Background
Phase 3, multicenter, open-label, randomized (1:1) trial; N=294; 17 sites in China. Treatment-naive stage IV or recurrent nonsquamous NSCLC harboring EGFR-sensitizing mutations with concurrent TP53 mutations — the first phase 3 to prospectively select this poor-prognosis co-mutated population for 1L intensification of osimertinib (3rd-generation EGFR TKI).
Results
Interventions and follow up: Arm A: Osimertinib + pemetrexed/carboplatin q3w ×4 cycles → maintenance osimertinib + pemetrexed (n=146)
Arm B: Osimertinib monotherapy (n=148)
Primary endpoint: PFS (investigator-assessed)
mFollow up: 25.1 mo (combination) / 26.1 mo (monotherapy); cutoff Nov 11, 2025
Results: PFS: 34.0 vs 15.6 mo; difference 18.4 mo (95% CI 9.9–22.3); HR 0.44 (95% CI 0.32–0.60); P<.001 — consistent across subgroups incl. brain metastases and L858R
ORR: 82.9% vs 71.6%
mDOR: 32.7 vs 15.3 mo
OS: immature (30.6% maturity); trend favoring combination
Arm B: Osimertinib monotherapy (n=148)
Primary endpoint: PFS (investigator-assessed)
mFollow up: 25.1 mo (combination) / 26.1 mo (monotherapy); cutoff Nov 11, 2025
Results: PFS: 34.0 vs 15.6 mo; difference 18.4 mo (95% CI 9.9–22.3); HR 0.44 (95% CI 0.32–0.60); P<.001 — consistent across subgroups incl. brain metastases and L858R
ORR: 82.9% vs 71.6%
mDOR: 32.7 vs 15.3 mo
OS: immature (30.6% maturity); trend favoring combination
Adverse events
Grade ≥3 TRAEs: higher with combination (rates NR in abstract)
Safety signals: none new identified; profile consistent with osimertinib + platinum-pemetrexed as in FLAURA2
Safety signals: none new identified; profile consistent with osimertinib + platinum-pemetrexed as in FLAURA2
Conclusions
In EGFR-mutated advanced NSCLC with concurrent TP53 mutations, first-line osimertinib plus chemotherapy more than doubled median PFS vs osimertinib alone (34.0 vs 15.6 mo, HR 0.44). Supports biomarker-directed intensification: TP53 co-mutation may identify the patients who benefit most from adding chemotherapy to osimertinib.
Key Limitations
Open-label with investigator-assessed primary endpoint (no blinded independent review). Conducted entirely in China — generalizability to other populations uncertain. Modest sample size (N=294); OS immature at 30.6% maturity. No direct comparison with all-comer intensification (FLAURA2); cross-trial inference required to position TP53 as a selection biomarker.
Clinical Context
FDA approved osimertinib + platinum-pemetrexed for 1L EGFR-mutated advanced NSCLC (all-comers) in Feb 2024 based on FLAURA2; NCCN lists both osimertinib monotherapy and osimertinib + chemotherapy as 1L options, without biomarker guidance on whom to intensify. TOP is the first randomized evidence that TP53 co-mutation (present in ~40–50% of EGFR-mutant NSCLC) may define the subgroup where intensification is most valuable, informing that choice.