Table 4.

Ongoing and published trials using epigenetic combination therapies in NSCLC. In this table, ongoing and finished trials using epigenetic combination therapies in NSCLC are displayed, including their phase, number of recruited patients, dose limiting toxicity, response rate respectively median survival, study population, and their status (ongoing or published).

Drugs	Phase	Patient number	Dose-Limiting Toxicities	Response rate, PFS, OS (months)	Study population	Reference
DNMTi combination therapy
Azacitidine + erlotinib	1	30	Conjunctivitis, infusion reaction in 2 of 5 cohorts	PR in 2, SD in 11 patients; Median PFS 2 months	Advanced solid tumors, among them 2 NSCLC patients, who had already received standard therapy	68
Oral azacitidine + pembrolizumab vs. placebo + pembrolizumab*	1	90	—	—	Patients with squamous or non-squamous stage IIIB or IV NSCLC pretreated with only 1 prior systemic platinum-based chemotherapy	95*
5-Fluoro-2-deoxycytidine + tetrahydrouridine*	2	Ca. 185	—	—	Advanced NSCLC, breast cancer, bladder cancer, or head or neck cancer that had progressed after standard treatment or for whom no effective therapy exists	78*
Decitabine + cisplatin	1/2	21/14	—	No objective response; OS 3,7 months	Phase 1: Patients with histopathologically confirmed diagnosis of malignancy and progressive disease; Phase 2: stage IIIB and IV NSCLC	69
Decitabine + genistein*	2	Ca. 48	—	—	Phase 1: Non-estrogen dependent advanced solid malignancy that has failed standard therapies and/or for which no curative therapeutic option exists, Phase 2a: NSCLC of stage IIIb or IV that has failed or is ineligible to standard therapies	77*
HDAC Combination therapy
Belinostat, carboplatin, paclitaxel* and bevacizumab*	1/2	7	—	—	Advanced NSCLC (stage IV), not previously treated with any chemotherapy regimen (prior adjuvant chemotherapy and/or chemotherapy/radiation for stage III allowed)	81*
Belinostat + Erlotinib*	1/2	5	—	—	Dose escalation phase: NSCLC patients suitable for treatment with Erlotinib; MTD expansion phase: patients with NSCLC rated suitable for treatment with Erlotinib and with measurable disease	82*
Entinostat + Pembrolizumab*	1b/2	158	—	—	Patients with recurrent/metastatic NSCLC tested for anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutations and, if positive, have been treated with prior EGFR or ALK therapy; at least 1 chemotherapeutic regimen; progressive disease; no prior treatment with a PD-1/PD-L1-blocking antibody	96*
Erlotinib +/− entinostat	2	132	—	Only patients with high E-cadherin levels at time of diagnosis benefit from combination	Stage III or stage IV NSCLC patents that had received one or 2 previous chemotherapy or chemoradiotherapy regimens for advanced NSCLC and their disease had progressed based on radiologic evidence	74
Paclitaxel + carboplatin +/− vorinostat*	2/3	253	—	—	NSCLC patients with no prior systemic treatment for lung cancer except patients at least 12 months from prior adjuvant therapy	80*
Panobinostat + erlotinib	1	33	2 grade 3 DLTs of nausea and grade 3 prolonged QTc	7 EGFR mutant patients: 3 PR, 3 SD, 1 progressed; PFS was 4.7 in EGFR-mutant vs. One.9 months in EGFR wild-type patients, OS est. 41 vs. Five.2 months	Patients with advanced/metastatic NSCLC or head and neck cancer, who had failed at least one line of systemic therapy	72
Vorinostat + bortezomib + Surgery	1	21	2 grade III DLTs of fatigue and hypophosphatemia	>60% histologic necrosis of tumor in 6 of 20 patients	NSCLC patient that had no clinical or pathologic evidence of N2, N3, or M1 disease	70
Vorinostat or placebo + Carboplatin + paclitaxel	2	94	—	PFS 6.0 vs. Four.1 months	Stage IIIB (with malignant pleural effusion) or IV NSCLC patients with no prior therapy for advanced-stage disease	75
Vorinostat + erlotinib	1/2		1 DLT of grade 3 diarrhea	No objective response; PFS 8 weeks, OS 10.3 months	NSCLC patients with advanced disease and EGFR mutations in exons 19 or 21, who had been treated with full doses of erlotinib for a minimum of 3 months	73
Vorinostat + gemcitabine + platinum*	1	61	—	—	Metastatic or locally advanced NSCLC patients that have not been previously treated with systemic chemotherapy or have received non-platinum and non- gemcitabine based neoadjuvant or adjuvant chemotherapy if the last dose was at least 6 months prior to study enrollment	79*
Vorinostat + sorafenib	1	35	—	1 PR, 8 SD; PFS 2.2 months	Locally advanced or metastatic solid tumors refractory to established forms of therapy or for which sorafenib alone would be considered as appropriate therapy, among them 15 NSCLC patients	71
DNMTi+HDACi combination therapy
Azacitidine (s.c.) + oral entinostat followed by chemotherapy*	2	Ca. 165	—	—	NSCLC patients that have received exactly one prior therapy; patients with epidermal growth factor receptor (EGFR) mutations in exon 19 or 21 and patients with detected anaplastic lymphoma kinase (ALK) translocation may have had 2 prior therapies if one was a tyrosine kinase inhibitor specific to their mutation	83*
Azacitidine (s.c.) + oral entinostat or oral azacitidine alone prior to nivolumab*	2	Ca. 120	—	—	Stage IIIB, IV or recurrent NSCLC patients with at least one platinum based chemotherapy, and not more than 3 prior therapies for stage IIIB/IV disease	93*
Decitabine + valproic acid	1	8	2 grade 3 DLTs of neurotoxicity	No objective response;	NSCLC patients	76
Azacitidine + entinostat	1/2	10/42	0	1 CR, 1 PR for 24 months	Metastatic NSCLC patients with disease progression after at least one prior anti-cancer regimen for metastatic disease; any number of prior therapies was allowed; patients with treated brain metastases were included	42
Azacitidine + entinostat*	1/2	162	—	—	Metastatic or unresectable NSCLC patients that have failed at least one previous chemotherapy regimen	84*
LSD1-inhibition (single treatment in SCLC)
GSK2879552*	1	100	—	—	SCLC patients with recurrent or refractory disease after receiving at least one prior standard/approved platinum-containing chemotherapy regimen, or where standard therapy is refused	86*

CR = Complete response, DLT = Dose limiting toxicity, OS = overall survival, PR = partial response, PFS = progression free survival, SD = stable disease, − = Information was not provided

^*= Ongoing