/ co-mutations in -mutant advanced non-small cell lung cancer: genetic characteristics and impact on immunotherapy efficacy.

BACKGROUND

The impact of co-mutations on the efficacy of immunotherapy in patients with -mutant advanced non-small cell lung cancer (NSCLC) remains incompletely understood. Our aim was to investigate the effects of co-mutations on the clinical prognosis of patients with -mutant advanced NSCLC receiving immunotherapy.

METHODS

We obtained 2,098 patients with stage IIIB-IV NSCLC from the cBioPortal database. Patients harboring , , and mutations were excluded. The impacts of and co-mutations on the efficacy of chemoimmunotherapy were analyzed, along with their associations with tumor mutational burden (TMB), programmed cell death ligand 1 (PD-L1) expression, and patient prognosis.

RESULTS

Among 2,098 patients with NSCLC, -mutant patients accounted for 7.7% (162/2,098), and wild-type patients accounted for 92.3% (1,936/2,098). mutations are more common in elderly patients, smokers, and patients with adrenal metastasis. Compared with wild-type patients, -mutant patients had significantly greater TMB (P<0.001) and poorer median overall survival (mOS) (10.6 17.5 months, P<0.001). Further analysis revealed that patients with class I alterations had significantly shorter mOS (8.7 14.1 months, P=0.008) and median first-line treatment progression-free survival (mPFS1) (3.7 6.6 months, P=0.003) than those with class II alterations. Multivariate regression analysis confirmed that mutations significantly increased the risk of death [hazard ratio (HR) =1.329, 95% confidence interval (CI): 1.106-1.596, P=0.002]. Compared with chemotherapy, chemoimmunotherapy significantly prolonged mPFS1 (5.6 3.9 months, P=0.01) but not mOS (10.8 9.5 months, P=0.91) in patients with mutations. Among patients receiving first-line chemoimmunotherapy, TMB levels had no significant effect on mPFS1 (5.6 6.6 months, P=0.83) or mOS (8.5 10.8 months, P=0.38), but PD-L1-positive patients had significantly longer mPFS1 (8.3 5.1 months, P=0.02) and mOS (18.9 9.3 months, P=0.03). and co-mutations were not significantly correlated with TMB (P=0.85) or PD-L1 expression (P=0.08). However, the patients with and co-mutations had significantly shorter mPFS1 (4.5 13.3 months, P<0.001) and mOS (8.7 20.1 months, P=0.005) in the chemoimmunotherapy group. Among -mutant patients, those without co-mutations derived longer mPFS1 (13.3 5.6 months, P=0.01) benefits from immunotherapy. In contrast, this benefit markedly reduced mPFS1 (4.5 2.9 months, P=0.16) in patients with co-mutations, suggesting that may affect the immunological efficacy in patients with mutations.

CONCLUSIONS

Patients with -mutant NSCLC can benefit from chemoimmunotherapy. However, co-mutations were associated with poorer prognosis and reduced immunotherapy efficacy in -mutant advanced NSCLC. Moreover, co-mutations may serve as key stratification markers for predicting the potential benefit of immunotherapy in -mutant NSCLC.