Background
Prospective randomized cohort study (TOP trial) in advanced/metastatic EGFR-mutated NSCLC with concomitant TP53 mutation — a poor-prognosis subset where first-line osimertinib monotherapy yields shorter PFS than in TP53-wildtype disease. N=98 enrolled across two Chinese institutions (January 2020–August 2023). Tested whether adding platinum-doublet chemotherapy to first-line osimertinib improves outcomes.
Interventions and follow up
Arm A: Osimertinib 80 mg PO daily + platinum-pemetrexed chemotherapy per institutional standard (n=47)
Arm B: Osimertinib 80 mg PO daily monotherapy (n=51)
Primary endpoint: Progression-free survival (PFS)
mFollow up: 19.2 months
Arm B: Osimertinib 80 mg PO daily monotherapy (n=51)
Primary endpoint: Progression-free survival (PFS)
mFollow up: 19.2 months
Results
mPFS (overall): 26.0 vs 20.7 mo (Osi+Chemo vs Osi); P=.34 (not significant)
mPFS (L858R subgroup): not reached vs 17.1 mo; P=.03 (favors combo)
mPFS (Ex19del subgroup): 20.6 mo vs not reached; P=.31 (no benefit)
ORR: 80.0% vs 71.7%; P=.36
DCR: 91.4% vs 80.4%; P=.45
OS: NR (not reported in abstract)
mPFS (L858R subgroup): not reached vs 17.1 mo; P=.03 (favors combo)
mPFS (Ex19del subgroup): 20.6 mo vs not reached; P=.31 (no benefit)
ORR: 80.0% vs 71.7%; P=.36
DCR: 91.4% vs 80.4%; P=.45
OS: NR (not reported in abstract)
Adverse events
Grade ≥3: detailed rates NR in published abstract
Chemotherapy-related (expected): cytopenias, fatigue, nephrotoxicity
Osimertinib class effects: rash, diarrhea, pneumonitis, QTc prolongation, cardiac dysfunction
Other: refer to full manuscript for safety table
Chemotherapy-related (expected): cytopenias, fatigue, nephrotoxicity
Osimertinib class effects: rash, diarrhea, pneumonitis, QTc prolongation, cardiac dysfunction
Other: refer to full manuscript for safety table
Conclusions
Adding platinum-pemetrexed chemotherapy to first-line osimertinib in EGFR/TP53 co-mutated advanced NSCLC produced a numerical PFS and response-rate advantage that did not reach statistical significance overall. A pre-specified L858R subgroup derived a significant PFS benefit, while exon 19 deletion patients did not. The L858R signal is hypothesis-generating and aligns with broader FLAURA-2 / Osi+Chemo data.
Key Limitations
Small sample size (N=98, with much smaller subgroups — underpowered for the L858R/Ex19del interaction). Two-center Chinese cohort — limits generalizability. Open-label design (no placebo, no central radiology review described). OS data not yet mature/reported. Subgroup analyses are hypothesis-generating, not definitive. Chemotherapy backbone details and Grade ≥3 AE rates not in abstract. Title labels this a 'prospective cohort study' while methods describe randomization — clarify with full text. Not a registration-quality phase 3 (compare FLAURA-2, NEJM 2024 PMID 38767249).
Clinical Context
The hypothesis that EGFR/TP53 co-mutated NSCLC benefits from upfront chemotherapy-plus-TKI is supported by this cohort (L858R subgroup) and the larger phase 3 FLAURA-2 (Planchard D et al, NEJM 2024; PMID 38767249): mPFS 25.5 vs 16.7 mo, HR 0.62, for osimertinib + chemo vs osimertinib alone in all-comers. Per ASCO and ESMO, osimertinib + platinum/pemetrexed is a first-line option for EGFR-mutated advanced NSCLC, with particular consideration in high-risk subsets (TP53 co-mutation, L858R, brain metastases). Trade-off: added toxicity and complexity vs modest absolute PFS gain.