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.
How did baseline TP53 status affect PFS and OS?
Baseline TP53 status was prognostic for both PFS and OS in both treatment arms: patients with TP53-altered tumors had shorter PFS and OS than those with wild-type TP53, but PFS and OS HRs numerically favored osimertinib plus platinum-pemetrexed over osimertinib alone regardless of baseline TP53 status.
A supporting analysis assessing the potential impact of clonal hematopoiesis of indeterminate potential (CHIP) on plasma TP53 calls found similar PFS/OS trends between plasma-based (n = 353) and tissue-based (n = 150) TP53 analyses. Among 108 patients with matched tissue and plasma samples, 84 (78%) had concordant TP53 status, suggesting CHIP has only a nominal impact on plasma TP53 calls and supporting the use of plasma TP53 status when assessing associations with survival.
Did baseline EGFR signal bypass alterations influence outcomes?
Within the osimertinib monotherapy arm, PFS and OS were shorter in patients with vs without baseline EGFR signal bypass pathway alterations (PFS, 13.7 vs 16.5 months; HR, 0.78; 95% CI, 0.54-1.13; OS, 29.7 vs 39.6 months; HR, 0.66; 95% CI, 0.46-0.95). This separation was less apparent in the osimertinib plus platinum-pemetrexed arm (PFS, 26.0 vs 24.7 months; HR, 0.95; 95% CI, 0.62-1.47; OS, 40.5 vs 42.0 months; HR, 0.81; 95% CI, 0.55-1.20), suggesting that adding platinum-pemetrexed to osimertinib may overcome intrinsic resistance driven by baseline EGFR signal bypass pathway alterations. Investigators reported no clear associations between survival outcomes and baseline alterations in the DDR or Rb/cell cycle pathways.
What acquired resistance mechanisms emerged at progression?
Paired baseline and post-progression or treatment-discontinuation plasma samples with detectable baseline EGFR mutation ctDNA were available for 245 of 557 patients (44%). Acquired resistance alterations were generally similar between arms, with 2 exceptions: acquired EGFR C797S was less common with osimertinib plus platinum-pemetrexed (5 of 105 patients [5%]) than with osimertinib alone (16 of 140 patients [11%]), as was acquired RB1 loss/mutation (1 of 105 patients [1%] vs 10 of 140 patients [7%]).
Overall, fewer patients had at least 1 potential resistance alteration with osimertinib plus platinum-pemetrexed (56%) than with osimertinib alone (61%), and the change in tumor mutational burden from baseline was similar across arms. No novel acquired resistance mechanisms were identified in either treatment arm.
References
- Lee CK, Robichaux J, Planchard D, et al. Baseline co-mutations and acquired resistance mechanisms in patients with EGFR-mutated advanced NSCLC: FLAURA2 exploratory analysis. Presented at: International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Poster P2.237.
- Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
- Jänne PA, Planchard D, Kobayashi K, et al. Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):27-38. doi:10.1056/NEJMoa2510308
- First-line osimertinib chemo vs osimertinib mono in EGFRm advanced NSCLC: FLAURA2 final overall survival. OncLive. Published September 18, 2025. Accessed September 15, 2026. https://www.onclive.com/view/firstline-osimertinib-chemo-vs-osimertinib-mono-in-egfrm-advanced-nsclc-flaura2-final-overall-survival
- TP53 status and treatment toxicity burden guide sequencing in EGFR-mutated NSCLC. OncLive. Published September 1, 2026. Accessed September 15, 2026. https://www.onclive.com/view/tp53-status-treatment-toxicity-burden-guide-sequencing-egfr-mutated-nsclc
