10% of the tumor area.

Roy S. Herbst, MD, PhD

Study Details

The open-label trial included 572 patients from sites in 19 countries who had metastatic nonsquamous or squamous NSCLC and PD-L1 expression on ≥ 1% of tumor cells or tumor-infiltrating immune cells. Patients were randomly assigned between July 2015 and February 2018 to receive atezolizumab (n = 285) or chemotherapy (n = 287). Random assignment was stratified according to sex, Eastern Cooperative Oncology Group performance status score, histologic type, and PD-L1 status. The population with EGFR and ALK wild-type tumors consisted of 554 patients, including 277 patients in each group. The 18 patients with an EGFR mutation or ALK translocation were excluded from the primary analysis population.

Treatment consisted of atezolizumab at 1,200 mg or 4 or 6 cycles of platinum-based chemotherapy once every 3 weeks. In the chemotherapy group, patients with nonsquamous NSCLC (69% of atezolizumab group, 70% of chemotherapy group) received either cisplatin at 75 mg/m² or carboplatin at AUC = 6 in addition to pemetrexed at 500 mg/m². Patients with squamous NSCLC received cisplatin at 75 mg/m² plus gemcitabine at 1,250 mg/m² or carboplatin AUC = 5 plus gemcitabine at 1,000 mg/m².

The primary endpoint was overall survival tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat primary analysis population. Testing was performed among patients with high PD-L1 expression, defined as expression on ≥ 50% of tumor cells or ≥ 10% of tumor-infiltrating immune cells; then among those with intermediate and high expression, defined as expression on ≥ 5% of tumor cells or tumor-infiltrating immune cells; and then among those with any expression, defined as expression on ≥ 1% of tumor cells or tumor-infiltrating immune cells.  

Overall Survival

Median follow-up ranged from 13.4 to 15.7 months according to PD-L1 groups. A total of 107 patients (38.6%) in the atezolizumab group and 98 (35.4%) in the chemotherapy group had high expression of PD-L1. Among these patients, median overall survival was 20.2 months in the atezolizumab group vs 13.1 months in the chemotherapy group (stratified hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.40–0.89, P = .01). Median overall survival was 20.2 vs 10.5 months (HR = 0.62, 95% CI = 0.40–0.96) among patients with nonsquamous histology and not reached vs 15.3 months (HR = 0.56, 95% CI = 0.23–1.37) among those with squamous histology.

A total of 166 patients (59.9%) in the atezolizumab group and 162 (58.5%) in the chemotherapy group had high or intermediate PD-L1 expression. Among these patients, median overall survival was 18.2 months vs 14.9 months (stratified HR = 0.72, 95% CI = 0.52–0.99, P = .04).

The testing boundary for overall survival was not crossed in this analysis, and thus overall survival among patients with any PD-L1 expression (277 in each group) was not formally tested. Median overall survival among these patients was 17.5 months vs 14.1 months (stratified HR = 0.83, 95% CI = 0.65–1.07).

Among patients with high PD-L1 expression, median progression-free survival was 8.1 months in the atezolizumab group vs 5.0 months in the chemotherapy group (stratified HR = 0.63, 95% CI = 0.45–0.88). Among patients with high or intermediate PD-L1 expression, median progression-free survival was 7.2 months vs 5.5 months (stratified HR = 0.67, 95% CI = 0.52–0.88).

Adverse Events

Grade 3 or 4 adverse events occurred in 30.1% of patients in the atezolizumab group and in 52.5% of the chemotherapy group. Those occurring in ≥ 5% of either group were anemia (18%), neutropenia (18%), and thrombocytopenia (7%), all in the chemotherapy group. Serious adverse events occurred in 28.3% vs 28.5% of patients. Adverse events led to death in 11 patients (3.8%) in the atezolizumab group and 11 patients (4.2%) in the chemotherapy group. Immune-related adverse events occurred in 40.2% vs 16.7% of patients and were grade 3 or 4 in 6.6% and 1.5%. No immune-related adverse events led to death.

The investigators concluded: “Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type.”

Disclosure: The study was funded by F. Hoffmann–La Roche/Genentech. For full disclosures of the study authors, visit nejm.org.