TP53 co-mutations as an independent prognostic factor in 2nd and further line therapy—EGFR mutated non-small cell lung cancer IV patients treated with osimertinib

Abstract

Background: The negative prognostic and predictive value of TP53 co-mutations (TP53 mt+) in EGFR mutated (EGFR mt+) non-small cell lung cancer (NSCLC) is increasingly being acknowledged. Data consistently show that TP53 mt+ impact negatively on 1st line objective response rate (ORR), progression free survival (PFS) and overall survival (OS) with 1st and 2nd generation tyrosine kinase inhibitors (TKI). However, a negative predictive impact has not been shown for the 3rd generation TKI Osimertinib. Therefore, we investigated the impact of TP53 mt+ in EGFR mt+ NSCLC carrying a T790M resistance mutation and treated in 2nd/further lines with Osimertinib.Methods: A total of 77 EGFR mt+ NSCLC IV patients carrying a T790M resistance mutation from two institutions were analyzed for TP53 mt+. Clinical data including sex, age, presence of CNS metastases, etc., as well as types of EGFR and TP53 mt+ were captured. PFS and OS were calculated from the start of Osimertinib.Results: TP53 mt+ were found in 32/77 patients (42%). TP53 mt+ was a statistically significant independent negative predictive factor for PFS and OS. PFS for TP53 mt+ patients were 9 months vs.14 months for patients with TP53 wild-type (TP53WT) (P<0.008). OS for TP53 mt+ patients was 16 months vs. 24 months patients with TP53WT (P<0.025).Conclusions: TP53 mt+ have a negative impact on PFS and OS in a group of patients carrying a sensitizing EGFR mt+ and a T790M resistance mutation treated with Osimertinib. These data, together with the data for 1st/2nd generation TKI in 1st line treatment call for additional therapeutic and management concepts for this subgroup of patients.

Acquired G2032R Resistance Mutation in ROS1 to Lorlatinib Therapy Detected with Liquid Biopsy

“…Mutations in the tumor suppressor gene p53 (TP53) are the most common mutations found in NSCLCs and co-occur in about 30% of NSCLC patients with ALK and ROS1 translocations [ 12 ]. The negative impact of co-mutations such as TP53 mutations on PFS and OS has been demonstrated in a small series of ROS1 patients and these data are consistent with ALK+ and EGFR mt+ patients [ 13 , 14 ]. When receiving crizotinib, concomitant TP53 mutations in ALK-rearranged NSCLC patients have been associated with unfavorable survival, a reduced response and shorter progression free survival (PFS) in multiple studies [ 12 , 15 , 16 , 17 , 18 , 19 ].…”

“…Comparing the 4 months of our patient on crizotinib to the 22.4 months reported in the PROFILE001 study [ 30 ], she progressed dramatically fast. One of the reasons for fast progression may be the inactivating TP53 mutation, as such alterations might represent an intrinsic mode of TKI resistance and are suggested to have a negative predictive and prognostic role in ALK+ [ 12 , 18 , 31 ], as well as in EGFRmt+ NSCLC [ 13 , 14 ].…”

Next‐generation sequencing clarified why first‐line treatment with osimertinib was ineffective in an autopsied case of EGFR‐mutated lung squamous cell carcinoma

“…The analysis revealed multiple genetic abnormalities, including TP53 mutation and amplification of CDK6 and KRAS, which have previously been associated with resistance to osimertinib. 15,16,[18][19][20] These tumor cell-associated gene abnormalities might explain the ineffectiveness of osimertinib in our case. Intriguingly, EGFR mutations were not detected in the autopsy specimens.…”

“… 6 Excellent reviews have been published on the mechanism of therapeutic resistance to osimertinib as first‐line therapy. 14 , 15 , 16 , 17 , 18 Resistance to osimertinib may occur via bypass mechanisms and activation of downstream pathways. 14 Genetic abnormalities detected by NGS, including EGFR mutations ( C797X , G796X , L92X , G724S , L7118Q ), amplifications ( MET , HER2 , KRAS , NRAS , YES1 , CDK ), and gene rearrangements ( RET , NTRK , ALK , BRAF , ROS1 , FCFR3 ) have been associated with resistance to osimertinib as first‐line therapy.…”

Can we cure metastatic EGFR-mutated lung cancer today?

“…One special advantage from such a broader approach is the additional coverage of genes with prognostic and predictive importance, like TP53, the wild-type status of which has been linked to durable responses under EGFR and ALK inhibitors (4,15). While no TP53 sequencing was performed here, as TP53 was not included in the 23-gene NGS panel used in April 2022 (3), it is reasonable to assume that this particular patient with >62-month-long response to late-line osimertinib lacked TP53 mutations, since these are strongly associated with shorter PFS and OS in this situation, with a hazard ratio >2.5 compared to TP53 wild-type in retrospective analyses (16). One additional possibility to further refine patient stratification are longitudinal circulating tumor DNA (ctDNA) assays under treatment, as clearance under EGFR TKI (13) and/or undetectable ctDNA at the time of oligoprogression (17) are associated with better outcomes in oncogene-driven NSCLC (Table 1).…”