Clinical outcomes of patients with TP53 pathway alterations by treatment type: The MD Anderson Cancer Center IMPACT 2 study.

3152 Background: TP53 pathway alterations are found in over 50% of human cancers, with variable frequency across tumor types. They are associated with aggressive tumor biology, increased metastatic potential, and poor prognosis. Herein, we report the clinical outcomes of patients with TP53 pathway alterations treated in the IMPACT 2 study (2014-2023; NCT02152254). Methods: Patients with advanced cancer underwent tumor biopsy and molecular profiling (CLIA-certified lab). Pathway analysis was conducted using the maftools R package. TP53 pathway alterations were defined as those involving the TP53 , ATM , CHEK1 , CHEK2 , MDM2 , and MDM4 genes. Patients were treated on clinical trials with investigational agents that included matched targeted therapies (MTTs) when available. MTT included anti-vascular endothelial growth factor (VEGF) targeted therapy, as previously published (PMID: 27466356). We analyzed the following outcomes by treatment type (MTT vs. non-matched targeted therapy NTT and immunotherapy IO vs. non-IO): objective response rate (ORR; complete response + partial response), clinical benefit rate (CBR; ORR + stable disease≥4 months), progression-free survival (PFS), and overall survival (OS). Results: Of 491 treated patients with targetable alterations, 278 (56.6%) had p53 pathway alterations (median age, 60.1 years range, 20.5-81.7; female, 51.4%; ECOG performance status 1, 86.0%; median number of prior therapies, 3 range, 0-11; liver metastases, 42.2%; >2 metastatic sites, 36.0%; high lactate dehydrogenase level, 41.0%; low albumin level, 9%). The most common tumors were colorectal (21.2%), sarcoma (13.7%), other gastrointestinal (12.2%), and breast (8.6%). Immune markers included PD-L1≥1%, 47.3% (78/165); MSI-H, 1% (2/199); and TMB-H, 10.5% (19/181). Concomitant pathway alterations were RTK-RAS (48.6%), PI3K (24.8%), and cell cycle (38.1%) pathways. MTT included VEGF/VEGFR inhibitors, N=57; MDM2 inhibitors, N=4; and TP53 activator, N=1. Clinical outcomes are shown in the Table. Conclusions: Median OS was significantly longer in patients with TP53 pathway alterations treated with IO compared with non-IO regimens. Considering the limited availability of TP53-targeted agents, no differences in clinical outcomes were noted for MTT compared with NTT. Further analyses are warranted to elucidate the molecular substrates underlying immunotherapy benefit. Clinical trial information: NCT02152254 . All patients MTT NTT P IO Non-IO P N=278 N=62 N=216 N=69 N=209 ORR 18/247 4/59 14/188 1.00 9/64 9/183 0.024* % 7.3 6.8 7.4 14.1 4.9 CBR 142/247 37/59 105/188 0.37 43/64 99/183 0.87 % 57.5 62.7 55.9 67.2 54.1 Median PFS, months 3.75 5.52 2.93 0.11 4.37 3.19 0.46 95% CI 2.89, 4.8 4.67, 8.19 2.5, 4.14 2.73, 5.56 <jats:td colspan