Guadecitabine Plus Ipilimumab in Unresectable Melanoma: The NIBIT-M4 Clinical Trial

Abstract

Purpose: The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab. Patients and Methods: Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m 2 /day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics. Results: Nineteen patients were treated; 84% had grade 3/4 adverse events, and neither dose-limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n ¼ 8) at week 4 (74.5%) and week 12 (75.5%) was significantly (P < 0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly (P < 0.05; Z score >2 or 2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis (n ¼ 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8 þ , PD-1 þ T cells and in CD20 þ B cells in posttreatment tumor cores. Conclusions: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.

Immune-Related Mutational Landscape and Gene Signatures: Prognostic Value and Therapeutic Impact for Head and Neck Cancer

“…Indeed, increased TE expression and de novo presentation of TE-derived peptides on MHC class I molecules were found upon treatment of cancer cells with a demethylation agent, indicating that therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy. In line with this assumption, the phase IbNIBIT-M4 trial reported that treatment of patients with advanced melanoma using the next-generation DNA hypomethylating agent guadecitabine combined with ipilimumab is safe and tolerable, and shows promising immunomodulatory and antitumor activity [71].However, in an open-label phase II multicohort study administration of the oral DNA hypomethylating agent CC-486 combined with durvalumab did not demonstrate robust pharmacodynamic or clinical activity in selected immunologically cold solid tumors consisting of PD-(L)1 inhibitor naïve patients with either advanced microsatellite stable colorectal cancer, platinum resistant ovarian cancer, or estrogen receptor positive, HER2 negative breast cancer [72].…”

The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies

“…T cell receptor (TCR) repertoire clonality of responders was found to be increased during therapy (36,131). In a trial combining CTLA-4 blockade with an demethylating agent, an increase in CD8+ T cell and PD-1 expression was reported (132).…”

Extracellular Vesicles and Epigenetic Modifications Are Hallmarks of Melanoma Progression

“…Next-generation DHAs, however, demonstrated promising immune-modulatory and anti-tumor activity in clinical trials [56]. In this continuously evolving scenario, the phase 1b NIBIT-M4 study recently confirmed the tolerability and safety of guadecitabine associated with ipilimumab in unresectable stage III/IV melanoma, which shows a unique objective response rate of 26% [108].…”