Combination of tulmimetostat and PD-1 blockade for patients with advanced non–small cell lung cancer who progressed from first or second line of treatments.

TPS8664 Background: Immune checkpoint inhibitors (ICIs) have transformed advanced non–small cell lung cancer (NSCLC) treatment, yet many patients exhibit primary ICI resistance or progression after initial response. Epigenetic dysregulation, including aberrant EZH2-mediated trimethylation of histone H3 (H3K27me3), has been implicated in tumor immune evasion and reduced responsiveness to ICIs. Preclinical studies suggest that EZH2 inhibition may enhance antitumor immunity and potentiate PD-1 blockade. Tulmimetostat, a potent dual EZH2/EZH1 inhibitor, demonstrates favorable tolerability and antitumor activity across multiple solid tumors. We hypothesize that the addition of tulmimetostat to pembrolizumab may reverse the resistance to pembrolizumab in patients with ICI-refractory NSCLC. Methods: The primary objective of this open-label, single-arm, phase Ib/II study is to evaluate the safety, tolerability, and preliminary efficacy of combining tulmimetostat with pembrolizumab in Veterans with advanced NSCLC who have progressed after first- or second-line therapy, one of which must have included ICI. Key eligibility criteria include measurable disease per RECIST v1.1 and provision of adequate tumor tissue (archive or new). Tulmimetostat (200 mg or 300 mg) is administered orally once daily, beginning with a 7-day run-in period during cycle 1, followed by pembrolizumab 200 mg IV every 3 weeks. Treatment continues until confirmed disease progression, unacceptable toxicity, or withdrawal. Safety assessments include clinical exams, laboratory evaluations, ECGs, and CTCAE v5.0 grading of adverse events. Imaging is performed at baseline and every 9 weeks. Secondary endpoints include disease control rate, progression-free survival, and duration of response. Up to 18 patients will be enrolled in Phase Ib using a BOIN method to determine the dose-limiting toxicities (DLTs) and the recommended phase II dose (RP2D) of tulmimetostat. Phase II is a Simon optimal two-stage design to assess objective response rate (ORR) per RECIST v1.1. Subjects treated at the RP2D during phase Ib will be included in the efficacy analysis. In total, up to 66 patients will be enrolled across multiple VA sites. Optional on-treatment biopsies will be obtained at select timepoints. Biomarker analyses will include an assessment of H3K27me3 (Methyl Mark) and PD-L1 expression in tumor biopsy samples to explore epigenetic and immunologic correlates of treatment response. Correlative biomarker analyses, including H3K27me3 and PD-L1 expression in tumor biopsies, will offer insight into epigenetic and immunologic determinants of treatment response. Findings from this trial may support the development of a novel therapeutic approach for patients with NSCLC who have progressed after on standard immunotherapy or chemo-immunotherapy. Enrollment was initiated in January 2026. Clinical trial information: NCT05467748 .