In platinum-ineligible patients with advanced non–small cell lung cancer (NSCLC), first-line treatment with the PD-L1 checkpoint inhibitor atezolizumab improved overall survival by an absolute value of about 1 month but almost doubled the rate of 2-year overall survival compared with chemotherapy (vinorelbine or gemcitabine), according to the results of the phase III IPSOS trial, which was presented as a Presidential Symposium by Siow Ming Lee, MD, Professor of Medical Oncology at University College London Hospitals, United Kingdom, at the European Society for Medical Oncology (ESMO) Congress 2022.1 IPSOS met its primary endpoint. The survival benefit of atezolizumab vs chemotherapy was evident across all subgroups, including PD-L1 expression levels, performance status, and histology, the study authors reported.
Siow Ming Lee, MD
At a median follow-up of 41.0 months, the median overall survival was 10.3 months in patients treated with atezolizumab vs 9.2 months in the chemotherapy arm, translating to a 22% reduction in the risk of death with atezolizumab (P = .028). At 12 months, the rate of overall survival was 43.7% with atezolizumab vs 38.6% with chemotherapy, and the 24-month overall survival rate was almost double that with chemotherapy (24.3% vs 12.4%).
“For more than 20 years, clinical trials have not brought significant improvement for this unmet-need population who were predominantly elderly with poor performance status or several comorbidities and treated with less effective single-agent chemotherapy or offered best supportive care. IPSOS is the first randomized trial to show that first-line atezolizumab treatment significantly improves overall survival compared with single-agent chemotherapy for these poor-prognosis patients with no EGFR and ALK alterations,” said Dr. Lee.
“Twice as many patients remained alive at 2 years when treated with atezolizumab, and an overall survival benefit was seen regardless of patients’ age, histology, PD-L1 status, and ECOG performance status. Atezolizumab also stabilized and/or improved some health-related quality-of-life measures…. Our results are just as good or better than many newer-generation platinum doublet chemotherapy trials conducted on patients with good performance status, including the classic ECOG 1594 trial comparing four different platinum-doublet regimens, where they had to stop recruiting performance status 2 patients because of an excessive serious toxicity problem,” Dr. Lee continued.2
Platinum-ineligible patients account for approximately 40% of patients with advanced NSCLC. Criteria include an Eastern Cooperative Oncology Group (ECOG) performance status of at least two and/or significant comorbidities. This population is typically excluded from the pivotal immunotherapy clinical trials with strict platinum eligibility criteria. IPSOS was designed to evaluate the efficacy of first-line immunotherapy in platinum-ineligible patients.
“Many patients with advanced-stage lung cancer cannot tolerate standard platinum-based chemotherapy. IPSOS is a randomized phase III trial [designed] to examine the role of immunotherapy with first-line atezolizumab for patients with advanced-stage NSCLC deemed not eligible to receive platinum-based chemotherapy because of poor performance status or elderly patients with significant contraindications,” Dr. Lee explained.
Study Design and Main Results
The study enrolled 453 treatment-naive, stage IIIB/IV, squamous or nonsquamous NSCLC. Reasons for platinum ineligibility included an ECOG performance status of 2 or 3 or age of at least 70 years as well as substantial comorbidities or contraindications to platinum. Asymptomatic, treated brain metastases were allowed. Patients with EGFR or ALK alterations were excluded. PD-L1 status was a stratification factor. A total of 83% had an ECOG performance status of at least 2.
Patients were randomly assigned 2:1 to receive 1,200 mg of intravenous (IV) atezolizumab every 3 weeks until progressive disease or loss of clinical benefit or either oral or IV vinorelbine or IV gemcitabine in three or four cycles or until progressive disease. Median patient age was 75 years, and 31% were 80 or older. The primary endpoint was overall survival. Secondary endpoints were 6-, 12-, 18-, and 24-month survival rates, progression-free survival, objective response rate, duration of response, as well as overall and progression-free survival in the PD-L1–positive subgroups.
Objective response rates and duration of response rates were approximately double with atezolizumab compared with chemotherapy. Objective response rates were 16.9% with atezolizumab vs 7.9% with chemotherapy, for an absolute difference of 9% between the two treatment arms. Median duration of response was 14.0 months vs 7.8 months, respectively. Median progression-free survival did not differ between the two treatment arms: 4.2 months vs 4.0 months, respectively, even though numerically there was an improved progression-free survival rate with longer follow-up, particularly at the 2-year mark (8.9% vs 1.6%) for the atezolizumab arm after the medidan was reached.
Quality of life was assessed by the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 functioning scales and symptoms questionnaires. Role function, cognitive function, and social function domains remained stable with atezolizumab patients, whereas chemotherapy patients showed deterioration from baseline to week 48 of treatment. Clinically meaningful changes were reported across several disease- and treatment-related symptoms, including an improvement in appetite loss, chest pain, and cough with atezolizumab; an improvement in insomnia with chemotherapy; and a worsening of appetite loss, peripheral neuropathy, and alopecia with chemotherapy.
No new or unexpected safety concerns emerged with atezolizumab treatment despite a longer duration of treatment. Treatment-related adverse effects occurred in 57.0% of patients in the atezolizumab arm vs 80.3% of those in the chemotherapy arm. Serious treatment-related adverse events were reported in 11.7% and 15.6% of patients, respectively. Three treatment-related deaths were reported in the atezolizumab arm vs four in the chemotherapy arm.
DISCLOSURE: Dr. Lee has received research grants from Roche for his academic investigator-initiated trials (TOPICAL and TACTIC).
“Platinum-ineligible patients are typically excluded from clinical trials, yet they represent the majority of patients that we diagnose and treat—patients with poor performance status and comorbidities,” said invited discussant Natasha Leighl, MD, of the Princess Margaret Cancer Centre, Toronto....