Table 2.
| a Epigenetic therapies combined with non-immune therapies in NSCLC patients | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||||||
| Epigenetic agent | Phase | Total patient # |
Patient # with NSCLC |
Response rate |
CR/PR | PFS month |
SD | OS month |
Side effects | Study status |
NCT number |
Reference | |
| DNMTi | Chemotherapy | ||||||||||||
|
| |||||||||||||
| azacitidine | cisplatin | 1 | - | - | - | - | - | - | - | not yet published | - | NCT00901537 | [54] |
| azacitidine | carboplatin or paclitaxel | 1 | - | - | - | - | - | - | - | not yet published | completed | NCT01478685 | [55] |
|
| |||||||||||||
| HDACi | Chemotherapy | ||||||||||||
|
| |||||||||||||
| belinostat | paclitaxel + carboplatin | 1 | 23 | 23 | 35% | 8 | - | 4 | - | fatigue (91%), nausea (78%), constipation (74%), anemia (65%), diarrhea (65%), alopecia, arthralgia, decreased appetite, insomnia, neutropenia (61%), dizziness, vomiting (57%), headache (52%) | completed | NCT01310244 | [51] |
| belinosta | standard of care chemotherapy | 1 | aimed 7 | aimed 7 | - | - | - | - | not yet published | terminated | NCT01090830 | [56] | |
| panobinostat | pemetrexed | 1 | - | - | - | - | - | - | - | not yet published | terminated | NCT00907179 | [57] |
| panobinostat | carboplatin + etoposid | 1 | 6 | 4 | - | - | - | - | dose-limiting toxicity (2), grade 4 thrombocytopenia and grade 4 febrile neutropenia (1) | terminated because of inacceptable toxicities | NCT00958022 | [58] | |
| panobinostat | cisplatin+ pemetrexed | 1 | - | - | - | - | - | - | - | not yet published | active, not recruiting | NCT01336842 | [59] |
| panobinostat | paclitaxel, carboplatin, bevacizumab | 1 | 22 | 4 | - | 3 | 11 | - | neutropenia (90%, 67% grade 4), thrombocytopenia (90%), anemia (76%), fatigue (71%), diarrhea (52%), vomiting (48%) | completed | NCT00556088 | [50] | |
| vorinostat | bevacizumab + carboplatin + paclitaxel | 1/2 | 25 | 25 | - | - | - | - | - | not yet published | terminated | NCT00702572 | [60] |
| vorinostat | topotecan | 1/2 | - | - | - | - | - | - | - | not yet published | terminated | NCT00697476 | [61] |
| vorinostat | gemcitabine + platinum-based agent | 1 | 61 (10 completed) | 61 | - | - | - | - | - | 39 SAE, 61 AE (most frequent anemia and asthenia) | completed | NCT00423449 | [62] |
| vorinostat | docetaxel | 1 | 12 | 3 | - | - | - | - | - | not separately documented for LC | NCT00565227 | [63] | |
| vorinostat vs placebo | carboplatin + paclitaxel | 2 | 62 (20 completed in vorinostat-arm) 32 (12 completed in placebo-arm) | 94 | 34% (vorinostat-arm) vs 12% | - | 6 vs 4.1 | 13 vs 9.7 | 29 SAE (vorinostat-arm):febrile neutropenia (2), anemia (2), cardiac disorders (3), gastrointestinal disorders (10), death (3), other general disorders (9), 100% other AE in vorinostat-arm: anemia (43), constipation (23), diarrhea (20), nausea (37), vomiting (25), PD (20), fatigue (52), leukocyte amount decreased (28), thrombocyte count decreased (36), anorexia (35), hyperglycemia (29), peripheral neuropathy (29), and others | completed | NCT00481078 | [49] | |
| vorinostat vs placebo (phase 2) | paclitaxel (phase 1), carboplatin (phase 2) | 1/2 | 12 (vorino-stat-arm 4) | 12 (vorino-stat-arm 4) | - | - | - | - | - | SAE 3/4: nausea (1), sepsis (1), platelet count decreased (1), hypotension (1), dehydratation (1), neutrophil count decreased (1), platelet count decreased (1), WBC decreased (1) AE 4/4: anemia (2), blurred vision (1), diarrhea (2), and others | terminated | NCT01413750 | [64] |
| vorinostat vs placebo | carboplatin + paclitaxel | 2/3 | 126 (vorino-stat-arm), completed 43 | 126 (vorino-stat-arm) | - | - | - | - | - | SAE 63 (vorinostat-arm) vs 45, AE 114 vs 117 | - | NCT00473889 | [65] |
| romidepsin | flavopiridol | 1 | aimed 23 | - | - | - | - | - | - | not yet published | terminated | NCT00094978 | [66] |
| vorinostat | bortezomib | 1 | 21 | neo-adjuvant (21) | 6 patients > 60% necrosis | - | - | - | - | most common toxicities included: grade 1 fatigue (14/20, 70%), grade I nausea (8/20, 40%), grade 1 neuropathy (4/20, 20%), and grade 1 diarrhea (4/20, 20%). DLT (2) | completed | NCT00731952 | [52] |
| vorinostat | bortezomib | 2 | 18 | 18 | - | - | 1.5 | 5 | 4.7 | grade 3 toxicities: thrombocytopenia (7), lymphopenia (3), fatigue (4), hyponatremia (3), dizziness (2), vomiting (2), syncope (2), neuropathy (2), grade 4 toxicities: thrombocytopenia (1), fatigue (1) | completed | NCT00798720 | [67] |
|
| |||||||||||||
| DNMTi | Targeted therapy | ||||||||||||
|
| |||||||||||||
| azacitidine | erlotinib | 1 | 30 | 2 | * | 1 | >4 in NSCLC, n/a for SCLC | 2 | - | not separately documented for LC, conjunctivitis, infusion reaction (2/5) | completed | NCT00996515 | [68] |
| azacitidine | erlotinib + mTOR inhibitor CC-223 | 1b | - | - | - | - | - | - | - | not yet published | completed, Celgene | NCT01545947 | [69] |
|
| |||||||||||||
| HDACi | Targeted therapy | ||||||||||||
|
| |||||||||||||
| belinostat | erlotinib | 1/2 | - | 5 (preliminary) | - | - | - | - | grade 3 diarrhea (3), grade 2 diarrhea(1), grade 2 rash (1), grade 1 diarrhea (1), grade 1 nausea (1), | terminated after 5 patients due to severe toxicities | NCT01188707 | [70] | |
| entinostat | erlotinib | 2 | 132 | 132 | prolonged OS with high expression of E-cadherin | - | - | - | 9.4 (patients with high levels of e-cadherin) vs5.9 | Fatigue (32), rash (35), diarrhea (30), dermatitis acneiformis (12), dyspnea (11), anemia (7), asthenia (7), hypokalemia (7), abdominal pain (7), hypoxia (4), pleural effusion (4), pneumonia (3), hypophosphatemia (3), syncope (1), | completed | NCT00750698 | [71] |
| panobinostat | erlotinib | 1 | 42 | 35 | - | 3 | 2.5 | 14 | 7.4 | most common AEs were fatigue and nausea (grades 1–3) and rash and anorexia (grades 1–2), not specified for LC | completed | NCT00738751 | [72] |
| panobinostat | sorafenib | 1 | - | - | - | - | - | - | - | not yet published | completed | NCT01005797 | [73] |
| romidepsin (phase 2) | erlotinib (phase 1) | 1/2 | 17 | 17 | - | 3.3, prolonged PFS >6 | 7 | - | nausea, vomiting, and fatigue (each 82%), diarrhea (65%), anorexia (53%), and rash (41%) | completed | NCT01302808 | [74] | |
| vorinostat | erlotinib | 1/2 | 33 EGFR mutant NSCLC | 33 | - | - | - | 7 | no significant difference | anemia (20), diarrhea (19), rash (12), fatigue (16), nausea (11), anorexia (12), vomiting (9), xerosis cutis (8), xerostomia (6), conjuncitivis (5), epigastralgia (4), leukopenia (3), neutropenia (3), mucositis (4), pneumonitis (1). | completed | NCT00503971 | [75] |
| vorinostat (phase 1) | erlotinib (phase 2) | 1/2 | 16 (1 completed)/ 9 discontinued due to PD | 16 | - | - | - | - | - | only 1 patient completed the study | terminated | NCT00251589 | [76] |
| vorinostat | gefitinib | 1 | EGFR mutant NSCLC | aimed 18 | - | - | - | - | - | not yet published | recruiting | NCT02151721 | [77] |
| vorinostat | gefitinib | 1/2 | 52/43 | 52/43 | see next columns | 16 | 3.2 | 6 | 19 | toxicities (grade 1–3) in phase I (15) in phase 2 (43) | completed | NCT01027676 | [78] |
| vorinostat | sorafenib | 1 | 35 | 15 | 1 | 2.2 | 5 | - | fatigue (8/15), rash (8/15), nausea (8/15), anorexia (7/15), diarrhea (6/15), hand-foot syndrome (5/15), others | completed | NCT00635791 | [79] | |
|
| |||||||||||||
| DNMTi | Other therapy | ||||||||||||
|
| |||||||||||||
| decitabine | genistein | 1/2 | 20 | - | - | - | - | - | - | not yet published | completed | NCT01628471 | [80] |
| decitabine | romidepsin + celecoxib | 1 | 34 | - | - | - | - | - | - | not yet published | completed | NCT00037817 | [81] |
| b Epigenetic therapies combined with immune therapies in NSCLC patients | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||||||
| Epigene tic agents |
Pha se |
Patients # |
Patient s # with NSCL C |
Respo nse rate |
PR | SD | Side Effects |
Estimat ed completi on |
Study Status |
NCT Number |
Refere nce |
||
| DNMTi | Immunotherapy | ||||||||||||
|
| |||||||||||||
| azacitidine | pembrolizumab | 2 | 12 (in 2016), aimed 90 | 12 | - | - | - | not yet published | - | recruiting | NCT02546986 | [124] | |
|
| |||||||||||||
| HDACi | Immunotherapy | ||||||||||||
|
| |||||||||||||
| ACY 241 | nivolumab + ipilimumab | 1b | not yet completed, aimed 41 | aimed 41 | - | - | - | not yet completed | 2017 | recruiting | NCT02635061 | [125] | |
| entinostat | pembrolizumab | 1b/2 | NSCLC and melanoma, 22 | not yet completed 22 | - | 1 (PD-1 naive) | 3 (PD-1 naive), 2 (prior PD-1 treatment) | not yet completed, first 22 patients 5 study related AE; 2017: treatment-related AEs occurred in 5 patients (most common: nausea and fatigue (2); grade 3/4 fatigue and rash (1). | 2019 | recruiting | NCT02437136 | [122] | |
| entinostat | pembrolizumab | 1 | NSCLC | aimed 30, not yet completed | - | - | - | not yet published | 2018 | recruiting | NCT02909452 | [126] | |
| entinostat | nivolumab + ipilimumab | solid tumors mainly BC | not yet completed | - | - | - | not yet completed | 2018 | recruiting | NCT02453620 | [127] | ||
| vorinostat | pembrolizumab | 1/2 | aimed 100, not completed | aimed 100, not completed | - | - | - | not yet completed | 2017 | recruiting | NCT02638090 | [128] | |
|
| |||||||||||||
| DNMTi | HDACi | Immunotherapy | |||||||||||
|
| |||||||||||||
| azacitidine | entinostat | nivolumab | 1 | not completed | - | - | - | - | not yet published | Aug-18 | recruiting | NCT01928576 | [129] |
|
| |||||||||||||
| DNMTi | others | Immunotherapy | |||||||||||
|
| |||||||||||||
| azacitidine | epacadostat | pembrolizumab | 1/2 | solid tumors and NSCLC | not completed | - | - | - | not yet published | 2021 | recruiting | NCT02959437 | [130] |
| decitabine | tetra-hydrouridine | nivolumab | 2 | not completed | NSCLC | - | - | - | not yet published | 2019 | not yet recruiting | NCT02664181 | [131] |
| azacitidine | paclitaxel | 1 (1+3, 3 mono, or 3+ durvalumab) | 2 | - | advanced NSCLC | - | - | - | not yet published | 2018 | recruiting | NCT02250326 | [132] |
Abbreviations: AE: adverse event; CR: complete response; DLT: dose limiting toxicities; DNMTi: DNA methyltransferase inhibitor; HDACi: histone deacetylase inhibitor; LC: lung cancer; n/a: not available; NCT Number: ClinicalTrials.gov identifier; NSCLC: non-small cell lung cancer; OS: overall survival; PD: progressive disease; PR: partial response; PFS: Progression free survival; SAE: serious adverse event; SCLC: small-cell lung cancer; SD: stable disease; WBC: white blood cells. (−): data not available.
*
not separately documented for lung cancer.
Abbreviations: AE: adverse event; BC: breast cancer; CR: complete response; CRS: cytokine release syndrome; EC: esophageal cancer; HL: Hodgkin's lymphoma; LC: lung cancer; NCT Number: ClinicalTrials.gov identifier; NHL: Non-Hodgkin's lymphoma; NSCLC: non-small cell lung cancer; PD: progressive disease; PR: partial response; SD: stable disease. (−): data not available.