PD-L1 Inhibitor Thwarts Recurrence in Early Lung Cancer

Patients with early-stage non-small cell lung cancer (NSCLC) lived significantly longer without disease recurrence if they received atezolizumab (Tecentriq) after surgery and chemotherapy, a large randomized trial showed.

Median disease-free survival (DFS) had yet to be reached after a median follow-up of 32.8 months, but the results met criteria for statistical significance, showing a 34% reduction in the hazard ratio for patients with stage II-IIIa disease and PD-L1 tumor cell expression ≥1%, said Heather Wakelee, MD, of Stanford University Medical Center in California, during a press briefing in advance of the virtual American Society of Clinical Oncology (ASCO) annual meeting.

An analysis limited to patients with stage II-IIIa disease (irrespective of PD-L1 expression) showed they were significantly more likely to be alive and disease free if they received atezolizumab instead of best supportive care (BSC) after chemotherapy. An intention-to-treat (ITT) analysis of all randomized patients showed a trend in favor of atezolizumab but has yet to achieve statistical superiority.

Beyond the DFS benefit, the trial further emphasized the importance of lung cancer screening and biomarker testing in patients with newly diagnosed NSCLC.

“IMpower010 is the first global phase III trial using an immune checkpoint inhibitor to show a disease-free survival outcome in early-stage non-small cell lung cancer,” said Wakelee. “It is important to emphasize that patients need screening to detect lung cancer early, when it is potentially curable.”

“We are now recommending to do biomarker testing for those patients who have had resected disease, to look for EGFR mutations, which can be treated with EGFR TKIs [tyrosine kinase inhibitors] and also, at some point, to check for PD-L1. In this trial, the vast majority of benefit seems to be in those patients who did have expression of PD-L1 in their tumors,” she added.

The findings represent another step forward in the investigation and discovery of the potential benefits of PD-1/L1 inhibitors in oncology, said ASCO Chief Medical Officer and Executive Vice President Julie Gralow, MD, of the University of Washington in Seattle.

“The IMpower010 study is the first time we’ve seen an immunotherapy that’s effective in treating early-stage non-small cell lung cancer,” she noted. “This is an important advance in understanding the role of immunotherapy in early-stage lung cancer, potentially a step forward for many patients with lung cancer.”

The emergence of cancer immunotherapy has transformed management of advanced NSCLC. However, standard of care for early-stage, operable disease has not changed in 15 years, and adjuvant platinum-based chemotherapy remains the primary option, said Wakelee. In patients with completely resected NSCLC, adjuvant chemotherapy reduces the risk of disease recurrence or death by 16%.

Recently, the ADAURA trial showed that adjuvant osimertinib (Tagrisso) significantly improved DFS in early-stage NSCLC associated with EGFR mutations. The IMpower010 trial evaluated the impact of adjuvant atezolizumab in early NSCLC without targetable mutations.

Investigators in the international trial enrolled patients with operable stage Ib-IIIa NSCLC and adequate tumor tissue for analysis of PD-L1 expression. Following surgery, all patients received investigator’s choice of chemotherapy and were randomized to atezolizumab administered every 21 days or BSC.

The primary endpoint was investigator-assessed DFS, which was evaluated in a hierarchical manner. The primary analysis was limited to patients with PD-L1 expression ≥1. If that analysis yielded positive results, subsequent analyses included all randomized patients with stage II-IIIa disease and the ITT population, which included stage Ib-IIIa disease. If all three DFS analyses were positive, investigators would formally compare overall survival (OS).

Data analysis included 1,005 randomized patients. An interim analysis of the primary endpoint (n=276) showed a median DFS of 35.3 months with BSC. The median had yet to be reached in the atezolizumab arm, but the data satisfied statistical criteria for superiority (95% CI 36.1 to NE). The difference translated into an HR of 0.66 (95% CI 0.50-0.88, P=0.004). Substantially more patients in the atezolizumab arm were alive and disease free at 24 months (74.6% vs 61.0%) and 36 months (60.0% vs 48.2%).

Analysis of the stage II-IIIa subgroup (n=882) showed a median DFS of 42.3 months in the atezolizumab arm and 35.3 months with BSC (HR 0.79, 95% CI 0.64-0.96, P=0.02). In the ITT analysis, median DFS had yet to be reached, but trended in favor of atezolizumab (HR 0.81, 95% CI 0.67-0.99, P=0.04).

The data for OS remain immature and were not formally tested at the interim analysis, said Wakelee. Follow-up continues for final DFS and OS outcomes in the ITT population.

Adverse events (AEs) were more common in the atezolizumab arm, including grade 3/4 AEs (21.8% vs 11.5%) and AEs leading to withdrawal (18.2% vs NA).

In response to a question from Gralow, Wakelee said subgroup analyses suggested greater benefit from atezolizumab in PD-L1-positive patients, who accounted for about half of the study population.