In a phase III IPSOS study, first-line treatment with the PD-L1 inhibitor atezolizumab improved overall survival (OS) and resulted in a clinically meaningful doubling of the 2-year survival rate in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who were unfit for platinum-doublet chemotherapy. Moreover, it was associated with maintenance of quality-of-life (QoL) and a favourable safety profile compared with third-generation single-agent chemotherapy. Objective response rates and duration of response were also approximately double with atezolizumab compared with chemotherapy.

This is the first randomised study examining the efficacy and safety of immune checkpoint inhibitor (ICI) in a population of patients with NSCLC who are ineligible for platinum-based chemotherapy. The findings are published by Prof. Siow Ming Lee of the Department of Oncology, UCLH NHS Foundation Trust in London, UK, and colleagues on 6 July 2023 in the Lancet.

The authors wrote in the background that first-line clinical studies with ICIs were conducted in patients with a good performance status or who were able to tolerate standard platinum-based chemotherapy and had a median age of 65 years or younger. Although platinum-based chemotherapy doublets are recommended for older patients (≥70 years) with ECOG performance status 0 to 1 and for some patients with a score of 2 who do not present with substantial comorbidities, there remains a large population of older patients with NSCLC who have poor performance status or comorbidities, many of whom cannot tolerate standard platinum-based chemotherapy. These patients are often treated with less-effective single-agent chemotherapy or offered active supportive care, including palliative radiotherapy.

The PD-L1 inhibitor atezolizumab has been shown to improve OS versus single-agent chemotherapy in patients with previously treated metastatic NSCLC and as first-line treatment in PD-L1–high NSCLC, but these studies only enrolled patients with good performance status. The phase III IPSOS study of first-line atezolizumab monotherapy versus single-agent chemotherapy in patients with NSCLC ineligible for treatment with a platinum-containing regimen was designed to address the gap in available ICI data from large randomised studies in patients with NSCLC who present with ECOG performance status 2 to 3 or were aged 70 years or older with comorbidities or contraindications to any platinum-based combinations.

This study was a phase III, open-label, randomised controlled study conducted at 91 sites in 23 countries across Asia, Europe, North America, and South America. Eligible patients had stage IIIB or IV NSCLC in whom platinum-doublet chemotherapy was deemed unsuitable by the investigator due to an ECOG performance status 2 or 3, or alternatively, being 70 years or older with an ECOG performance status 0 to 1 with substantial comorbidities or contraindications for platinum-doublet chemotherapy. Patients were randomised 2:1 to receive 1200 mg of atezolizumab given intravenously every 3 weeks or single-agent chemotherapy (vinorelbine given orally or intravenously or gemcitabine given intravenously; dosing per local label) at 3-weekly or 4-weekly cycles.

The primary endpoint was OS assessed in the intention-to-treat population. Safety analyses were conducted in the safety-evaluable population, which included all randomised patients who received any amount of atezolizumab or chemotherapy.

Between 11 September 2017 and 23 September 2019, 453 patients were enrolled and 302 randomised to receive atezolizumab and 151 to chemotherapy. Atezolizumab improved OS compared with chemotherapy; median OS was 10.3 months (95% confidence interval [CI] 9.4–11.9) versus 9.2 months (5.9–11.2) with stratified hazard ratio 0.78 (0.63–0.97, p = 0.028), with a 2-year survival rate of 24% (95% CI 19.3–29.4) with atezolizumab compared with 12% (6.7–18.0) with chemotherapy.

Compared with chemotherapy, atezolizumab was associated with stabilisation or improvement of patient-reported health-related QoL functioning scales and symptoms and fewer grade 3-4 treatment-related adverse events (16% versus 33%) and treatment-related deaths (1% versus 3%).

The authors wrote that IPSOS provides new insights into the benefits of atezolizumab in a NSCLC population who are older, frail, or have substantial comorbidities. However, in an accompanied comment, Dr. Hazel O’Sullivan of the Department of Medical Oncology, Cork University Hospital in Cork, Ireland and Prof. Sanjay Popat of the Section of Clinical Trials, Institute of Cancer Research and Lung Unit, Royal Marsden Hospital in London, UK underlined that although the OS benefit with atezolizumab is important, some questions remain.

Chronological age does not simply equal biological age, and due to its superiority to single-agent chemotherapy in patients 70 years and older or with an ECOG performance status of 2, guidelines recommend platinum-doublet chemotherapy for older patients if toxicity is deemed tolerable. However, in IPSOS, the control group was single-agent chemotherapy and platinum ineligibility was subjective, with platinum-ineligibility reasons not captured. Furthermore, objective standardised measures of comorbidity or frailty were not used, limiting objective interpretation of the study population and applicability to the clinic.

IPSOS also highlights a need for better patient selection and predictive biomarkers, as PD-L1 expression of 50% or more did not predict atezolizumab benefit, unlike in studies of fit patients, potentially related to immunosenescence (an increased immunosuppressive tumour microenvironment with advancing age) possibly abrogating ICI efficacy, or simply the dominant prognostic effect of comorbidity. IPSOS has identified a potential new indication for atezolizumab proving that randomised phase III studies can succeed in this population according to the editorialists.

This study was sponsored by F Hoffmann-La Roche and Genentech Inc, a member of the Roche group.