An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors.

To evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically 'cold' solid tumors to immune checkpoint inhibitor durvalumab. PD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colorectal cancer; platinum resistant ovarian cancer; and estrogen receptor positive, HER2 negative breast cancer were enrolled in this single-institution, investigator-initiated trial. Two 28 day regimens, regimen A (CC-486 300 mg QD Days 1-14 (cycles 1-3 only) in combination with durvalumab 1500 mg intravenous day 15) and regimen B (CC-486 100 mg QD days 1-21 (cycle 1 and beyond), vitamin C 500 mg once a day continuously and durvalumab 1500 mg intravenous day 15) were investigated. Patients underwent paired tumor biopsies and serial peripheral blood mononuclear cells (PBMCs) collection for immune-profiling, transcriptomic and epigenomic analyzes. A total of 28 patients were enrolled, 19 patients treated on regimen A and 9 on regimen B. The combination of CC-486 and durvalumab was tolerable. Regimen B, with a lower dose of CC-486 extended over a longer treatment course, showed less grade 3/4 adverse effects. Global LINE-1 methylation assessment of serial PBMCs and genome-wide DNA methylation profile in paired tumor biopsies demonstrated minimal changes in global methylation in both regimens. The lack of robust tumor DNA demethylation was accompanied by an absence of the expected 'viral mimicry' inflammatory response, and consequently, no clinical responses were observed. The disease control rate was 7.1%. The median progression-free survival was 1.9 months (95% CI 1.5 to 2.3) and median overall survival was 5 months (95% CI 4.5 to 10). The evaluated treatment schedules of CC-486 in combination with durvalumab did not demonstrate robust pharmacodynamic or clinical activity in selected immunologically cold solid tumors. Lessons learned from this biomarker-rich study should inform continued drug development efforts using these agents. NCT02811497.

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Competing interests: PLB: Consultant for: Bristol-Myers Squibb (compensated), Sanofi (compensated), Pfizer (compensated). Grant/Research support from (Clinical Trials for aarinstitution): Bristol-Myers Squibb, Sanofi, AstraZeneca, Genentech/Roche, Servier, GlaxoSmithKline, Novartis, SignalChem, PTC Therapeutics, Nektar, Merck, Seattle Genetics, Mersana, Immunomedics, Lilly. AAR: Honoraria: Boehringer Ingelheim. Consultant for: Lilly (compensated), Merck (compensated), Boehringer Ingelheim (compensated). Grant/Research support from (Clinical Trials): CASI Pharmaceuticals, Boehringer Ingelheim, Lilly, Novartis, Deciphera, Karyopharm Therapeutics, Pfizer, Genentech/Roche, Boston Biomedical, Bristol-Myers Squibb, MedImmune, Amgen, GlaxoSmithKline, Blueprint Medicines, Merck, Abbvie, Adaptimmune. ARH: Advisory/Consulting/Research for Genentech/Roche, Merck, GSK, Bristol-Myers Squibb, Novartis, Boston Biomedical, Boehringer-Ingelheim, AstraZeneca, Medimmune. AS: Consultant for (Advisory Board): Merck (compensated), Bristol-Myers Squibb (compensated), Novartis (compensated), Oncorus (compensated), Janssen (compensated). Grant/Research support from (Clinical Trials): Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma. DC: Consulting/Advisory: Agendia, AstraZeneca, GSK, Merck, Novartis, Pfizer, Puma, Roche, Dynamo Therapeutics. Grant/Research support from (Clinical Trials): GlaxoSmithKline, Merck, Pfizer. Intellectual Property: Biomarkers for TTK inhibitors (assigned to institution). MOB: Consulting for: Bristol-Myers Squibb, Novartis, Merck, GlaxoSmithKline, EMD Serono, Sanofi, Immunocore. Grant/Research support from (Clinical Trials): Merck, Takara Bio. AMO: Consultant for: AstraZeneca, MERCK, Clovis Oncology, TESARO (all non-compensated). SL: Consultant for: Merck (compensated), AstraZeneca (compensated), GlaxoSmithKline (compensated), Roche (compensated). PO: Consulatnt for: Providence (compensated), Symphogen (compensated), Tessa (compensated), Research support from: EMD Serono. LS: Consultant for: Merck (compensated), Pfizer (compensated), Celgene (compensated), AstraZeneca/Medimmune (compensated), Morphosys (compensated), Roche (compensated), GeneSeeq (compensated), Loxo (compensated), Oncorus (compensated), Symphogen (compensated), Seattle Genetics (compensated), GSK (compensated), Voronoi (compensated), Treadwell Therapeutics (compensated), Arvinas (compensated), Tessa (compensated), Navire (compensated). Grant/Research support from (Clinical Trials for institution): Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks, Avid. Stockholder in: Agios (spouse). DDC: Research support from Pfizer and Nektar therapeutics.