Age-related efficacy of antibody-drug conjugates in solid tumors: A meta-analysis.

Abstract

1664 Background: Antibody–drug conjugates (ADC) have revolutionized cancer therapeutics, with various ADC improving clinical outcomes across solid tumors and several now approved as standard of care. Older adults with cancer are historically underrepresented in trials. As therapies with ADC are shifting to earlier lines of therapy, investigating whether clinical outcomes differ from those of younger patients with cancer is of interest. Methods: We searched PubMed, Embase, and the CENTRAL databases from inception through Dec 2025 for phase III randomized controlled trials (RCTs) that included adult patients with metastatic solid tumors treated with ADC and reported survival outcomes stratified by age group: elderly (>65 years) and younger (<65 years). The co-primary endpoints were progression-free survival (PFS) and overall survival (OS) across these age subgroups. Pre-specified subgroup analyses were performed according to ADC drug, target, and cancer types. Time-to-event outcomes were pooled as hazard ratios (HR) using the inverse-variance method with random-effects models. Heterogeneity was assessed using the I². PROSPERO: CRD4202612924710. Results: Of 2194 records, 17 RCTs (phase 3) met eligibility, including 9,929 patients, spanning breast (n=12), lung (n=2), urothelial (n=1), ovarian (n=1), and gastric cancer(n=1). ADCs were stratified by payloads: topoisomerase I inhibitors (TOPO1i; 65%), microtubule inhibitors (MMAE; 29%), alkylating agents (6%); and targets: TROP-2 (53%), HER2 (41%), and FRα (6%). Elderly pts treated with ADC exhibited significant improvement in PFS with a HR of 0.57 (95% CI 0.46-0.71; p < 0.01; I 2 = 62%). Similarly, younger pts exhibited longer PFS, with a HR of 0.55 (95% CI 0.45-0.67; p < 0.01; I 2 = 86%). Likewise, elderly patients exhibited significantly greater OS with a HR of 0.78 (95% CI 0.66-0.91; p < 0.01; I 2 = 41%), comparable to that observed in younger pts (HR 0.74; 95% CI 0.65-0.85; p < 0.01; I 2 = 63%). Specifically, in elderly patients with breast cancer treated with ADC (n=7,213), significant improvements were seen with an HR of 0.49 (95% CI 0.36-0.67; p < 0.01) and 0.65 (95% CI 0.48-0.87; p < 0.01; I 2 = 39%) for PFS and OS, respectively. Similar improvements in survival outcomes were seen in younger pts (HR of 0.53; 95% CI 0.42-0.67 and HR of 0.66; 95% CI 0.57-0.77, for PFS and OS, respectively. Pre-specified subgroup analyses according to ADC payloads showed no differences in pts treated with ADC plus TOPO1i (HR 0.76 and 0.70, p <0.01). Notably, ADCs with MMAE payloads were associated with benefit only in the elderly (HR 0.77, p <0.01), with no significant benefit in younger patients (HR 0.82, p =0.11). Conclusions: In this pooled analysis, including 5,111 pts treated with ADC under phase III RCTs, survival outcomes with ADC therapies were similar regardless of age. As the number of ADCs approved for the standard of care setting is expected to increase, age should not be an exclusion criteria.