e14547 Background: Despite advances in immune checkpoint inhibition, clinical responses remain highly variable, highlighting the need to better understand host-related determinants of immunotherapy outcomes. Human leukocyte antigen (HLA) class I genotype, has emerged as a potential modulator of immune checkpoint inhibitor (ICI) efficacy. A large epidemiological study published in The Lancet Oncology (2025) reported an association between HLA-A*03 carriage and reduced overall survival (OS) following ICI, providing high-level evidence for a role of host HLA variation. In contrast, evidence for other HLA alleles is limited. For HLA-A*01, small studies in non-small cell lung cancer (NSCLC) have reported both improved OS (Shohdy et al., 2025) and inferior OS (Abed et al., 2024). We therefore evaluated the association of HLA-A*01 status with survival and response outcomes in early-phase ICI clinical trials. Methods: We conducted a retrospective analysis of 186 patients with advanced solid tumors treated with ICI within early-phase clinical trials, either as monotherapy or in combination with other agents. High-resolution HLA class I genotyping was performed during clinical trial prescreening, and HLA-A*01 status was classified as carrier or non-carrier. OS, PFS (progression-free survival) and objective response rate (ORR) were analyzed. Results: A total of 186 patients were included, of whom 43 (23%) were HLA-A01 carriers. In the overall cohort, median OS was shorter in HLA-A*01 carriers than in non-carriers (9.2 vs 20.4 months; p < 0.001 ), as was median PFS (4.0 vs 8.1 months; p = 0.003 ). ORR was numerically higher in HLA-A*01–negative patients (38.6% vs 25.6%; p = 0.147 ). In patients with NSCLC, HLA-A*01–positive patients (n = 21) had shorter OS (9.2 vs 17.6 months; p = 0.008 ) and PFS (3.4 vs 6.7 months; p = 0.008 ) than HLA-A*01–negative patients (n = 75). When stratified by treatment strategy, inferior outcomes associated with HLA-A*01 carriage were observed across PD-(L)1- containing regimens. Among patients treated with PD-(L)1 monotherapy (n = 41), median OS and PFS were shorter in HLA-A*01 carriers (n = 9) than in non-carriers (OS: 10.4 vs 27.3 months, p < 0.001 ; PFS: 2.8 vs 17.9 months, p = 0.001 ). Among patients receiving PD-(L)1–based combination therapy (n = 145), HLA-A*01 carriers (n = 34) had shorter median OS (9.0 vs 17.3 months; p = 0.01 ), while median PFS was numerically shorter (5.3 vs 6.9 months; p = 0.073 ). Conclusions: In this early-phase clinical trial cohort, HLA-A*01 status was associated with shorter OS and PFS in patients treated with ICI. Similar associations were observed in the NSCLC subgroup and across PD-(L)1 treatment strategies, including both monotherapy and PD-(L)1–based combination regimens. These findings suggest that HLA-A*01 status may be relevant to clinical outcomes in the context of immune checkpoint inhibition and support further prospective evaluation.
Villalba-Cuesta et al. (Thu,) studied this question.