Abstract A018: HLA-B44 Supertypes as Immune Biomarkers of Anti–PD-1/PD-L1 Response: Results from a Retrospective Analysis of a Spanish Precision Oncology Population

Abstract Background: The human leukocyte antigen (HLA) system regulates adaptive immunity. The B44 Supertype (S), defined by shared peptide-binding motifs, has been associated with improved outcomes to programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) blockade in solid tumors, though its role in combinations is unclear. Data from ASCO 2020 (Tatiana Hernandez et al.) suggested a survival benefit for HLA-B44 S patients receiving PD-(L)1 monotherapy. This cohort evaluates whether HLA-B44 S retains predictive value when PD-(L)1 inhibitors are given alone or combined with novel agents. Methods: We conducted a retrospective study of 176 patients with advanced solid tumors treated in early-phase trials (2017–24). Patients received PD-(L)1 monotherapy (n=37) or PD-(L)1-based combinations (n=139). HLA class I genotyping was performed and classified by supertype. Outcomes included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR), stratified by HLA-B44 supertype. Results: The most common tumor types were non-small cell lung cancer (n=90, 51%), head and neck cancer (n=27, 15%), urothelial carcinoma (n=19, 11%), melanoma (n=14, 8%), and other solid tumors (n=26, 15%). PD-1 or PD-L1–based combination regimens included immune checkpoint inhibitors administered alongside immunomodulatory agents such as anti-LAG3, TIGIT, ICOS, OX40, 4-1BB, CD40, and GITR antibodies. Among patients treated with PD-(L)1 monotherapy (n=37), those with HLA-B44 S+ (n=20) had significantly longer median PFS (14.5 vs. 3.5 months; p=0.025) and OS (39.2 vs. 14.5 months; p=0.009) compared to HLA-B44 S− patients. ORR was also significantly higher in B44 S+ patients (65% vs. 29%; p=0.01). In contrast, among patients receiving combinations (n=139), no significant differences were observed in PFS (4.3 vs. 4.9 months; p=0.718), OS (12.6 vs. 13.2 months; p=0.838), or ORR (29% vs. 34%; p=0.51) between HLA-B44 S+ and S− patients. Conclusions: HLA-B44 S+ status was strongly associated with better outcomes in PD-(L)1 monotherapy. These patients showed substantial benefit, whereas no significant difference was observed in combination therapies, suggesting combinatorial approaches be explored more in HLA-B44 S− patients. These findings require prospective validation and will be further explored within an ongoing project investigating HLA class I supertypes as biomarkers for immunotherapy response. Citation Format: Paula Villalba-Cuesta, Tatiana Hernandez, Bernard Doger de Spéville, Manuel Pedregal, Ester Garcia-Lorenzo, Victor Moreno. HLA-B44 Supertypes as Immune Biomarkers of Anti–PD-1/PD-L1 Response: Results from a Retrospective Analysis of a Spanish Precision Oncology Population [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A018.