Table 3.
Histone modification-based completed and ongoing clinical trials for NSCLC
| Drugs | Trial phase | Patients | Outcomes | Reference |
|---|---|---|---|---|
| Completed clinical trials | ||||
| Single therapy | ||||
| Pivanex | II | 47 previously treated advanced NSCLC patients | ORR 6.4%, SD 30%, mPFS 1.5 mo, mOS 6.2 mo | [110] |
| Romidepsin | II | 19 previously treated advanced NSCLC patients | No objective responses | [108] |
| Vorinostat | II | 16 previously treated advanced NSCLC patients | No objective responses. mTTP 2.3 mo, mOS 7.1 mo | [109] |
| Entinostat | I | previously treated advanced solid tumors (n = 31; 4 NSCLC patients) | No PR or CR. One NSCLC patient had stable disease | [111] |
| Cl-994 | I | 53 previously treated solid tumors |
PR = 1 heavily pre-treated NSCLC patient SD = 3 (1 NSCLC patient) |
[112] |
| Combination with chemotherapy | ||||
| Vorinostat 400 mg/day orally or placebo + Chemotherapy (Carboplatin + Paclitaxel) | Randomized phase II | 94 previously untreated advanced NSCLC | ORR: 34% with vorinostat vs. 12.5% with placebo (p = 0.02), mPFS: 6 months vs. 4.1 months (p = 0.48), mOS: 13 months vs. 9.7 months (p = 0.17) | [113] |
| Belinostat (starting at 1000 mg/m2 dose) + Chemotherapy (Carboplatin + Paclitaxel) | I | 23 previously untreated advanced NSCLC | MTD 1400 mg/m2, ORR: 35%, mPFS: 5.7 mo | |
| Panobinostat orally 3 times a week + (Carboplatin + Etoposide) | I | 6 previously treated advanced NSCLC | No objective responses | [114] |
| Vorinostat + Carboplatin /Paclitaxel | I | 28 advanced solid tumor patients |
PR = 11 (10 NSCLC), SD = 7 Linear Pharmacokinetics |
[115] |
| Cl-994 + Gemcitabine | II | 26 NSCLC/174 patients | PR = 8, OR = 12%, MS = 194 days | [116] |
| Cl-994 + Carboplatin + Paclitaxel | I | 30 patients with advanced solid tumors | PR = 5 (3 NSCLC) | [117] |
| Decitabine + valproic acid | I | 8 patients with advanced NSCLC with prior chemotherapy | SD = 1 | [118] |
| Decitabine + vorinostat | I | 2 patients with NSCLC/44 with advanced tumors | SD = 29% | [119] |
| Azacitidine + sodium phenylbutyrate | I | 1 NSCLC/27 refractory solid tumors | SD = 1, PD = 26 | [120] |
| Hydralazine + magnesium valproate | II | 1 NSCLC/17 refractory solid tumors | PR = 4, SD = 8 | [121] |
| Combination with EGFR TKIs | ||||
| Panobinostat + Erlotinib | I | 15 Previously treated NSCLC patients | Of 12 evaluable patients, 7 had SD and 5 had PD | |
| Vorinostat + Gefitinib | I | 12 BIM deletion polymorphism/EGFR mutation double-positive NSCLC | mPFS: 5.2 mo, 6 weeks DCR: 83.3% | [122] |
| Erlotinib + Entinostat or Erlotinib + Placebo | Randomized phase II | 132 previously treated patients with stage IIIB/IV NSCLC, no prior EGFR-TKIs | ORR: 3% with EE vs. 9.2% with EP (p = 0.13), mPFS: 1.97 months with EE vs. 1.88 with EP (p = 0.98), mOS: 8.9 months with EE vs. 6.7 months with EP (p = 0.39) | [123] |
| Vorinostat + Sorafenib | I | 17 patients with advanced solid tumors | Unconfirmed PR = 2 (1 NSCLC patient) | [124] |
| Vorinostat + Erlotinib | I/II | 33 advanced NSCLC EGFR mutant patients | PFS = 8 weeks, OS = 10.3 months | [125] |
| Panobinostat + Erlotinib | I | 35 NSCLC/42 patients with advanced tumors | Disease control rate = 54%, NSCLC PR = 3, SD = 3, PFS = 4.7 months, OS = 41 months, (EGFR mutation) | [126] |
| Combination with hypomethylating agent | ||||
| Azacitidine + Entinostat | I/II | 45 advanced, refractory NSCLC | MS = 6.4 months, CR = 1, PR = 1 | [119] |
| Combination with radiation | ||||
| Vorinostat (200, 300, 400 mg/day) orally for 14 days + SRS for brain metastasis on day 3 | I | 17 NSCLC with up to 4 brain metastasis, ≤ 2 cm in size | No local failures with median follow-up of 12 months | [127] |
| Combination with ICI | ||||
| Vorinostat orally + Pembrolizumab | Phase I/Ib | ICI-naïve and ICI-pretreated advanced NSCLC patients in phase I, ICI-naïve patients only in phase Ib (n = 33) | ORR: 13%, SD: 53%, ICI-pretreated patients: ORR 12.5%, SD 42% | [128] |
| Ongoing clinical trials | ||||
| Vorinostat + Pembrolizumab | II | NCT02638090 | ||
| Entinostat + Pembrolizumab | II | NCT02638090 | ||
| Entinostat + Azacitidine + Nivolumab | II | NCT01928576 | ||
| Panobinostat + Anti PD-1 antibody PDR001 | I | NCT02890069 | ||
| Mocetinostat + Nivolumab | II | NCT02954991 | ||
| ACY-241 + Nivolumab | I | NCT02635061 | ||
| Abexinostat + Pembrolizumab | I | NCT03590054 | ||