Is It Worth Adding Chemo to ICI for NSCLC in Older Adults?

Immune checkpoint inhibitors (ICI) are a cornerstone of non-small cell lung cancer (NSCLC) treatment, but it’s not clear whether adding chemotherapy to ICI — a common practice with younger patients with NSCLC — helps older ones.

No randomized trial has directly compared stand-alone ICI with chemoimmunotherapy in geriatric patients with NSCLC. Without strong data supporting the combined approach, oncologists may stay away from offering chemoimmunotherapy to older patients, especially to those with multiple comorbidities, given concerns about increased toxicity.

To address the evidence gap, investigators linked Medicare and Surveillance, Epidemiology, and End Results data to compare outcomes between 14,249 older patients with NSCLC who received ICI alone (pembrolizumab or nivolumab) and 3432 treated with ICI and platinum doublet chemotherapy. Patients were aged 74 years, on average, and at least 66 years. The median follow-up duration was 211 days.

The team weighed the risks and benefits of chemoimmunotherapy vs stand-alone ICI to answer a key question: Is adding chemotherapy to ICI worth it for elderly patients with NSCLC?

The findings were recently published in Jama Oncology.

Benefits: Prolonged Survival in First Line

In the upfront setting, chemotherapy add-on reduced patients’ mortality risk by 34% compared with ICI alone. Benefits were slightly more notable in women (hazard ratio [HR], 0.62) than in men (HR, 0.72).

Patients with autoimmune disease — who are often excluded from trials and who made up almost 20% of the study population — benefited the most, with a mortality risk reduction of 49%.

A similar mortality benefit was observed in patients aged 66-75 years and those aged 76 years or older, “which is notable given that immune senescence is hypothesized to lessen ICI treatment response in patients older than 75 years,” wrote the investigators, led by James Heyward, PhD, a pharmacoepidemiologist at Johns Hopkins Bloomberg School of Public Health in Baltimore.

However, in the second or later lines of treatment, patients did not experience a significant survival benefit with chemoimmunotherapy (HR, 0.94; 95% CI, 0.68-1.03).

Risks: Increased Toxicity

Adding chemotherapy in the first-line setting increased the risk for severe immune-related adverse events (AEs), which can include pneumonitis, colitis, hepatitis, and myocarditis, by 18%. Severe AEs were more common in men (HR, 1.29) than in women (HR, 1.08).

Patients aged 76 years or older had the highest risk (30%) for severe immune-related AEs.

However, older patients did not have an increased risk for severe immune-related AEs in second and later lines.

The study did not consider chemotherapy toxicities.

Is It Worth It?

The team extrapolated from their data to calculate the harm-benefit trade-off of adding ICI to chemotherapy in older patients.

The researchers found that for each extra year of life gained with first-line chemoimmunotherapy, the risk for severe immune-related AEs would be 0.31. Put differently, 31% of patients predicted to gain 1 extra year of life were likely to experience one severe immune-related AE.

Past studies have found that patients are often willing to accept one severe AE for 1 year of added survival, which indicates that chemoimmunotherapy in the first line may be worth it for older patients with NSCLC.

“Given patient prioritization of survival benefits vs prevention of adverse effects, patients may prefer to initiate treatment with ICI + chemotherapy, albeit with careful follow-up for mitigation of severe immune-related AEs,” the investigators wrote.

But, the authors noted, “men experienced more harm and less benefit than women” in the first-line setting, which is consistent with previous research.

And patients with an autoimmune disorder who received chemoimmunotherapy had a slightly higher risk for severe immune-related AEs (HR, 1.22) than those without a disorder (HR, 1.16).

Still, the authors said, “the reduction in mortality was also the highest for this group of patients, suggesting that the potential benefits of treatment may outweigh the potential harms.”

In the second and later lines, the researchers found no increased risk for immune-related AEs with chemoimmunotherapy. Given the lack of statistically significant mortality benefit, the results suggest that stand-alone ICI are a better approach in this setting.

Overall, this study provides “a valuable contribution to an ongoing and complex discussion,” said medical oncologist Alessio Cortellini, MD, PhD, an immunotherapy and lung cancer specialist at Imperial College London, London, England, who was not involved in the research.

However, it will be important to closely monitor patients for severe immune-related AEs.

“While adding chemotherapy to immunotherapy may be appropriate for selected older adults with NSCLC, I remain cautious about its widespread use in frail patients,” Cortellini added. “Until we have dedicated trials in frail populations, the decision to use [chemotherapy-ICI]combinations in older adults should be highly individualized.”

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]