Immune checkpoint inhibitors (ICIs) therapy has been a pivotal treatment for NSCLC. However, additional biomarkers should be found out to cover more patients who may derive the greatest benefit from ICIs. Frameshift mutation by insertion or deletion (fsindel) has come to prominence due to its higher immunogenicity. Previous study has identified a positive correlation between fsindel and favorable clinical benefit in NSCLC. But it still requires validation. Therefore, we conducted a study to further assess the predictive role of fsindel.
A publicly available cohort of 385 ICIs-treated NSCLC patients from MSKCC were analyzed. We categorized patients into two groups; 0 fsindel (FS-) and more than 1 fsindel (FS+). The OS, PFS and response to ICIs therapy (ORR, DCR and DCB) were evaluated. We also developed a combined model of TMB and fsindel to further clarify the role of fsindel.
214 patients (55.58%) were found to be fsindel present (FS+). 189 patients (88.32%) were treated with PD-1/PD-L1 inhibitor monotherapy. Among the 356 patients with OS data, the OS of the FS+ patients was similar with that of FS- patients (median OS: 11 months vs. 12 months, P = 0.615). 240 patients (131 FS+, 109 FS-) were able to be evaluated for response to ICIs therapy. The median PFS was similar between FS+ and FS- group (median PFS, 3.43 months vs. 3.17 months, P = 0.114). The presence of fsindel was correlated with higher ORR (24.43% vs 15.60%, P = 0.091), DCR (56.49% vs 53.21%, P = 0.611) and DCB (35.77% vs. 24.04%, P = 0.055). TMB-H patients show significant difference in OS (median OS: 15 months vs. 10 months, P = 0.017) and marginally-significant difference in PFS (median PFS, 4.73 months vs. 2.60 months, P = 0.051). Moreover, TMB-H and FS+ patients had significantly better PFS and OS compared to patients who had either TMB-H or FS+ or neither (TMB-L and FS-) (median PFS = 6.17 months, P pfs = 0.004; median OS = 19 months, P os = 0.013).
Our study supported that fsindel might serve as a synergistic biomarker which could predict the efficacy of ICIs therapy for NSCLC patients. It might help us to precisely identify patients who could derive more benefit from ICIs therapy, especially in the fsindel present patients with higher TMB.
The authors.
National Key R&D Program of China (Grant No.2016YFC0905500, 2016YFC0905503).
All authors have declared no conflicts of interest.