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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid
Kirsty Taylor1, Helen Loo Yau2, Ankur Chakravarthy2,3
1Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Purpose:
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.
Experimental Design:
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.
Results:
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).
Conclusions:
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.
Trial Registration Number:
NCT02811497.
Insights
The combination of oral CC-486 and durvalumab did not improve responses in cold solid tumors. Minimal DNA methylation changes and lack of inflammatory response suggest limited efficacy for this immunotherapy combination.
Area of Science:
- Oncology
- Immunology
- Pharmacodynamics
Background:
- Immunologically 'cold' solid tumors exhibit poor response rates to immune checkpoint inhibitors.
- Durvalumab, an immune checkpoint inhibitor, targets the PD-L1/PD-1 pathway.
- CC-486 is an oral DNA hypomethylating agent with potential to enhance anti-tumor immunity.
Purpose of the Study:
- To evaluate if CC-486 enhances the response of cold solid tumors to durvalumab.
- To assess the safety and tolerability of combined CC-486 and durvalumab therapy.
Main Methods:
- A single-institution, investigator-initiated trial enrolled PD-L1/PD-1 inhibitor-naïve patients with advanced microsatellite stable colorectal, platinum-resistant ovarian, or ER+/HER2- breast cancer.
- Two regimens were investigated: Regimen A (CC-486 300mg QD Days 1-14 (cycles 1-3) + durvalumab 1500mg IV Day 15) and Regimen B (CC-486 100mg QD Days 1-21 + vitamin C 500mg QD + durvalumab 1500mg IV Day 15).
- Paired tumor biopsies and serial peripheral blood mononuclear cells (PBMCs) were collected for immune-profiling, transcriptomic, and epigenomic analyses.
Main Results:
- Twenty-eight patients were enrolled (19 on Regimen A, 9 on Regimen B). The combination was tolerable, with Regimen B showing fewer grade 3/4 adverse effects.
- Global LINE-1 methylation and genome-wide DNA methylation profiles showed minimal changes in PBMCs and tumor biopsies.
- No robust tumor DNA demethylation or 'viral mimicry' inflammatory response was observed, correlating with no clinical responses (Disease Control Rate: 7.1%). Median progression-free survival was 1.9 months, and median overall survival was 5 months.
Conclusions:
- The evaluated CC-486 and durvalumab treatment schedules did not demonstrate significant pharmacodynamic or clinical activity in cold solid tumors.
- This biomarker-rich study provides valuable insights for future drug development involving these agents.
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