PO.CT01.04 · 临床试验

Pembrolizumab and epigenetic modification with azacitidine reprogram the tumor microenvironment of platinum-resistant epithelial ovarian cancer: clinical and translational findings from a phase II study

海报缩略图：Pembrolizumab and epigenetic modification with azacitidine reprogram the tumor microenvironment of platinum-resistant epithelial ovarian cancer: clinical and translational findings from a phase II study

编号 CT260 展板 25 时间 4/21 02:00–05:00 区域 Section 50 主讲 Blair Landon, BS;PhD

分会场 Phase II Clinical Trials

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作者与单位

Blair V. Landon¹, Julia L. Boland², Andrea E. Wahner Hendrickson³, Deborah K. Armstrong¹, Boris Winterhoff⁴, Jaime Wehr¹, Akshaya V. Annapragada¹, Christopher Cherry¹, Archana Balan¹, Guneet Kaleka², Victor E. Velculescu¹, Stephen B. Baylin¹, Cynthia A. Zahnow¹, Dennis J. Slamon², Gottfried E. Konecny², John A. Glaspy², Valsamo (Elsa) Anagnostou¹

¹Johns Hopkins University School of Medicine, Baltimore, MD,²University of California Los Angeles, Los Angeles, CA,³Mayo Clinic, Rochester, MN,⁴University of Minnesota, Minneapolis, MN

摘要 Abstract

Introduction: Epigenetic modulators may sensitize platinum-resistant ovarian cancer (PROC) to immune checkpoint inhibition by reprogramming the tumor microenvironment. Methods: 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, ECOG performance status of 0-1, measurable disease and platinum-resistant, 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 modulation and immunotherapy was evaluated by transcriptomic analyses of 72 serially biopsied tumors. Target gene expression analyses were used to identify differentially expressed genes and pathways, and bulk RNA sequencing was used for gene set enrichment analyses (GSEA) and to infer T cell receptor (TCR) assemblies. Results: The combination of azacitidine and pembrolizumab was moderately well tolerated, and the most common grade 3-4 adverse events were gastrointestinal side effects and anemia. ORR was 2.9% and DCR was 50%; with 3 of the 27 evaluable patients attaining a CA-125 response. Differential gene expression analyses revealed an upregulation of inflammatory and cytolytic genes (FDR-adjusted p=0.005) and co-inhibitory checkpoints (p=0.005) 6 weeks on-therapy. Upregulation of interferon signaling (p=0.006), antigen presentation (p=0.003), costimulatory signaling (p=0.002), and immune cell adhesion and migration (p=0.005) pathways were prominent on-therapy, together with an increase in CD8+ T-cell density (p=0.05). GSEA analyses were concordant with these findings, showing enrichment of immune and inflammatory gene sets on-therapy and upregulation of gene sets linked to IFN-gamma response, natural killer cell-mediated cytotoxicity, and immunoregulatory interactions (p < 10e-13). Findings were not confounded by histological subtype. TCR abundance analyses evaluating significant TCR clonotypic expansions and regressions showed that intra-tumoral TCR repertoires were reshaped on-therapy. Furthermore, patients with a CA-125 and/or clinical response showed enrichment of hallmark inflammatory gene sets at baseline (p < 10e-10) and of adaptive and conserved immune response gene sets on therapy (p < 10e-09). Conclusions: Our findings highlight the potential of epigenetic modulators to reshape the tumor microenvironment of PROC toward a more inflammatory phenotype and may point to approaches to augment immunotherapy response.

利益披露 Disclosure

B. V. Landon, None.. J. L. Boland, None.. A. E. Wahner Hendrickson, None.. D. K. Armstrong, None.. B. Winterhoff, None.. J. Wehr, None. A. V. Annapragada, Delfi Diagnostics Patent. Artemyx Stock, Patent. C. Cherry, C M Cherry Consulting LLC Other, Business Ownership. A. Balan, None.. G. Kaleka, None. V. E. Velculescu, Delfi Diagnostics Stock, Patent, Other, Founder, Serves on board of directors, and inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Artemyx Stock, Patent, Founder, Serves on board of directors as officer, and inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. LabCorp Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Qiagen Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Sysmex Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Agios Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Genzyme Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Esoterix Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Ventana Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. ManaT Bio Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Viron Therapeutics Other, Advisor. Epitope Other, Advisor. S. B. Baylin, None.. C. A. Zahnow, None. D. J. Slamon, BioMarin Other, Corporate board member, Equity ownership. TORL BioTherapeutics Other, Corporate board member, Equity ownership. 1200 Pharma Other, Corporate board member, Equity ownership. Lilly Other, Consultant. Novartis ), Other, Consultant, Speaker bureau, Travel support, Honoraria. Pfizer ), Other, Consultant, Equity ownership, Travel support. Seagen ), Other, Consultant, Equity ownership. Amgen Other, Equity ownership. Merck Sharp & Dohme Other, Equity ownership. Vertex Other, Equity ownership. G. E. Konecny, AstraZeneca Other, Speaker bureaus. Merck ), Other, Speaker bureaus. Immunogen/Genmab Other, Speaker bureaus. Lilly Inc. ). TORL Biotherapeutics Other, Travel support. Foundation Medicine Other, Honoraria. J. A. Glaspy, None. V. Anagnostou, AstraZeneca ), Other, Advisory Board Member. Bristol Myers Squibb ). Personal Genome Diagnostics/Labcorp ), Other, Honoraria. Delfi Diagnostics ). Neogenomics Other, Advisory Board Member. Foundation Medicine Other, Honoraria. Roche Other, Honoraria. ThermoFisher Other, Honoraria. Guardant Health Other, Honoraria.

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