Abstract
Introduction/Background Advanced/recurrent EC has poor prognosis with 5-year survival rate of ~17% (Colombo 2016; Siegel 2022). Maintenance treatment may improve and extend the durability of response to initial chemo/chemoimmunotherapy; novel agents are being tested in this setting to improve survival outcomes. The tumor suppressor protein p53 can detect intracellular DNA damage and oncogenic aberrations leading to orderly apoptosis of tumorigenic cells. Mouse double minute 2 (MDM2), the key negative regulator of p53, is upregulated by some cancers to prevent p53 tumor suppressor function, while other cancers inactivate p53 by direct loss or mutation. MDM2 is upregulated in ~50% of EC patients (Jeczen 2007) due to loss of p14ARF, a critical modulator of intranuclear MDM2 levels. Navtemadlin is a potent, selective, orally available MDM2 inhibitor that restores p53-mediated apoptosis in TP53WT tumors. The sensitivity of EC to genotoxic chemotherapy (Miller 2020) suggests susceptibility to p53-mediated apoptosis. Post-chemotherapy maintenance treatment with navtemadlin may provide a non-genotoxic way to maintain p53-driven activity and tumor cell control in the ~50% of EC patients who are TP53WT (Nakamura 2019). KRT-232–118 is a Global 2-part Phase 2/3 study evaluating the safety and efficacy of navtemadlin as maintenance therapy in TP53WT advanced/recurrent EC patients following response to chemotherapy (EudraCT 2022–5002196-31; NCT05797831). Methodology Eligible patients are adults with ECOG PS 0–1 who completed up to 6 cycles of chemotherapy excluding adjuvant/neo-adjuvant therapy and achieved CR or PR per RECIST v1.1. The open-label Phase 2 randomizes patients 1:1:1 to oral navtemadlin at a dose of 180 mg or 240 mg QD (Day 1–7/28-day cycle), or observation; primary endpoint is recommended Phase 3 dose (RP3D). The double-blind Phase 3 will randomize patients (2:1) to the RP3D vs placebo QD (Day 1–7/28-day cycle); stratification is by response and disease stage. Primary endpoint for Phase 3 is progression-free survival by blinded independent review. Results NA Abstract #84 Figure 1 Study schema of KRT-232–118 [Figure omitted. See PDF] Conclusion NA Disclosures Funded by Kartos Therapeutics Inc.