LRP1Bmutations are associated with favorable outcomes to immune checkpoint inhibitors across multiple cancer types

• DOI: 10.1136/jitc-2020-001792
• Publication Date: 2021-03-02T16:02:47Z
• Authors: Landon C Brown; Matthew D Tucker; Ramy Sedhom; Eric B Schwartz; Jason Zhu; Chester Kao; Matthew K Labriola; Rajan T Gupta; Daniele Marin; Yuan Wu; Santosh Gupta; Tian Zhang; Michael R Harrison; Daniel J George; Ajjai Alva; Emmanuel S Antona...; Andrew J Armstrong
• Keywords: Adult; Male; Time Factors; 610; lung neoplasms; Risk Assessment; prostatic neoplasms; 03 medical and health sciences; Risk Factors; Neoplasms; 616; Immunotherapy Biomarkers; Biomarkers, Tumor; Humans; Immune Checkpoint Inhibitors; RC254-282; Aged; Retrospective Studies; Aged, 80 and over; 0303 health sciences; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Middle Aged; Progression-Free Survival; United States; 3. Good health; Receptors, LDL; Mutation; genetic markers; Female; immunotherapy

Background Low-density lipoprotein receptor-related protein 1b (encoded by LRP1B ) is a putative tumor suppressor, and preliminary evidence suggests LRP1B- mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI). Methods We conducted multicenter, retrospective pan-cancer analysis of patients alterations treated ICI at Duke University, Johns Hopkins University (JHU) Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) pathogenic or likely (P/LP) compared variants unknown significance (VUS). Secondary were associations progression-free survival (PFS) (OS) status. Results identified 101 (44 Duke, 35 JHU, 22 UM) who ICI. most common types alteration (P/LP vs VUS%) lung (36% 49%), prostate (9% 7%), sarcoma (5% melanoma 0%) breast cancer (3% 7%). ORR for P/LP versus VUS 54% 13%, respectively (OR 7.5, 95% CI 2.9 22.3, p=0.0009). associated longer PFS (HR 0.42, 0.26 0.68, p=0.0003) OS 0.62, 0.39 1.01, p=0.053). These results remained consistent when excluding harboring microsatellite instability (MSI) controlling mutational burden (TMB). Conclusions This multicenter study shows significantly better therapy in alterations, independently TMB/MSI Further mechanistic prospective validation studies are warranted.