As reported in The New England Journal of Medicine by Roy S. Herbst, MD, PhD, of Yale School of Medicine, and colleagues, the phase III IMpower110 trial has shown significantly prolonged overall survival with first-line atezolizumab vs platinum-based chemotherapy in metastatic non–small cell lung cancer (NSCLC) with high PD-L1 expression and no EGFR or ALK aberrations.¹

Roy S. Herbst, MD, PhD

The trial supported the May 2020 approval of atezolizumab for the first-line treatment of patients who have 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 at least 50% of tumor cells or PD-L1–stained tumor-infiltrating immune cells covering at least 10% of the tumor area.

Study Details

In the open-label trial, 572 patients from sites in 19 countries who had metastatic nonsquamous or squamous NSCLC and PD-L1 expression of tumor cells or immune cells ≥ 1% were randomly assigned between July 2015 and February 2018 to receive atezolizumab (n = 285) or chemotherapy (n = 287). Randomization 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 EGFR mutation or ALK translocation were excluded from the primary analysis population.

Treatment consisted of atezolizumab at 1,200 mg or four or six 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 at 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 tumor cells at least 50% or immune cells at least 10%, then intermediate and high expression, defined as tumor cells or immune cells at least 5%, and then any expression, defined as tumor cells or immune cells at least 1%.

Overall Survival and Other Efficacy Outcomes

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).

Objective response rates were 38.3% vs 28.6% among patients with high PD-L1 expression, 30.7% vs 32.1% among those with high or intermediate expression, and 29.2% vs 31.8% among those with any expression. Median durations of response were not reached (range = 1.8+ to 29.3+ months) vs 6.7 months (range = 2.6 to 23.9+ months), not reached (range = 1.8+ to 29.3+ months) vs 5.8 months (range = 2.6 to 23.9+ months), and not reached (range = 1.8+ to 29.3+ months) vs 5.7 months (range = 2.4 to 23.9+ months) in the respective PD-L1 expression categories.

A total of 389 patients were evaluated for blood-based tumor mutational burden; 22.4% of them had a tumor mutational burden score of at least 16 and constituted a population distinct from the high PD-L1 expression population. Median overall survival among these patients was 13.9 months in the atezolizumab group vs 8.5 months in the chemotherapy group (HR = 0.75, 95% CI = 0.41–1.35). Median progression-free survival was 6.8 months vs 4.4 months (HR = 0.55, 95% CI = 0.33–0.92).

Adverse Events

Adverse events of any grade that occurred with a at least 5% incidence in either group were anemia, nausea, neutropenia, constipation, thrombocytopenia, vomiting, increased creatinine, decreased platelets, leukopenia, and decreased neutrophils in the chemotherapy group and increased aspartate aminotransferase, pruritus, and hypothyroidism in the atezolizumab group. Grade 3 or 4 adverse events occurred in 30.1% of the atezolizumab group and in 52.5% of 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%. The most common of any grade in the atezolizumab group were rash (15.4%) and hypothyroidism (9.4%). 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. Dr. Herbst has served in a leadership position for Jun Shi Pharmaceuticals; has served as a consultant or advisor to AbbVie, ARMO Biosciences, AstraZeneca, Biodesix, Bolt Biotherapeutics, Bristol Myers Squibb, Cybrexa Therapeutics, EMD Serono, Genentech/Roche, Genmab, Halozyme, Heat Biologics, IMAB Biopharma, Immunocore, Infinity Pharmaceuticals, Jun Shi Pharmaceuticals, Lilly, Loxo, Merck, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Takeda, Tesaro, and Tocagen; and has received research funding from AstraZeneca, Genentech/Roche, Lilly, and Merck. For full disclosures of the study authors, visit nejm.org.

REFERENCE

1. Herbst RS, Giaccone G, de Marinis F, et al: Atezolizumab for first-line treatment of PD-L1–selected patients with NSCLC. N Engl J Med 383:1328-1339, 2020.