Immunotherapy has made remarkable achievements in the field of cancer treatment. However, not all patients can benefit from treatment, about 70% of non-small cell lung cancer (NSCLC) patients still do not benefit from immunotherapy, and even a small number of patients have experienced tumor hyperprogression after. Unpredictable therapeutic effects, potential immune-related adverse events, and high treatment costs have received our attention during the large-scale promotion of immunotherapy in cancer centers. 

Potential benefit patients can be identified based on predictive biomarkers, or ineffective patients can be excluded in a timely manner, thereby achieving accurate medication administration for patients and improving the efficiency of immunotherapy. Finding reliable biomarkers is a hot research issue that needs to be solved urgently. With the popularization of next-generation sequencing technology, our understanding of the relationship between specific gene mutations and immunotherapy is also deepening. Different molecular subtypes may affect the human immune surveillance function and the escape ability of tumor cells. Many studies have improved the overall effectiveness of immunotherapy by identifying specific gene mutations.

Polybromo-1 (PBRM1) gene has been reported as a promising biomarker for immunotherapy in clear cell renal cell carcinoma (ccRCC). As was reported by Miao et al., loss-of-function PBRM1 mutation was associated with clinical benefit from immunotherapy for ccRCC in both the discovery cohort (P = 0.012) and the validation cohort (P = 0.0071).¹ This study was supported by Braun et al. in JAMA Oncology.² According to Braun et al., the prevalence of PBRM1 mutation was 29% in nivolumab-treated patients and 23% in everolimus-treated patients. Truncating PBRM1 mutations were correlated to response to and clinical benefit from immunotherapy in ccRCC. Progression-free survival (PFS) and overall survival (OS) after programmed death-1 (PD-1) inhibitor therapy was also longer in patients with PBRM1 mutation. 

The positive predictive role of PBRM1 mutation in immunotherapy of ccRCC reminded us of the potential predictive effect of PBRM1 mutation in NSCLC. In patients with lung adenocarcinoma and bone metastasis, prevalence of PBRM1 mutation was reported as 22.38% in lung adenocarcinoma samples and 25.51% in bone metastasis samples by Huang et al.³ Considering the predictive effect of PBRM1 in ccRCC and its prevalence in advanced lung cancer, we started to estimate the correlation between PBRM1 mutation and the efficacy of NSCLC immunotherapy, regarding that there was no such report.⁴

In our study, PBRM1 mutation was identified in 84 NSCLC patients (3.04%) in the whole NSCLC cohort. The OS of the PBRM1-mutant patients was worse than that of those without the mutation (median OS, 6 months vs. 13 months , P = 0.03). After adjusting these covariates (mono vs. combo therapy, lines of treatment, smoking, sex, and age), PBRM1 mutation was still negatively associated with OS (hazard ratio 2.16, 95% confidence interval 1.03 – 4.51, P =  0.041). There seems to be marginally significant difference in OS between the PBRM1 mutation subgroup and the PBRM1 wild type subgroup in the cohort of non-immune checkpoint blockade treated patients. Taken together, our results indicated that PBRM1 was more likely to be a negative predictive biomarker for immune checkpoint blockade therapy in NSCLC. But due to some limitations shown in the article, further prospective research is warranted to confirm the negative predictive role of PBRM1 in NSCLC immunotherapy.

Co-written by: Jiayi Shen, Huaqiang Zhou, Jiaqing Liu and Li Zhang (Sun Yat-sen University Cancer Center)

References

1.    Miao D, Margolis CA, Gao W, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 2018; 359: 801–6.

2.    Braun DA, Ishii Y, Walsh AM, et al. Clinical Validation of PBRM1 Alterations as a Marker of Immune Checkpoint Inhibitor Response in Renal Cell Carcinoma. JAMA Oncol 2019; published online Sept 5. DOI:10.1001/jamaoncol.2019.3158.

3.    Huang L, Liu A. P001 Discrepancy of Oncogenic Mutations in Bone Metastasis Derived from Lung Adenocarcinoma. J Thorac Oncol 2018; 13: S1051.

4.    Zhou H, Liu J, Zhang Y, et al. PBRM1 mutation and preliminary response to immune checkpoint blockade treatment in non-small cell lung cancer. npj Precision Oncology 2020; 4: 6.