Does Immunotherapy Offer Survival Gain in Older NSCLC Patients?

Nancy A. Melville

February 01, 2023

Immune checkpoint inhibitors are used at nearly the same rates in younger and older patients with non–small cell lung cancer (NSCLC), yet the survival benefit observed in younger patients does not appear to extend to older individuals, who represent the majority of patients.

A new analysis found that in 2019, 4 years after the first immune checkpoint inhibitor was approved, median survival among treated patients younger than 55 had increased by about 6 months since 2011, while survival among those 75 and older had increased by only about 2 months in that time.

In a large cohort of patients with advanced NSCLC, "we found that the population-level increases in survival after [immune checkpoint inhibitor] implementation varied substantially by age despite similarly rapid and substantial uptake," senior author Cary P. Gross, MD, of the Yale School of Medicine, in New Haven, Connecticut, and co-authors write. "As the median age at diagnosis of lung cancer is 70 years, examining outcomes in this older patient population is crucial to understanding the true impact of new treatments."

The findings were published last week in JAMA Oncology.

Immune checkpoint inhibitors have been credited with transforming the treatment of NSCLC in recent years. Clinical trials have shown significant benefits that span age groups. However, survival gains observed in real-world clinical practice among older patients don't appear to be measuring up to those reported in the clinical trials.

In the current study, Gross and colleagues explored whether the increasing use of immune checkpoint inhibitors has had a bearing on survival among younger and older patients with NSCLC. The researchers evaluated data on 53,719 patients with stage IIIB, IIIC or IV NSCLC who were enrolled at about 280 US-based cancer clinics. The patients were diagnosed between January 2011 and December 2019. Follow-up occurred through December 2020.

At the initial diagnosis, nearly 62% of patients were diagnosed with stage IV disease.

Overall, the use of immune checkpoint inhibitors in NSCLC increased from 4.7% in 2015, after the first agent was approved, to 45.6% in 2019. The uptake among older (43.8%) and younger patients (45.2%) was similar.

The authors saw little variability in median overall survival from 2011 to 2015 across all age groups, but after 2015, median survival began to improve for younger patients, though not much in older ones.

Overall, among treated individuals, between 2011 and 2019, median overall survival increased by about 6 months — from nearly 13 to 19 months — among those younger than 55, while survival increased by just 2 months — from about 11 months to 13 months — among those 75 and older.

The survival gains observed among younger patients were most pronounced after 2015. Among individuals treated between 2015 and 2019, median overall survival increased by 4.2 months — from 14.8 to 19 months — for younger patients, vs just 0.7 months — 12.3 to 13 months — for older patients (P = .02).

In addition, the predicted probability of 2-year survival among patients younger than 55 years increased from 37.7% to 50.3% between 2011 to 2018, while the rate only increased from 30.6% to 36.2% among those 75 and older.

"We were surprised to see such a modest improvement in survival in older patients with lung cancer during the study period," Gross told Medscape Medical News.

"Clinically Meaningful" Survival Benefit?

On the basis of definitions of a "clinically meaningful" benefit, the survival gains observed in older patients appear to fall short.

According to American Society of Clinical Oncology (ASCO), a clinically meaningful improvement in lung cancer is defined as an improvement in survival of more than 3.25 months for patients with nonsquamous and more than 2.5 months for patients with squamous disease. The scale used by the European Society for Medical Oncology's indicates that for conditions with a baseline survival of less than 1 year, a survival increase of 3 months or more is deemed a substantial benefit.

On the basis of those definitions alone, the study results suggest that immune checkpoint inhibitors may not be providing a meaningful benefit for those over 75.

The authors say, however, that a notable study limitation was that other meaningful outcomes relevant to an older population — treatment burden, quality of life, and symptom severity — were not evaluated in the trial.

Nevertheless, the findings raise questions about the benefits of these agents for older patients.

"Given that nearly half of newly diagnosed older patients were receiving [immune checkpoint inhibitors] by the end of the study period, this suggests that the substantial change in NSCLC treatment patterns has had minimal implications for the survival of older patients," the authors say.

The results underscore the need to reconsider age limitations in clinical trials.

"For years, older persons have been underrepresented in clinical trials," Gross said. The results indicate "a tremendous evidence gap — we simply don't know the true benefits and risks of many treatments in the older population."

Given this uncertainty, Gross and colleagues also questioned the cost-effectiveness of prescribing expensive drugs that may "not meet criteria for clinically meaningful survival benefits." In 2019, nivolumab and pembrolizumab were the top two drugs in terms of Medicare Part B spending.

"It is simply not sustainable from an economic perspective, and not ethical from a patient perspective, to keep pushing out new and expensive therapies with uncertain benefits," Gross said.

Kenneth L. Kehl, MD, MPH, who was not involved in the research, agreed that the new research "raises questions about how effectively immunotherapy is being used in older patients."

But "I don't think it implies that immunotherapy should not be used in such patients," said Kehl, of Dana-Farber Cancer Institute in Boston. "There are multiple potential reasons for the observed outcomes in this study, including shifts in patterns of referral to oncology practices from which this cohort was derived."

Chee Khoon Lee, MD, of St. George Hospital, Sydney, Australia, further noted that the subgroup data in the study "need to be interpreted with caution."

"Clinically meaningful benefit defined by ASCO is for the overall trial population and not necessarily based on subgroups," said Chee, also not involved in the research. Just as some young patients may have poor prognostic factors, likewise, some older people could "have good functional status and hence should be offered treatment," which is why "treatment decisions should never be based on age but a mixture of all other factors."

Gross has received grants from Johnson & Johnson and the National Comprehensive Cancer Network (AstraZeneca) and personal fees from Genentech outside the submitted work. The other authors' disclosures are detailed in the published study. Kehl and Chee have disclosed no relevant financial relationships.

JAMA Oncol. Published January 26, 2023. Abstract, Editorial

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