Modest Population-Level Increases in Survival Observed After Implementation of Immune Checkpoint Inhibitors in the Treatment of Advanced NSCLC, Particularly Among the Older Patients

A large cohort study found that, among patients with advanced non-small cell lung cancer (NSCLC), the uptake of immune checkpoint inhibitors (ICIs) was rapid across all age groups. However, corresponding survival gains varied substantially by age. Among patients younger than 55 years, median survival increased on the order of 4 to 5 months. Conversely, survival improvements were less impressive in patients older than 75 years, with survival improving by approximately 1 month, failing to meet either ASCO or ESMO criteria for clinically meaningful survival benefit. The implications for cancer-related symptoms and quality-of-life (QoL) were not evaluated in the present study. The findings are published by Dr. Cary P. Gross of the Cancer Outcomes, Public Policy and Effectiveness Research (COPPER) Center, Yale School of Medicine in New Haven, CT, US and colleagues on 26 January 2023 in the JAMA Oncology.

The authors wrote in the background that several ICIs substantially prolong survival after a diagnosis of advanced NSCLC in the clinical trial setting and the use of newly approved treatments has been rapid. Although clinical trials suggest substantial survival benefits, it is unclear how outcomes have changed in clinical practice as the patients in community setting tend to differ from those who participate in clinical trials. For example, one study of pembrolizumab as an initial treatment in patients with metastatic NSCLC found that median overall survival (OS) among patients in the non-clinical trial setting was about 16 months compared with 30 months among those in a clinical trial. Furthermore, it is unclear whether improvement in survival after a diagnosis of advanced NSCLC is similar across age groups.

The aim of the current study was to assess the implications of the adoption of ICIs by evaluating treatment patterns and survival trends across age groups, with an emphasis on comparing the outcomes of patients with advanced NSCLC diagnosed before and after ICIs became widely available. The study team used the ASCO and ESMO clinical benefit frameworks to guide interpretation of whether changes in survival were clinically meaningful. In a secondary analysis, they evaluated patterns of ICI use with and without concomitant chemotherapy because evidence has suggested superiority of ICIs in combination with chemotherapy in some settings.

This cohort study was performed in approximately 280 predominantly community-based US cancer clinics and included patients aged 18 years or older with advanced NSCLC diagnosed between 1 January 2011 and 31 December 2019, with follow-up through 31 December 2020. Data were analyzed from 1 April 2021 to 19 October 2022. Main outcomes and measures were median OS and 2-year survival probability. The predicted probability of 2-year survival was calculated using a mixed-effects logit model adjusting for demographic and clinical characteristics.

The study sample included 53719 patients with mean age of 68.5 years of whom 28374 were men (52.8%) and the majority were White individuals (67.6%). The overall receipt of cancer-directed therapy increased from 69.0% in 2011 to 77.2% in 2019. After the first approval of an ICI for NSCLC by US Food and Drug Administration, the use of ICIs increased from 4.7% in 2015 to 45.6% in 2019 (p < 0.001). Use of ICIs in 2019 was similar between the youngest (aged <55 years, 45.2%) and oldest patients (aged ≥75 years, 43.8%).

From 2011 to 2018, the predicted probability of 2-year survival increased from 37.7% to 50.3% among patients younger than 55 years and from 30.6% to 36.2% in patients 75 years or older (p < 0.001). Similarly, median survival in patients younger than 55 years increased from 11.5 months to 16.0 months during the study period, while survival among patients 75 years or older increased from 9.1 months in 2011 to 10.2 months in 2019.

The authors commented that regular testing of PD-L1 expression started only partway through the study period and was not included as a variable. More than half of the patients in sample were receiving ICIs by the end of the study period. The study focused on survival; however, it is also critical to assess temporal trends in QoL, including physical and financial burden. The authors pointed out that the findings of the present study underscore the importance of generating evidence that can inform decision-making for older patients, their physicians, and payers who are increasingly calling for value-based pricing.

In an accompanied editorial article, Dr. Marjory Charlot of the Division of Hematology and Oncology, University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, NC, US and Dr. Jhanelle Gray of the Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute in Tampa, FL, US wrote that this is the first report to assess clinically meaningful survival gains in the era of ICIs in advanced NSCLC across age strata using clinical practice data. The authors should be commended for considering the complexities of ICI use by assessing 2-year survival probability with ICIs alone or in combination with chemotherapy as a function of age, as they demonstrated that the oldest age group was more likely to be treated with ICI alone compared with the youngest age group and showed that survival was inversely associated with age within each treatment strata.

Although data on PD-L1 expression level, performance status, and stratification of results by tumour histology were not included, this study still represents an important step in defining clinically meaningful benefits of ICIs in clinical practice across all age strata with opportunities to further gain a deeper understanding of the effect of ICIs on survival.