The Impact Of Tp53 Mutations On Egfr Mt Plus Nsclc Iv Patients Treated With 3rd Generation Tki On Second-Line Or Further Line Therapy: Real World Data From The German Crisp Registry

TP53 co-mutations are frequent in EGFR mt+ NSCLC and have a strong negative impact on all clinical endpoints in 1st and 2nd generation TKI therapy. However, it is unclear, whether TP53 mutations also have an impact on the effectiveness of 3rd generation TKI. Therefore, we retrospectively analyzed the impact of TP53 co-mutations on PFS and OS in a cohort of EGFR mt+ NSCLC IV patients (UICC 7/8) who developed T790M resistance to 1st and 2nd generation TKI and were treated with 3rd generation TKI in 2nd or further line. 78 EGFR mt+ NSCLC IV patients tested for TP53 co-mutations and showing a T790M resistance mechanism against 1st or 2nd generation TKI were treated with 3rd generation TKI (Osimertinib) in 2nd or further lines. The endpoints PFS and OS were investigated in the TP53mt+ vs. TP53WT groups for only 2nd line (25 TP53 mt+ vs. 28 TP WT) and for the complete population (2nd and further line). Baseline characteristics of the 78 EGFR mt+ NSCLC IV patients: median age was 64 years (28-92 years), 65.4% were female (n=51/78), 70.5% were never/light smoker (n=55/78) and 91% had an ECOG of 0 or 1 (n=71/78). 33/78 (42.3%) had a TP53 mutation, 45/78 (57.7%) were TP53 WT. Median PFS of 3rd generation TKI in 2nd line was 8 (n=25) vs. 11 months (n=28) for TP53 mt+ vs. WT (HR 0.492; p<0.037). Median PFS of 3rd generation TKI in 2nd and further lines was 9 (n=33) vs. 13 (n=45) months for TP53 mt+ vs. WT (HR 0.461; p<0.005). Median OS of 3rd generation TKI in 2nd line therapy was 24 vs. 41 months, for TP53 mt+ vs. WT (HR 0.514; p<0.126). Median OS of 3rd generation TKI in 2nd and further lines was 14 vs. 26 months for TP53mt+ vs. WT (HR 0.483; p<0.029). TP53 co-mutations have a negative impact on PFS and OS in EGFR mt+ NSCLC IV patients treated with 3rd generation TKI (Osimertinib) in 2nd line and 2nd/further lines. Thus, p53 is a negative predictor in EGFR mt+ NSCLC patients treated with Osimertinib. TP53 might be an important target to drug in EGFR mt+ NSCLC in combination with Osimertinib.