Atezolizumab given after chemotherapy to patients with resected stage II to IIIA non–small cell lung cancer (NSCLC) significantly improved disease-free survival compared with best supportive care alone in patients whose tumors expressed PD-L1.¹ These results of the global phase III IMpower010 trial suggest that the addition of atezolizumab to adjuvant chemotherapy has the potential to become a standard of care earlier in the course of disease for this selected group of patients.

“The advances in treating NSCLC have primarily been in the setting of advanced disease. This is the first phase III study to demonstrate that [atezolizumab] after surgery and chemotherapy can significantly delay recurrence in patients with early-stage lung cancer,” stated lead author Heather A. Wakelee, MD, FASCO, Chief of the Division of Oncology, Stanford University Medical Center, at a press briefing held prior to the 2021 ASCO Annual Meeting.

Heather A. Wakelee, MD, FASCO

The standard of care for many patients with stage IB to IIIA NSCLC has not changed in many years, although treatments have improved for stage IV NSCLC. “The recent ADAURA trial found that adjuvant treatment with osimertinib improved outcomes for resected EGFR-mutated NSCLC,² but for the vast majority of these patients, the standard of care has not changed in over 15 years and remains four cycles of platinum-based chemotherapy,” Dr. Wakelee told listeners.

With adjuvant chemotherapy in patients with completely resected NSCLC, the risk of death and recurrence is reduced by 16%,³ and disease recurrence is still common. The IMpower010 trial was designed to see whether the immune checkpoint inhibitor atezolizu­mab added to chemotherapy for patients with completely resected stage IB to IIIA NSCLC would improve outcomes.

Study Details

The phase III IMpower010 trial enrolled 1,280 patients, who were all treated with adjuvant cisplatin-based chemotherapy after undergoing complete surgical resection for stage IB to IIIA NSCLC. Those patients still meeting eligibility criteria after completion of chemotherapy (n = 1,005) were randomly assigned 1:1 to receive atezolizumab at 1,200 mg every 21 days (for up to 16 cycles) vs best supportive care.

The primary endpoint of disease-free survival was analyzed in three subgroups: patients with stage II to IIIA tumors and a PD-L1 tumor composite score ≥ 1%; all randomly assigned patients with stage II to IIIA NSCLC; and an intention-to-treat analysis of patients with stage IB to IIIA NSCLC. In this analysis, about half of all patients diagnosed with early-stage NSCLC have tumors that express PD-L1.

Major Findings

At a median follow-up of 32.8 months, in patients with stage II to IIIA resected NSCLC and a PD-LI tumor composite score ≥ 1%, atezolizumab, given after adjuvant chemotherapy, reduced the risk of disease progression or death by 34% vs best supportive care (P = .004). Median disease-free survival was not reached in the atezolizumab-treated group vs 35.3 months for those given best supportive care.

For all patients with stage II to IIIA ­NSCLC, the addition of atezolizumab reduced the risk of disease progression by 21% vs best supportive care. Median disease-free survival was 42.3 months for the atezolizumab-treated group and 35.3 months for those given best ­supportive care. 

In the intention-to-treat analysis of all patients, which included all patients with stage IB to IIIA NSCLC, the significance boundaries have not been crossed for disease-free survival at this interim analysis.

“We haven’t analyzed the data separately yet for the patients with stage IB disease, but overall in stage II to IIIA patients, we are not seeing a benefit for atezolizumab in those without PD-L1 expression. Only 12% of patients on the trial had stage IB disease, and this group tends to do better overall, with lower rates of recurrence, so we are not surprised that we will have to wait a bit longer to see the outcomes in those patients,” Dr. Wakelee explained. The study is ongoing, and survival data are still immature.

Safety data were consistent with the known safety profile of atezolizumab, and no new safety signals emerged over the course of the trial. More patients who received atezolizumab after chemotherapy and surgery had any-grade adverse events: 92.7% vs 70.7% for best supportive care. Grade 3 to 4 adverse events were reported in 21.8% and 11.5% of patients, respectively, with or without atezolizumab. Grade 5 treatment-related adverse events occurred in 0.8% of the atezolizumab group and were not applicable in the control arm. Adverse events leading to treatment withdrawal were reported in 18.2% of the atezolizumab arm and were not applicable in the control arm.

Study Implications

Given the significantly improved disease-free survival with adjuvant atezolizumab in patients with tumors expressing PD-L1, it is more important than ever to screen high-risk people for lung cancer to improve detection of NSCLC at early stages, and if NSCLC is detected, to do biomarker testing for EGFR mutations and now for PD-L1 expression. “In the IMpower010 trial, the vast majority of the benefit appeared to be in those patients whose tumors express PD-L1,” said Dr. Wakelee.

When asked whether adjuvant atezolizumab would become a new standard of care earlier in the course of lung cancer, Dr. Wakelee said: “Obviously, we need U.S. Food and Drug Administration [FDA] approval before this is offered as standard of care. The FDA has approved osimertinib in resected early-stage NSCLC with EGFR mutations based on a disease-free survival endpoint. The ­IMpower010 study showed that in patients with stage II to IIIA NSCLC and PD-L1 expression, atezolizu­mab after chemotherapy improved ­disease-free survival, and it is a more profound disease-free survival benefit than what was seen with chemotherapy alone in the ealier adjuvant trials. If approved, atezolizumab would be something I would want to offer my patients in that setting.”

Comments on IMpower010

Julie R. Gralow, MD, FACP, FASCO, ASCO Chief Medical Officer and Executive Vice President, commented on these study findings: “New checkpoint inhibitors have changed the landscape for the treatment of NSCLC. The first approval was for ipilimumab in metastatic melanoma in 2010. Since then, several checkpoint inhibitors have been approved for other cancers. Most target PD-1/PD-L1. The first approval of a checkpoint inhibitor in metastatic lung cancer was in 2014.”

Julie R. Gralow, MD, FACP, FASCO

Vamsidhar Velcheti, MD

Dr. Gralow continued: “The IMpower study is the first to show [atezolizumab] is effective in early-stage NSCLC. This is an important advance in understanding the role of immunotherapy in early-stage lung cancer. This trial represents a potential step forward for certain patients with lung cancer, in whom atezolizumab can reduce recurrences and [disease] progression.”

Vamsidhar Velcheti, MD, Director of Thoracic Oncology at NYU Langone’s Perlmutter Cancer Center, also commented on these results. “IMpower010 is the first study of [atezolizumab] that demonstrates improved disease-free survival in patients with early-stage NSCLC. Patients with stage II to IIIA resectable NSCLC have high rates of disease recurrence despite adjuvant chemotherapy. There is clearly an unmet need for systemic therapy here to improve the potential for cure in this setting.” 

Dr. Velcheti added: “Though we don’t have overall survival readout from the trial yet, the improvement in disease-free survival with atezolizumab [in PD-L1–positive NSCLC] is a promising sign that we may be able to improve long-term survival for these patients. Further data, including overall survival analysis and subgroup analysis based on PD-L1, are awaited.” 

DISCLOSURE: The IMpower010 study was funded by F. Hoffmann–LaRoche Ltd. Dr. Wakelee has served as a consultant or advisor to AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Helsinn Therapeutics, Janssen Oncology, Mirati Therapeutics, and Xcovery; has received institutional research funding from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/MedImmune, Bristol Myers Squibb, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead Sciences, Merck, Novartis, Pharmacyclics, Seattle Genetics, and Xcovery; and has held uncompensated relationships with Genentech/Roche, Merck, and Takeda. Dr. Gralow has served as a consultant or advisor to AstraZeneca, Genentech, Genomic Health, Hexal, Novartis, Puma Biotechnology, Roche, and Seagen. Dr. Velcheti has served as a consultant or advisor to Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, EMD Serono, Foundation Medicine, GSK, Lilly, Merck, Novartis, and Novocure; and has received institutional research funding from Alkermes, Altor BioScience, Atreca, Bristol Myers Squibb, Eisai, Genentech, Genoptix, GlaxoSmithKline, Heat Biologics, Leap Therapeutics, Merck, NantOmics, OncoPlex Diagnostics, RSIP Vision, and Trovagene.

REFERENCES

1. Wakelee H, Altorki N, Zhou C, et al: IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer. 2021 ASCO Annual Meeting. Abstract 8500. Presented June 6, 2021.

2. Wu YL, Tsuboi M, He J, et al: Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med 383:1711-1723, 2020.

3. Pignon JP, Tribodet H, Scagliotti G, et al: Lung adjuvant cisplatin evaluation. J Clin Oncol 26:3552-3559, 2008.