As reported in The Lancet by ­Enriqueta Felip, MD, of Vall d’Hebron University Hospital, Barcelona, and colleagues, the phase III IMpower010 trial has shown improved disease-free survival with adjuvant atezolizumab vs best supportive care in the predefined population of patients with resected stage II to IIIA non–small cell lung cancer (NSCLC) with tumor cell PD-L1 expression ≥ 1% who had received adjuvant platinum-based chemotherapy.¹ Improvement was also observed in the entire stage II to IIA population irrespective of PD-L1 status. Improvement was not significant in the total intention-to-treat population with stage IB to IIIA disease on hierarchical testing.

The findings in the stage II to IIIA PD-L1–positive population supported the October 2021 approval of atezolizumab in this setting.

Enriqueta Felip, MD

In the open-label trial, 1,005 patients with stage IB to IIIA disease (intention-to-treat population [AJCC/UICC 7th edition staging]) from sites in 22 countries who had undergone complete resection and received one to four cycles of adjuvant platinum-based chemotherapy were randomly assigned to receive atezolizumab at 1,200 mg every 21 days for 16 cycles or 1 year (n = 507) or best supportive care (n = 498). Randomization was stratified by sex, tumor histology, disease stage, and PD-L1 expression status as measured by the SP142 immunohistochemistry assay. The primary endpoint of investigator-assessed disease-free survival was tested hierarchically in the stage II to IIIA population with tumor cell PD-L1 expression ≥ 1% by the SP263 immunohistochemistry assay (n = 248 in the atezolizumab group; n = 228 in the control group), in all patients in the stage II to IIIA population (n = 442; n = 440), and in the intention-to-treat population.

Survival Outcomes

Median follow-up was 32 to 33 months among all populations tested. In the stage II to IIIA population with tumor cell PD-L1 expression ≥ 1% by SP263, median disease-free survival was not reached (95% confidence interval [CI] = 36.1 months to not evaluable) in the atezolizumab group vs 35.3 months (95% CI = 29.0 months to not evaluable) in the best supportive care group (stratified hazard ratio [HR] = 0.66, 95% CI = 0.50–0.88, P = .0039). Rates at 3 years were 60% vs 48%. In a subgroup analysis, unstratified hazard ratios were 0.43 (95% CI = 0.27–0.68) among patients with PD-L1 expression of ≥ 50% by SP263 and 0.87 (95% CI = 0.60–1.26) among patients with PD-L1 expression of 1% to 49% by SP263.

In the stage II to IIIA population, median disease-free survival was 42.3 months (95% CI = 36.0 months to not evaluable) in the atezolizumab group vs 35.3 months (95% CI = 30.4–46.4 months) in the best supportive care group (stratified HR = 0.79, 95% CI = 0.64–0.96, P = .020). Rates at 3 years were 56% vs 49%. Among patients with PD-L1 expression of < 1% by SP263, the unstratified hazard ratio was 0.97 (95% CI = 0.72–1.31).

In the intention-to-treat population, median disease-free survival was not reached (95% CI = 36.1 months to not evaluable) in the atezolizumab group vs 37.2 months (95% CI = 31.6 months to not evaluable) in the best supportive care group (HR = 0.81, 95% CI = 0.67–0.99, P = .040), with the prespecified boundary for statistical significance in the intention-to-treat analysis not being met. Rates at 3 years were 58% vs 53%.

Subsequent treatments included radiotherapy in 11% of the atezolizumab group vs 16% of the best supportive care group, surgery in 5% vs 7%, and systemic therapy in 20% vs 26%.

Overall survival was not formally tested due to the absence of statistical significance in the intention-to-treat disease-free survival analysis. In the intention-to-treat population, death had occurred in 19% of the atezolizumab group vs 18% of the control group at the time of analysis. Stratified hazard ratios were 1.07 (95% CI = 0.80–1.42) in the intention-to-treat population, 0.99 (95% CI = 0.73–1.33) in the stage II to IIIA population, and 0.77 (95% CI = 0.51–1.17) in the stage II to IIIA population with PD-L1 ≥ 1%.

Although the subgroup analyses in patients with PD-L1 ≥ 1% by SP263 showed a similar disease-free survival benefit of adjuvant atezolizumab in patients with EGFR-positive, EGFR-negative, and unknown status, the investigators noted: “These data should be interpreted with caution due to the small number of patients with a positive EGFR status (n = 43). Most patients with unknown EGFR (89%) or ALK status (81%) had squamous NSCLC, as testing was not required in these patients.”

Adverse Events

Among all patients, grade 3 or 4 adverse events occurred in 22% of the atezolizumab group vs 12% of the control group; the most common adverse events in the atezolizumab group were increased alanine aminotransferase (2%), pneumonia (1%), and increased aspartate aminotransferase (AST, 1%). Serious adverse events occurred in 18% vs 8% of patients. Adverse events led to discontinuation of atezolizumab in 18% of patients, most commonly due to pneumonitis, hypothyroidism, and increased AST (1% each).

Treatment-related adverse events occurred in 68% of the atezolizumab group (grade 3 or 4 in 11%). The most common adverse events of any grade were hypothyroidism (11%), pruritus (9%), and rash (8%). Immune-mediated adverse events of any grade occurred in 52% of the atezolizumab group and were grade 3 or 4 in 8%; 12% of patients required systemic corticosteroid treatment, and 11% of patients discontinued treatment due to immune-mediated events. Immune mediated adverse events were also reported in 9% of patients in the best supportive care arm and were grade 3 or 4 in 1%, with 1% requiring steroids. Treatment-related death occurred in four patients in the atezolizumab group.

The investigators concluded: “IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II–IIIA NSCLC, with pronounced benefit in the subgroup whose tumors expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC.” 

DISCLOSURE: The study was funded by F. Hoffmann–La Roche and Genentech. Dr. Felip has served as an advisor or consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono, MSD Oncology, Novaris, Pfizer, Roche, Peptomyc, and Takeda; has served on a speakers bureau for AstraZeneca, Bristol Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dohme, PeerVoice, Pfizer, Roche, Takeda, and CME Outfitters; has received research funding from Fundación Merck Salud, and Merck KGaA; and is an independent member of the board for and has received personal fees from Grifols. 

REFERENCE

1. Felip E, Altorki N, Zhou C, et al: Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB–IIIA non-small-cell lung cancer (IMpower010): A randomised, multicentre, open-label, phase 3 trial. Lancet 398:1344-1357, 2021.