A Phase I/II Study of Valemetostat (DS-3201b), an EZH1/2 Inhibitor, in Combination with Irinotecan in Patients with Recurrent Small-Cell Lung Cancer

Abstract

Purpose: Recurrent small-cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted.

Patients and methods: This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety, tolerability, and a recommended phase II dose (RP2D). The phase II primary objective was overall response rate (ORR), with secondary objectives of determining duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Correlative analyses included immunohistochemistry of pretreatment and on-treatment tumor biopsies and pharmacokinetics analysis.

Results: Twenty-two patients were enrolled (phase I, n = 12; phase II, n = 10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLT) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; three patients discontinued treatment for toxicity. Three of the first 10 patients in phase II experienced DLTs triggering a stopping rule. The ORR was 4/19 or 21% [95% confidence interval (CI), 6%-46%]. The median DoR, PFS, and OS were 4.6 months, 2.2 months (95% CI, 1.3-7.6 months), and 6.6 months (95% CI, 4.3 to not reached), respectively. SLFN11/EZH2 expression and SCLC subtyping markers did not correlate with response, but MHC-I expression did increase with treatment. Two responders demonstrated subtype switching on treatment.

Conclusions: Combination valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat, combined with agents without overlapping toxicity, warrants further investigation in SCLC.

Figure 1:. Efficacy of valemetostat and irinotecan.

A) Best objective responses and greatest percent tumor shrinkage by radiographic imaging are shown. Empty cells in below table signify no sample available for testing; all samples are from pre-treatment tumors. B) Time on therapy for each patient is shown. PD, progressive disease; SD, stable disease; PR, partial response; POD, progression of disease; DLT, dose-limiting toxicity; DR, dose reduction. C) Kaplan-Meier curve for progression-free survival. D) Kaplan-Meier curve for overall survival.

Figure 2:. Tumor immunohistochemical (IHC) analysis.

SLFN11 expression (A) and MHC-I (B) assessed by IHC in available pre- and on-treatment tissue samples. Paired samples are connected via a solid line. Responders are included in both left and right plots, identified by patient IDs in right plot. C) Small cell lung cancer (SCLC) subtyping assessed by IHC displayed as heatmap. White cells indicate H-score 0; samples completely unavailable for any IHC are not shown, while samples with some unavailable IHC results are shown with an X through cell. Pre-tx, pre-treatment; on-tx; on-treatment; PD, progressive disease; SD, stable disease; PR, partial response.