EA5221 – A Randomized Phase III Trial of Chemo-Immunotherapy vs Immunotherapy Alone for the Vulnerable Older Adult with Advanced Non-Small Cell Lung Cancer: The ACHIEVE Study

By Megan A. Baumgart, MD

Lung cancer is the leading cause of cancer death in the United States, with nearly 70% of cases diagnosed in individuals age 65 or older. Yet despite this, the evidence base does not adequately reflect this population. In fact, about 40% of patients presenting with advanced disease have meaningful impairments in functional status at baseline—factors that can significantly influence treatment tolerance and outcomes. Still, vulnerable older adults have been underrepresented in clinical trials and largely excluded from the pivotal immunotherapy studies that have transformed the treatment landscape for advanced non–small cell lung cancer (NSCLC).

Today, pembrolizumab-based therapy has become a cornerstone of first-line treatment for advanced NSCLC. Both chemo-immunotherapy and single-agent immunotherapy approaches have demonstrated improved outcomes compared with chemotherapy alone. However, important questions remain. The benefit of single-agent pembrolizumab appears to be greatest in patients with high PD-L1 expression, and there is less clarity for those with PD-L1 tumor proportion scores (TPS) in the 1–49% range. This uncertainty is even more pronounced in older, more vulnerable patients, for whom the balance between efficacy and tolerability is especially critical. At present, we do not have clear, evidence-based guidance to inform optimal treatment selection for this group.

To address this gap, ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) designed the EA5221/ACHIEVE trial—a randomized phase 3 study focused specifically on vulnerable older adults with advanced NSCLC and PD-L1 TPS 1–49%. This study is comparing outcomes for patients treated with pembrolizumab alone versus pembrolizumab in combination with chemotherapy. The goal is to better understand which strategy provides the most meaningful clinical benefit for this population.

Recognizing the heterogeneity of older adults, the study incorporates a geriatric assessment (GA) into the design. At registration, investigators select a chemotherapy regimen they feel is most appropriate for the patient if assigned to the combination arm. Patients then complete an abbreviated baseline GA, which evaluates functional status, nutrition, cognition, and quality of life. These results are shared with investigators before final chemotherapy selection, allowing them to refine their approach based on a more comprehensive understanding of the patient’s overall health. The GA also generates supportive care recommendations tailored to each patient’s needs.

The primary endpoint of ACHIEVE is overall survival; additional endpoints include progression-free survival, treatment tolerability, and the relationship between geriatric assessment findings and clinical outcomes. Importantly, investigators are assessing patient-reported quality of life across both treatment arms to ensure that the findings reflect not only how long patients live, but how well they live during treatment.

To be eligible for the study, patients must be age 70 or older with stage IIIB, IIIC, or IV NSCLC, PD-L1 TPS of 1–49%, and no prior treatment for metastatic disease. These are patients who are often seen in clinical practice but insufficiently represented in trials.

ACHIEVE represents the continued commitment of the ECOG-ACRIN Geriatric Oncology Committee to generate more inclusive, clinically meaningful evidence.

Learn more about EA5221/ACHIEVE at ecog-acrin.org.