PALO ALTO, CA — Immune checkpoint inhibitor (ICI) monotherapy is often preferred over intensive ICI treatment for frail patients and those with poor performance status (PS) in advanced non-small cell lung cancer (NSCLC). But what about patients without both situations?
To help answer that question, researchers from the VA Palo Alto Healthcare System and Stanford University, both in Palo Alto, CA, and colleagues followed patients who had received first-line ICI for advanced NSCLC in the VA National Precision Oncology program from January 2019 to December 2021 until death or study end in June 2022.
Also participating in the investigation were researchers from the VA Boston and Durham, NC, VAMCs.
Intensive treatment was defined as concurrent use of platinum-doublet chemotherapy and/or dual checkpoint blockade, while non-intensive was defined as ICI monotherapy. Results were published in Cancer Immunology, Immunotherapy.1
Of the 1,547 patients in the study receiving any ICI, 66.2% were frail, 33.8% had poor PS (≥ 2), and 25.8% were both.
The study found that frail patients received less intensive treatment than non-frail patients in both PS subgroups (Good PS: odds ratio [OR] 0.67, 95% confidence interval [CI] 0.51 – 0.88; Poor PS: OR 0.69, 95% CI 0.44 – 1.10). It also determined that, among 731 patients receiving intensive treatment, frailty was associated with lower overall survival for those with good PS (hazard ratio [HR] 1.53, 95% CI 1.2 – 1.96), but no association was observed with poor PS (HR 1.03, 95% CI 0.67 – 1.58).
“Frail patients with both good and poor PS received less intensive treatment,” the authors conclude. “However, frailty has a limited effect on survival among those with poor PS. These findings suggest that PS, not frailty, drives survival on intensive treatment.”
Background information in the study notes that lung cancer is the leading cause of cancer-related mortality and is common among older patients, who are frequently more frail than younger patients.
“Frail patients have reduced physiological reserve and increased vulnerability to stressors like cancer,” the researchers point out. “Frailty often encompasses functional domains but also includes nutritional, cognitive, physical and social domains of frailty. It is distinct from performance status (PS), a well-established measure of functional status defined by patients’ ability to carry out daily activities and self-care. “The study explains that frailty, as measured by an electronic index, refers to a pre-existing state before cancer, adding, “However, patients with advanced non-small cell lung cancer (NSCLC) commonly present with acute, cancer-related symptoms that rapidly decrease their function and therefore their PS score.”
The study team notes that oncologists often use “intuitive assessments” to adjust treatment intensity for frailty and poor PS, often choosing to administer immune checkpoint inhibitor (ICI) monotherapy instead of more intensive options like chemoimmunotherapy in advanced NSCLC.
“Frail patients may be unable to receive intense chemotherapy due to impaired kidney or liver function, leading to a lower rate of response and shorter treatment duration,” according to the authors. “They may also face a higher risk of treatment-related complications that require early cessation of treatment. Patients with poor PS face similar risks of increased toxicity, which may worsen outcomes. However, the risks for patients with both frailty and poor PS, frequently observed in those with advanced NSCLC., are unknown. It’s uncertain if poor PS would worsen treatment toxicity due to frailty, potentially negatively impacting survival, or if the significant negative prognostic effects of poor PS would outweigh any additional negative impact from frailty.”
The study team found that patients who are frail but without PS are disadvantaged by the current situation. “Oncologists preferred ICI monotherapy for frail patients, irrespective of low or negative PD-L1 expression, indicating that concerns about frailty-related toxicity may have guided them away from the more intensive treatment that would be indicated based solely on PD-L1 levels,” according to the study. “Frailty had a more significant impact on oncologists’ choice of administering ICI monotherapy with negative PD-L1 when PS was poor, and a lesser impact when PS was good. This indicates that oncologists might be concerned about additive treatment toxicity in patients with both frailty and poor PS. Additionally, they might opt for ICI monotherapy in frail patients with poor PS who would otherwise not receive any treatment, despite low or negative PD-L1 expression.”
The study found, however, that, unlike frailty, “older age reduced survival for those with poor PS, especially those who survived beyond 6 months. Further studies are warranted to validate these findings and explore potential differing mechanisms of treatment resistance, such as immunosenescence in older adults.”
They advise that clinicians should consider both PS and frailty to balance the expected benefits of treatment with patient goals and preferences.
- Wu JT, Corrigan J, Su C, Dumontier C, et. Al. The performance status gap in immunotherapy for frail patients with advanced non-small cell lung cancer. Cancer Immunol Immunother. 2024 Jul 2;73(9):172. doi: 10.1007/s00262-024-03763-w. PMID: 38954019; PMCID: PMC11219626.
