Immune checkpoint blockade (ICB) therapy has been a pivotal treatment for lung cancer, yet predictive biomarkers are still lacking. PBRM1 mutation is associated with greater sensitivity to immunotherapy for clear cell renal cell carcinoma. To our knowledge, the frequency and clinical relevance of PBRM1 mutation in lung cancer remain unknown. Therefore, we conducted a retrospective study to evaluate the prevalence of PBRM1 mutation and its preliminary response to ICB therapy in NSCLC.
We analyzed the combined NSCLC cohort of 2767 patients, from 3 sources: (1) The Cancer Genome Atlas (TCGA) (N = 1144), (2) Memorial Sloan Kettering Cancer Center (MSKCC) (N = 1567), and (3) Dana Farber Cancer Institute (DFCI) (N = 56). We first estimated the prevalence of PBRM1 mutation in the whole NSCLC cohort. A subset of ICB-treated patients (N = 441) with annotated clinical records were further analyzed for association between PBRM1 mutation and response to ICB therapy. We also calculated the overall survival (OS) of 454 non-ICB treated patients. Institutional review board approval and informed consent were waived because all data were de-identified and publicly available.
Of 2767 patients included in our study, PBRM1 mutation was identified in 75 NSCLC patients (2.70%). Among 39 PBRM1-mutant patients with annotated clinical records, 25 patients (64.1%) were treated with PD-1/PD-L1 inhibitor monotherapy. In the cohort of ICB-treated patients (N = 441, PBRM1 MT=25), the OS of the PBRM1-mutant patients was worse than that of those without mutation (P = 0.03, median OS 6 vs. 13 months). In total, 14 patients, all with PBRM1 mutation, were able to be evaluated for response to ICB therapy. The median PFS was 2.1 months. The ORR was 28.6%, the DCR was 50%, and the DCB was 14.29%. In the cohort of non-ICB-treated patients (N = 454, PBRM1 MT=14), there seems to be no difference between the OS of the PBRM1 mutation subgroup and PBRM1 wild type subgroup (P = 0.097).
Our findings suggested that PBRM1-mutant NSCLC patients might get less survival benefit from ICB therapy, unlike previously reported data in clear cell renal cell carcinoma. Further prospective research is warranted to confirm the negative predictive role of PBRM1 in NSCLC ICB therapy.
This work was supported by: National Key R&D Program of China (Grant No. 2016YFC0905500, 2016YFC0905503), Chinese National Natural Science Foundation project (Grant No. 81872499, 81772476), Science and Technology Program of Guangdong (Grant No. 2017B020227001), and Science and Technology Program of Guangzhou (Grant No. 201607020031, 201704020072).
All authors have declared no conflicts of interest.