EZH2 Inhibitor, Tulmimetostat, and PD-1 Blockade for Treatment of Advanced Non-small Cell Lung Cancer

It is pleasing to witness the fulfillment of the promise of cancer immunotherapy becoming a reality for patients with many types of advanced cancer. However, even with this remarkable progress, majority of patients are not responding and substantial number of patients are progressing after initial response to checkpoint blockade immunotherapy. The field is undertaking major task to identify suitable combinatorial approach to improve the efficacy of checkpoint blockade immunotherapy and biomarker for better patient selection. Evidence suggests that EZH2 (Enhancer Zeste Homolog: enzymatic component of Polycomb Repressive Complex 2) plays a significant role in prognosis of patients with non-small cell lung cancer and animal studies showed that EZH2 targeting can improve the efficacy of immunotherapy. Based on this, it was hypothesized that EZH2 inhibitor, tulmimetostat can re-sensitive cancer cells to respond to PD-1 blockade, pembrolizumab and designed phase Ib/II single arm, open label study to test this hypothesis for patients with advanced non-small cell lung cancer who progressed from front or second line of therapy (expecting majority of patients experienced checkpoint blockade immunotherapy). The primary objectives of this study are safety/tolerability and Objective Response Rate (ORR: Complete Response and Partial Response) evaluated by RECIST v1.1. Key secondary objectives are disease control rate, progression free survival at 1 year, and duration of response. The study will employ safety lead-in phase Ib using BOIN (Bayesian Optimal Interval Design) with 2 dose levels (200 and 300 mg) for tulmimetostat, starting 200mg mg orally once daily. Tulmimetostat will be administered for 7 days prior to pembrolizumab 200 mg intravenous every 3 weeks that is defined as run-in phase (only prior to first cycle). It is planned to enroll 18 patients during phase Ib to determine recommended dose for phase II (RP2D). The sample size for phase II was calculated using Simon optimum two-stage design in order to determine the futility at early time. In the first stage, 15 subjects will be enrolled. If 2 or more responses are observed, an additional 39 subjects will be accrued during second phase. If in total there are 8 or more responses, we will consider the drug combination worthy of further clinical development, provided other factors such as toxicity and progression-free survival also appear favorable. For this phase II portion, up to 54 subjects are enrolled. This design has a one-sided alpha of 5% and a power of 80%. Planned duration of enrollment is 2 years, correlative studies (methyl marker: H3K27me3 and PD-L1, exome, RNA, circulating ctDNA sequencing and immune monitoring) are proposed using tumor biopsies (on treatment biopsy is optional) and blood samples before and after the treatment.