# Pembrolizumab and epigenetic modification with azacitidine reshapes the tumor microenvironment of platinum-resistant epithelial ovarian cancer: a phase 2 non-randomized clinical trial

## TL;DR

This study shows that combining pembrolizumab and azacitidine in platinum-resistant ovarian cancer moderately controls tumor growth and changes the tumor environment to be more inflammatory, potentially improving immunotherapy response.

## Contribution

The study demonstrates that epigenetic modulation with azacitidine can reshape the tumor microenvironment to enhance immunotherapy in platinum-resistant ovarian cancer.

## Key findings

- The combination therapy was moderately well tolerated with gastrointestinal side effects and anemia as the most common grade 3–4 adverse events.
- Transcriptomic analyses revealed upregulation of inflammatory genes, interferon signaling, and increased CD8+ T-cell density in the tumor microenvironment.
- Patients with a CA-125 or clinical response showed enrichment of adaptive immune response gene sets during treatment.

## Abstract

Epigenetic modulators may sensitize platinum-resistant ovarian cancer (PROC) to immune checkpoint inhibition by reprogramming the tumor microenvironment.

We report clinical and translational findings from a phase II non-randomized study of pembrolizumab and oral azacitidine in 34 women with PROC (NCT02900560). Key eligibility criteria included age 18 years or older, performance status of 0–1, measurable disease, platinum-resistant disease and histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma. Primary endpoints included safety, tolerability, overall response rate (ORR) and disease control rate (DCR). Secondary endpoints included CA-125 response. The effect of combined epigenetic and immunotherapy was evaluated by transcriptomic analyses of 72 serially biopsied tumors.

We show that the combination is moderately well tolerated and most common grade 3–4 adverse events are gastrointestinal side effects and anemia. ORR is 2.9% and DCR is 50%; with 3 of the 27 evaluable patients attaining a CA-125 response. Differential gene expression analyses reveal an upregulation of inflammatory and cytolytic genes and co-inhibitory checkpoints 6 weeks on-therapy. Upregulation of interferon signaling, antigen presentation and immune cell adhesion and migration gene sets are prominent on-therapy, together with an increase in density of CD8 + T-cells. Patients with a CA-125 and/or clinical response show an enrichment of adaptive and conserved immune response gene sets on-therapy.

Our findings highlight the potential of epigenetic modulators to re-shape the tumor microenvironment of PROC toward a more inflammed phenotype and may point to approaches to augment immunotherapy response.

Landon, Boland et al. investigate the clinical and molecular impact of a combination of epigenetic modulation and immune checkpoint inhibition in platinum-resistant ovarian cancer. Serial transcriptomic analyses reveal reshaping of the tumor microenvironment toward a more inflammatory state that may enhance immunotherapy response.

A type of cancer immunotherapy called immune checkpoint inhibition (ICI) has shown limited effectiveness in ovarian cancer. This might be because of few active immune cells in the area surrounding the tumor, called the tumor microenvironment. Additional treatments called epigenetic modulators can be used to increase anti-tumor immune responses. Here we investigate if the combination of an epigenetic modulator with ICI can be used in women with ovarian cancer who have not significantly benefited from standard chemotherapy. The combination of epigenetic therapy with ICI was moderately well tolerated, and tumor growth was controlled in half of the women in the study. There was evidence that the tumor microenvironment changed by inducing an inflammatory profile. These findings show the potential of this combination therapy to alter the tumor microenvironment, and that this could enhance outcomes to cancer treatments.