Abstract C046: Natural history and prognostic value of <i>TP53</i> Y220C mutation in advanced solid tumors: A real-world study

Abstract Background: TP53 mutations, the most common genomic alterations in cancer, are associated with poor prognoses across many tumor types. The TP53 Y220C mutation occurs in ∼1% of solid tumors and destabilizes p53, causing loss of tumor suppressor function. Impact of the TP53 Y220C mutation on survival in patients (pts) with solid tumors has not been previously assessed. This real-world study evaluates the natural history of locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation and the prognostic significance of TP53 Y220C. Methods: Pts with locally advanced or metastatic solid tumors with a TP53 Y220C mutation were selected from the US-based deidentified Flatiron Health-Foundation Medicine ClinicoGenomic Database (Jan 1, 2011–Sep 30, 2023). Primary objective was to describe demographic, clinical, and tumor (including genomic) characteristics, and treatment outcomes in these pts. Secondary objectives included real-world overall survival (rwOS), progression-free survival (rwPFS), and overall response rate (rwORR). An exploratory objective compared rwOS between pts with a TP53 Y220C mutation vs pts with no TP53 Y220C mutation (all other mutations or TP53 wild-type) in the population of pts with no KRAS single nucleotide variant (SNV). Results: As of data cut, March 31, 2024, this study included 615 pts with a TP53 Y220C mutation who received first-line (1L; n=366), second-line (2L; n=202) and third-line (3L; n=99) therapy. Most pts (95.8%) were tested for TP53 Y220C after advanced/metastatic diagnosis (median: 129 days after). KRAS SNVs were present in 21.8% of pts, with highest frequency in pts with pancreatic cancer (100%) and lowest in pts with ovarian (1%), breast (0%), and prostate cancers (0%). Median rwOS was 25.3 months overall. Pts with tumors harboring KRAS SNVs had shorter rwOS vs pts lacking KRAS SNVs (16.0 vs 30.3 months). Pts with pancreatic cancer had the shortest rwOS (12.7 months); pts with ovarian cancer had the longest (56.0 months). For pts receiving 1L, 2L, and 3L therapy, rwORR and rwPFS decreased as lines of systemic therapy increased. Among pts with no KRAS SNV baseline characteristics were generally well balanced across TP53 Y220C (n=525) and non-TP53 Y220C pts (n=1,733) and across tumor types. Most pts (&amp;gt;95%) were tested for TP53 Y220C after advanced/metastatic diagnosis (median TP53 Y220C: 164.5 days; non-TP53 Y220C: 150.0 days). Median rwOS was shorter in TP53 Y220C vs non-TP53 Y220C pts (28.5 vs 35.8 months; hazard ratio 1.14 [95% confidence interval:1.01–1.29]). Similar trends were seen in non-small cell lung, breast, and endometrial cancer subgroups. Most pts with ovarian cancer (94.2%) had another TP53 mutation likely inactivating p53 in the non-TP53 Y220C group; no difference in rwOS was observed here. Conclusions: In this real-world study, pts with a TP53 Y220C mutation appeared to have poor prognoses. Reactivating p53 offers an attractive therapeutic approach in pts with solid tumors harboring TP53 mutations, addressing a high unmet medical need where targeted treatments are lacking. Citation Format: Marc Fellous, Catherine Green, Patricia Prince, John Shen, Cheryl Cho-Phan, Spencer Langerman, Gerald Li, Ryon Graf, Ecaterina E. Dumbrava, Alison M. Schram. Natural history and prognostic value of TP53 Y220C mutation in advanced solid tumors: A real-world study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C046.