1359P - Relationship between tumor TP53 gene mutation, circulating anti-p53 antibodies and response to first-line osimertinib in EGFR-mutated NSCLC patients

Background

Osimertinib is the standard of care in Epidermal Growth Factor Receptor (EGFR)-mutated advanced Non-Small-Cell Lung Cancer (NSCLC). The MELROSE study, a multicentric phase II trial (NCT03865511) was designed to identify resistance mechanisms in treatment-naive EGFR-mutated NSCLC patients receiving osimertinib. We have evaluated the impact of TP53 mutations on the response to osimertinib.

Methods

The MELROSE trial enrolled 150 patients with EGFR-mutated (exon 19 deletion, n=88; L858R mutation, n=62) NSCLC. All patients received osimertinib. Tumor assessment was performed every 3 months, with brain and thoracoabdominal CT-scan. Tumor tissues collected at diagnosis were analyzed by next generation sequencing (QIAseq targeted DNA custom panel, QIAGEN). Anti-p53 antibodies were quantified in plasma using the automated Elecsys anti-p53 immunoassay (Cobas, Roche).

Results

Primary analysis of the whole cohort (data cutoff on April 4, 2023) showed a median PFS of 17.4 months (95% CI: 14.9-21.8). Tumor TP53 genotyping was successfully performed for 116 patients. TP53 mutations were detected in tumors of 74 patients (63.8%). Most mutations were present on exons 5 (n=14), 6 (n=13), 7 (n=12) and 8 (n=18). The presence of a TP53 mutation was associated with a reduced median PFS (16.4 months) as compared to wild type tumors (27.5 months; p=0.0034; HR 2.15; 95% CI: 1.29-3.60). Anti-p53 antibodies were detected at baseline in the plasma of 17.8% of the patients tested (26/146). The presence of antibodies was strongly associated with the existence of a TP53 mutation (p=0.001). Patients presenting detectable anti-p53 antibodies at baseline had a significantly lower median PFS (16.4 months) as compared to patients not presenting antibodies (20.0 months; p=0.034; HR 1.72; 95% CI: 1.04-2.83).

Conclusions

The existence of a TP53 gene mutation in patients’ tumor significantly impacted their PFS, suggesting that future clinical trials should include TP53 genotyping at randomization. Baseline quantification of anti-p53 antibodies could also be used to early identify a fraction of patients presenting a TP53 alteration, and identify patients who may benefit less from osimertinib treatment.

Clinical trial identification

NCT03865511.

Editorial acknowledgement

Legal entity responsible for the study

Nantes University Hospital.

Funding

AstraZeneca.

Disclosure

All authors have declared no conflicts of interest.