Baseline TP53 co-mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) than wild-type TP53 in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), regardless of treatment arm, according to an exploratory analysis of the phase 3 FLAURA2 trial (NCT04035486) presented in a poster session at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC).¹
In FLAURA2, 557 patients with previously untreated, locally advanced or metastatic EGFR-mutated NSCLC were randomly assigned to first-line osimertinib (Tagrisso) plus platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed, or to osimertinib monotherapy. The combination previously produced a statistically significant improvement in investigator-assessed PFS (HR, 0.62; 95% CI, 0.49-0.79; P < .001) and, in the planned final analysis, OS (HR, 0.77; 95% CI, 0.61-0.96; P = .02) vs osimertinib alone.²,³ In this exploratory analysis of baseline plasma samples from 353 patients, TP53 was the most common co-occurring alteration with EGFR, detected in 67% of samples; all other individual co-occurring alterations were rare (each ≤8% across arms).1
FLAURA2 Exploratory Analysis at a Glance
- TP53 co-mutations, present in 67% of baseline plasma samples, were prognostic for shorter PFS and OS regardless of treatment arm.
- PFS and OS numerically favored osimertinib plus platinum-pemetrexed over osimertinib alone irrespective of baseline TP53 status.
- Adding platinum-pemetrexed to osimertinib appeared to overcome intrinsic resistance associated with baseline EGFR signal bypass pathway alterations.
- Acquired EGFR C797S and RB1 loss/mutation were less frequent with osimertinib plus platinum-pemetrexed than with osimertinib alone at progression.
Among patients with TP53-altered tumors, median PFS was 21.0 months (95% CI, 16.6-27.7) with osimertinib plus platinum-pemetrexed vs 13.8 months (95% CI, 12.2-16.4) with osimertinib alone (HR, 0.60; 95% CI, 0.43-0.82), and median OS was 38.4 months (95% CI, 31.6-46.6) vs 32.4 months (95% CI, 24.6-36.5), respectively (HR, 0.73; 95% CI, 0.53-1.00). Among patients with wild-type TP53, median PFS was 27.6 months (95% CI, 24.7-not reached [NR]) vs 22.3 months (95% CI, 13.6-NR), respectively (HR, 0.74; 95% CI, 0.42-1.27), and median OS was 48.3 months (95% CI, 38.0-NR) vs 44.5 months (95% CI, 32.5-NR), respectively (HR, 0.88; 95% CI, 0.54-1.45).
What were the most common baseline co-mutations with EGFR?
Because individual co-occurring alterations other than TP53 were infrequent, investigators, led by Chee Koohn Lee of the Cancer Care Centre at St. George Hospital in Kogarah, Australia, grouped baseline gene alterations into 3 signaling-pathway categories: DNA damage response (DDR: ATM, ATR, BRCA1/2), retinoblastoma (Rb) and cell cycle (RB1, CDKN2A/B, CCND/CCNE1, ARID1/2), and EGFR signal bypass (NKX2-1, MYC, CTNNB1, APC, PTEN, PIK3CA, ALK, KRAS, NF1, DNMT3A, ERBB2-4, FGFR1-4, MET, TET2).
At baseline, alterations in the EGFR signal bypass pathway were most frequent, occurring in 75 of 175 patients (21%) in the osimertinib plus platinum-pemetrexed arm and 64 of 178 patients (18%) in the osimertinib monotherapy arm. Rb/cell cycle pathway alterations were seen in 25 patients (7%) vs 31 patients (9%), respectively, and DDR pathway alterations in 12 patients (3%) vs 9 patients (3%), respectively.
