21P - Impact of TP53 mutation subtypes on the efficacy of anti-PD-(L)1 immunotherapy in patients with non-small cell lung cancer

Background

The mutation rate of TP53 in non-small cell lung cancer (NSCLC) ranges from 50% to 60%, but the impact of specific TP53 mutation types on anti-PD-(L)1 therapy efficacy remains unknown.

Methods

A cohort of NSCLC patients without EGFR/ALK/ROS1 mutations was retrospectively assembled and categorized. Enrolled patients received anti-PD-(L)1 immunotherapy, with periodic radiographic evaluation of efficacy, and all participants underwent NGS large panel testing before starting therapy. Chi-square test and survival curve evaluation were subsequently conducted.

Results

From Nov 2021 to Nov 2023, a total of 51 patients were included in TP53-mutant group and 34 in TP53-wild group. There were no significant differences between the two groups regarding gender, age, pathological subtype, driver gene mutation profile (except TP53), TNM staging, PD-L1 TPS, timing of immunotherapy and immunotherapy regimens. As of Sep 25, 2024, the median progression-free survival (mPFS) was 11.43 months (95% CI 7.93-14.93m) in TP53-mutant group and 7.71 months (95% CI 3.84-11.58m) in TP53-wild group (HR 0.68 [95% CI 0.38-1.23], p=0.175). The TP53-mutant group comprised 29 missense (17 DNA contact mutants and 12 conformational mutants), 6 frameshift, 6 truncating, 5 deletion, 4 splice, and 1 deletion-insertion mutation. In a subgroup analysis of patients with TP53 missense mutations, the mPFS was 21.36 months (95% CI 1.67-41.06m) in conformational mutant group and 10.64 months (95% CI 7.52-13.76m) in DNA contact mutant group (HR 0.41 [95% CI 0.14-1.17], p=0.110). The two curves intersect at the onset and then diverge distinctly. The study also found a significant improvement in PFS for patients with TP53 conformational mutant compared to those without TP53 mutations (mPFS: 21.36m vs. 7.71m, HR 0.36 [95% CI 0.16-0.82], p=0.047). Hence, the impact of TP53 mutation types on anti-PD-(L)1 antibody efficacy varies, and TP53 conformational mutants may be potential prognostic indicators for longer PFS in immunotherapy.

Conclusions

The impact of distinct TP53 mutation types on immunotherapy efficacy should be addressed separately. Patients with TP53 conformational mutations may exhibit prolonged PFS in response to anti-PD-(L)1 immunotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.