A study of using epigenetic modulators to enhance response to pembrolizumab (MK-3475) in microsatellite stable
Marina Baretti1, Adrian G Murphy1, Marianna Zahurak1
1The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Background:
Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis.
Results:
From January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40-69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%).
Conclusions:
The combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting.
Insights
This pilot trial combined epigenetic drugs with PD-1 blockade for advanced colorectal cancer (CRC) patients. The combination was safe but showed minimal activity, indicating a need for further research in MMR-proficient CRC.
Area of Science:
- Oncology
- Immunotherapy
- Epigenetics
Background:
- Advanced colorectal cancer (CRC) with mismatch repair-proficient (MMRp) tumors (95% of cases) shows limited response to PD-1 blockade alone.
- Preclinical data suggest combining epigenetic modifiers (HDAC and/or DNMT inhibitors) with immune checkpoint therapy can enhance anti-tumor immunity.
- This study aimed to evaluate PD-1 inhibitor therapy combined with DNMT and HDAC inhibitors in MMRp CRC patients.
Purpose of the Study:
- To assess the safety and tolerability of combining PD-1 inhibitors with DNMT and HDAC inhibitors in advanced MMRp CRC.
- To evaluate the clinical activity and immune cell infiltration changes in the tumor microenvironment.
- To determine the optimal epigenetic combination for enhancing immunotherapy response in MMRp CRC.
Main Methods:
- A pilot trial involving 27 patients with advanced MMRp CRC.
- Patients received a combination of PD-1 immune checkpoint inhibitor therapy with DNMT and HDAC inhibitors (5-azacitidine and romidepsin).
- Biological endpoint focused on changes in immune cell infiltration to optimize the tumor microenvironment.
Main Results:
- Median progression-free survival was 2.79 months; median overall survival was 9.17 months.
- One patient achieved a durable partial response lasting approximately 19 months.
- Common adverse events included anemia, lymphopenia, thrombocytopenia, anorexia, nausea, and vomiting.
Conclusions:
- The combination of 5-azacitidine, romidepsin, and pembrolizumab demonstrated safety and tolerability in advanced MMRp CRC.
- The combination exhibited minimal clinical activity, suggesting limited efficacy in this patient group.
- Further mechanistic studies are required to understand epigenetic-induced immunologic shifts and broaden the application of checkpoint inhibitors.
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