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

BACKGROUND

Low-density lipoprotein receptor-related protein 1b (encoded by ) is a putative tumor suppressor, and preliminary evidence suggests mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI).

METHODS

We conducted a multicenter, retrospective pan-cancer analysis of patients with alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) alterations compared with variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by status.

RESULTS

We identified 101 patients (44 Duke, 35 JHU, 22 UM) with alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB).

CONCLUSIONS

This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.