1338P - TP53 truncating and missense mutations are linked to differential response to checkpoint blockade in patients with advanced non-small cell lung cancer (NSCLC)

Background

Several evidence indicates a link between TP53 mutations and response to ICI in patients with NSCLC with conflicting results. While TP53 missense mutations have been associated with anti-tumor immune response, mechanistic studies suggest an immune-suppressive role for TP53 loss.

Methods

Patients with advanced, non-oncogene addicted NSCLC, treated with ICI-based regimens from Sep 2017 to Nov 2023 at 6 European institutions with available TP53 profiling were included. Patients were categorized as TP53 truncating (nonsense/frameshift), TP53 missense, TP53 others (splice sites, deletion), TP53 wild type. TP53 missense mutations were additionally screened through the GenomeNexus.org web tool. Clinical outcomes were overall survival (OS), real-world progression free survival (rwPFS). Data cut-off was March 2024.

Results

The final population consisted of 219 patients, mostly tested with F1DX1 (89%), of whom 81 (37.0%), 79 (36.1%), 43 (19.6%) and 16 (7.3%) were TP53 wt, TP53 missense, TP53 truncating and TP53 others. None of the baseline clinic-pathologic features was associated with the TP53 status, except for the increased PD-L1 expression, TMB and higher KRAS mutation rate reported for the TP53 missense group. The median FUP was 35.1 months. TP53 missense mutation was associated with a longer OS compared to TP53 truncating group (HR 0.62, 95%CI: 0.39-0.99) and longer PFS (HR 0.69, 95%CI: 0.49-0.97) compared to the TP53 wt group. In the multivariable analysis (including TMB, PD-L1, KRAS and STK11 and all available clinic-pathologic factors) confirmed that both TP53 wt (HR 0.58, 95%CI: 0.34-0.99) and TP53 missense (HR 0.49, 95%CI: 0.29-0.83) groups had a significantly decreased risk of death compared to TP53 truncating group, and that only the TP53 missense group had a significantly decreased risk of disease progression compared to both TP53 wt (HR 0.64, 95%CI: 0.42-0.95) and TP53 truncating (HR 0.56, 95CI%: 0.34-0.91) groups.

Conclusions

Our results highlight the heterogeneity linked to the TP53 mutational status, with tumors harbouring TP53 missense mutations possibly more immune-responsive than TP53 truncating/TP53 wt.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.