Immune Checkpoint Inhibitor Response In Tumors With Lrp1b Variants.

e14291 Background: Low-density lipoprotein receptor-related protein 1B (LRP1B) is a putative tumor suppressor gene spanning > 500 kb on chromosome 2. A melanoma study previously reported enrichment of LRP1B mutations in responders (34%) to immune checkpoint inhibitors (ICIs) compared with non-responders (3%). Deep deletions in LRP1B are frequently observed in non-small cell lung cancer (NSCLC, 12%), head and neck (11%), cervical (9%), bladder (8%), and prostate cancers (8%). This study examines the clinical response to ICIs in a diverse group of tumor types with LRP1B alterations. Methods: We conducted a single center retrospective study inclusive of all patients (pts) with tumors containing any LRP1B variant who were treated with an ICI between 01/2015 and 11/2018. The primary outcome of the study was to describe the clinical outcomes of patients with LRP1B alterations, with respect to radiographic response to therapy, time on therapy, duration of response, and overall survival. Results: 44 pts with an LRP1B variant were treated with an ICI at Duke between 01/2015 and 11/2018. The most common ICIs were pembrolizumab (29/44, 66%) and nivolumab (12/44, 27%). Tumor types included NSCLC (24/44, 55%), renal cell carcinoma (RCC, 5/44, 11%), and prostate cancer (5/44, 11%). 14 (32%) pts had pathogenic variants (PVs) and 30 pts (68%) had variants of uncertain significance (VUS). Among pts with LRP1b PVs, 36% (95%CI 14%-64%) had radiographic responses (5/14, 2 lung, 1 prostate, 1 RCC, 1 endometrial carcinoma), two of whom were MSI high. As a control, the radiographic response rate among patients with a LRP1b VUS was 10% (95%CI 3%-28%). Of those with PVs, 3 pts had stable disease, one of whom has been on CPI therapy for > 22 months and 5 (36%) remain on therapy, with 2 (14%) pts discontinued due to immune toxicities, and 7 (50%) pts discontinued due to disease progression. The median TMB among responders was 12 (2-150.05 mut/Mb) and the median TMB amongst non-responders was 9.5 (6-18 mut/Mb). Conclusions: In a tumor agnostic population of pts harboring LRP1B PVs, 36% of pts have responses to ICI. The majority of responders were MSS and TMB low, which may suggest that PV in LRP1B may independently predict for response to ICI. Prospective and multicenter validation is now needed.