Epi-immunotherapy for cancers: rationales of epi-drugs in combination with immunotherapy and advances in clinical trials

3.1.1 Hodgkin's lymphoma

Currently, there are various FDA-approved ICIs, including antibodies against PD-1 (pembrolizumab and nivolumab), PD-L1 (atezolizumab), and CTLA4 (ipilimumab). In cHL, nivolumab or pembrolizumab alone elicits overall response rates (ORR) of 70%-85% [104-106]. However, the CR rate was only 25%-30%, suggesting that a great proportion of cHLs remain resistant to anti-PD-1 treatment [107, 108]. Nie et al. [44] performed a proof-of-concept study to investigate whether DAC could improve the efficacy of camrelizumab, a PD-1 antibody approved in China, in patients with R/R cHL. In this prospective, open-label, phase II trial (NCT02961101), among anti-PD-1-naïve patients, camrelizumab alone was compared with low-dose DAC (10 mg/day, days 1 to 5) plus camrelizumab. At a median follow-up of 14.9 months, CR rates were 32% and 71% in camrelizumab alone and DAC-camrelizumab combination groups, respectively [44]. When the median follow-up extended to 34.5 months, a greater improvement in CR rate was achieved in patients receiving DAC plus camrelizumab (79% vs. 32%). Progression-free survival (PFS) was longer for those receiving DAC plus camrelizumab compared with camrelizumab alone (35.0 vs. 15.5 months). The benefit of adding DAC to camrelizumab was observed especially in patients who had relatively high tumor burdens or received ≥3 prior lines of therapies. Interestingly, the increase in circulating peripheral central memory T cells was associated with improved clinical response and PFS, suggesting a potential biomarker for epi-immunotherapy in cHL [109]. Lately, Wang et al. [110] updated the clinical results of DAC combined with camrelizumab in cHL patients receiving prior anti-PD-1 (NCT02961101 and NCT03250962). Of 50 patients with progressed or relapsed cHL after anti-PD-1 treatment, the combined treatment resulted in an objective response rate of 52%, CR rate of 36% and longer PFS compared with prior anti-PD-1 monotherapy. The response appears durable once CR is achieved at 24 months. The exploratory studies showed that, when the tumor progresses, the ratio of peripheral CCR7⁺CD45RA^– central memory T cells (T_cm) over total CD8⁺ or CD4+ cells decrease from the baseline level; after treatment with DAC plus camrelizumab, the Tcm ratio increases and persists in patients who obtained partial response (PR) or better, but not in those with stable disease (SD) or progressive disease (PD) [110].

In preclinical studies using various tumor models, ICIs also had been demonstrated to have synergistic effects when combined with HDACis [111, 112]. In a phase II trial (NCT03179930), R/R cHL patients were given ENT, an oral class I-specific HDACi, plus pembrolizumab [113]. Of 13 evaluable patients, ORR was 92%, including 3 patients who progressed on prior anti-PD-1 therapy, suggesting that the combination of ICI and HDACi have promising clinical activity. The study also showed a reasonable safety profile. Chidamide, a novel, orally active benzamide class of selective inhibitors against HDAC 1, 2, 3 and 10, was evaluated in a clinical study in cHL patients who were resistant to or relapsed after DAC plus camrelizumab treatment [114]. Of 14 evaluable patients, 13 (93%) achieved objective response, including 6 CRs. The toxicities were acceptable without any immune-related AEs. Collectively, compared with ICI alone, the combination of DMNTi or HDACi with ICI resulted in higher CR rate in anti-PD-1-naïve patients with R/R cHL. Epigenetic agents appear to partially reverse the resistance to ICIs since a proportion of patients with prior anti-PD-1 exposure still respond well when an epi-drug is added to anti-PD-1.

3.1.2 B-cell lymphoma

Unlike cHL, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) generally do not respond well to PD-1 blocker, although EBV-positive status associates with reasonable efficacy of pembrolizumab [115, 116]. Primary mediastinal large B-cell lymphoma (PMBCL), a DLBCL subtype, is characterized by chromosome 9p24 aberrations and upregulated PD-L1 [117]. A phase Ib and phase II trials (KEYNOTE-013/KEYNOTE-170) have shown that pembrolizumab produced durable responses and acceptable toxicity in R/R PMBCL [118]. To improve the anti-lymphoma activity, several ongoing clinical studies are assessing the combination of PD-1 blockade with DAC or vorinostat in DLBCL, FL and HL (NCT03346642 and NCT03150329). A high frequency of somatic mutations in epigenetic modifier genes, including CREBBP and EZH2, are identified in B cell lymphoma [115]. The mutant EZH2 reprograms germinal center B cells to alter their interactions with follicular Th cells and follicular dendritic cells, promoting B cell transformation in FL [119, 120]. CREBBP mutant-associated program can be reversed by HDAC3 inhibitor, which induces transcription of BCL6 targets to restore immune surveillance [121]. HDAC3 inhibitor can also enable TILs to eradicate DLBCL cells in an MHC-dependent manner and has synergistic effects with PD-L1 antibody in vivo [121].

Recently, multiple new epi-drugs are being evaluated for cytotoxicity against B-cell lymphoma and their mechanisms of action in preclinical and clinical studies. Tazemetostat, an oral first-in-class EZH2 inhibitor, has single-agent activity against DLBCL and FL [122-124]. Interestingly, a phase Ib study (NCT02220842) was performed to assess the efficacy of tazemetostat in combination with atezolizumab on R/R DLBCL [125]. A total of 43 patients were enrolled. However, at the data cut-off, 19 (44%) had discontinued study treatment because of death (n = 17) and withdrawal (n = 2). Best ORR was 16%, including 2 (5%) CRs and 5 (12%) PRs. Among the 5 patients with EZH2 mutations, 3 achieved a response.

3.1.3 T-cell lymphoma

PD-1 is considered a potential therapeutic target of T-cell lymphoma (TCL) because PD-1 is frequently overexpressed in angioimmunoblastic T-cell lymphoma (AITL), natural killer-/T-cell lymphoma (NKTCL), and peripheral T-cell lymphoma (PTCL) [126]. It has been shown that nivolumab results in an ORR of 40% in R/R TCL, and pembrolizumab leads to an ORR of 100% in EBV-associated NK cell lymphoma and TCL [127, 128]. Additionally, several HDACis, including belinostat, romidepsin and chidamide, have been indicated for certain TCL subtypes, but the efficacy of single agents rarely exceeded 30% [129]. It was also well known that azacitidine is effective in follicular Th cell-derived PTCL by targeting recurrent ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A) and isocitrate dehydrogenase 2 (IDH2) mutations [130]. Thus, the incorporation of epi-drugs into PD-1 checkpoint inhibition is worth further clinical assessment in TCL.

Recently, a phase I/II trial of pembrolizumab combined with romidepsin and pralatrexate for R/R AITL and PTCL with follicular Th cells was conducted (NCT03278782) [131]. Among 14 patients who received pembrolizumab in combination with romidepsin, the ORR was 50%, including 5 CRs and 2 PRs, which was durable with 18-month follow-up and with acceptable safety. High level of PD-L1 is predictive of good response [131]. Pembrolizumab is also being tested along with DAC and pralatrexate in a phase I clinical trial (NCT03240211) [132]. In this study, 13 patients with R/R PTCL and cutaneous T-cell lymphoma (CTCL) were enrolled, and the patients who received triplet combination treatment achieved objective responses with a duration of response (DOR) of 18 months. The preliminary data from another phase I/IIa trial (NCT03161223) showed that the epi-immunotherapy was tolerable in PTCL patients, and 3/5 evaluable patients achieved CR when treated with durvalumab, oral azacitidine, and romidepsin [132].

Extranodal NK/T cell lymphoma (ENKTL) is an aggressive Epstein-Barr virus-related lymphoma with a high incidence in Asia [115]. Abnormal PD-1/PD-L1 expression was demonstrated in both neoplastic and immune cells in the TME, which offers opportunities for applying ICIs in this lymphoma subtype [115, 133]. On the other hand, the tumor suppressor epigenetic regulators, lysine methyltransferase 2D (KMT2D) and BCL6 corepressor (BCOR), were frequently mutated in ENKTL [134]. Kwong et al. [135] first demonstrated the effectiveness of pembrolizumab in a small series of patients with R/R ENKTL. In a phase II ORIENT-4 study, sintilimab, another anti-PD-1 antibody, also showed efficacy, and ORR and disease control rate (DCR) were 67.9% (19/28) and 85.7% (24/28), respectively [136]. Recently, a single-arm, open-label, multicenter clinical trial (NCT03820596) was designed to evaluate the safety and efficacy of sintilimab combined with chidamide for R/R ENKTL, showing an impressive response in 36 evaluable patients [137]. In this study, the combination therapy yielded an ORR of 58.3% with CR in 16 (44.4%) patients. Notably, tumor PD-L1 expression could predict clinical response [137]. Furthermore, a single-arm phase II trial is conducted to test the combination of sintilimab, chidamide and azacitidine in patients with R/R PTCLs, and the results are pending [138].

3.1.4 Acute myeloid leukemia and myelodysplastic syndrome

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are highly heterogenous myeloid malignancies with complex molecular genetic abnormalities, and the prognosis remains poor for elderly or refractory patients. Yang et al. [139] first reported that PD-1, PD-L1/L2 and CTLA4 are overexpressed in 8%-34% of bone marrow CD34⁺ cells from patients with MDS and AML. Currently, there is great clinical interest in immunotherapies for AML, with over 30 clinical studies evaluating ICIs for AML and MDS, which included PD-1, CTLA4, and T cell immunoglobulin mucin-3 (TIM3) blockade [140-142]. However, ICIs, especially anti-PD-1 antibodies, have limited activity in these diseases [143, 144]. Given their potential for induction of checkpoint molecules, HMAs have been combined with PD-1/PD-L1 inhibitors in several studies. In an open-label, phase II study, 70 patients with R/R AML were treated with nivolumab and AZA [145]. The ORR was 33%, including 15 (22%) CR or CR with insufficient recovery of counts (CRi), 1 PR, and 7 hematological improvement (HI). Importantly, the ORR of 58% in HMA-naive R/R AML patients compared favorably with the historical controls treated with AZA alone [145]. Combinations of HMAs with another anti-PD-1 antibody, pembrolizumab, produced similar benefits to those observed with AZA and nivolumab in R/R AML patients [146]. Pembrolizumab-AZA combination therapy also had been investigated in a clinical trial for newly diagnosed AML (NCT02845297), in which 22 unfit, elderly patients were enrolled [147]. Seventeen patients were evaluable with CR/Cri 47% (8/17) and PR 12% (2/17). This front-line treatment resulted in a median OS of 13.1 months [147]. For high-risk MDS (HR-MDS), a phase II trial (NCT03094637) evaluated AZA plus pembrolizumab in patients with HR-MDS after failure of HMA therapy. The combination treatment of pembrolizumab and AZA was well tolerated in 17 therapy-naive patients and showed an ORR of 80%, including 3 CR, 7 marrow CRs and 1 HI [148]. This clinical study showed that the combination therapy might have anticancer activity in certain HMA-failure patients, but no significant improvement in OS was demonstrated. Interestingly, a recent study of triple combination showed encouraging CR/CRi and OS [149]. In this study, 31 R/R AML patients were given nivolumab, AZA and ipilimumab, and the ORR was 60%, including 9 (36%) CR/CRi, 2 (8%) HI lasting over 6 months, and 4 (16%) SD.

The efficacy of PD-1 or PD-L1 blockade appears to vary between AML and MDS [150]. In a single-arm phase I study, avelumab in combination with DAC was evaluated in newly-diagnosed AML patients ineligible for intensive therapy [151]. Only 1 of 5 patient (20%) achieved CR, 3 had SD, and 1 experienced PD. In the first large randomized trial (NCT02845297), 129 AML patients of 65 years or older were randomized to receive AZA plus durvalumab or AZA alone [152]. No significant difference was found in the ORR (31.3% vs. 35.4%) or CR rate (17.2% vs. 21.5%) between 2 arms, and the median OS was 13.0 and 14.4 months, respectively. Similar results were reported in the patients with HR-MDS [152]. In a phase Ib study, the efficacy of atezolizumab, with or without AZA, was evaluated in HMA-failure and HMA-naive MDS patients (NCT02508870) [153]. Despite little effects in HMA-failure MDS patients, atezolizumab, with or without AZA, indeed produces an ORR of 62% (CR, 14%; mCR, 19%; mCR + HI, 10%; HI, 19%) in HMA-naïve patients with median OS not reached.

However, clinical studies in AML and MDS have raised safety concerns about epi-immunotherapy. For example, in HMA-naïve patients receiving AZA and atezolizumab, frequent febrile neutropenia (29%) accounted for 3-month mortality of 29%, which caused early termination of the study (NCT02508870) [146]. In addition, SWOG 1612, a randomized phase III trial in AML and HR-MDS, also showed excessive early deaths in the AZA/nivolumab arm compared with the control arm [154]. Based on our previous studies in cHL [44, 109, 110], we suggest that low-dose HMA should be tested in combination with PD-1 or PD-L1 inhibitors in AML and MDS patients.

Lirilumab is a fully-humanized IgG4 monoclonal antibody that is designed to block the killer cell immunoglobulin-like receptor (KIR)/HLA-C interaction, thereby enhancing NK cell-mediated cytotoxicity against AML in KIR-mismatched haploidentical stem cell transplantation (SCT) [155, 156]. Previously, lirilumab in combination with AZA was evaluated in relapsed AML in a phase Ib/II study (NCT02399917) [157]. Twenty-five patients were included and achieved an ORR of 20%, including a CR/CRi of 8% (2/25) and HI 12% (3/25). The median DOR and overall OS were 2.0 months and 4.0 months, respectively. In another pilot trial (NCT02599649), 8 HR-MDS patients received a median of 4 cycles of treatment with AZA plus lirilumab [158]. Overall, 2 patients achieved CR, 4 had marrow CR, and 2 had SD.

Despite significant advances, epi-immunotherapy has shown variable efficacies. Many patients do not experience a CR, and some are non-responders, highlighting the need to improve our understanding of the clinical features and molecular events associated with response. In AML and HR-MDS, a good response is associated with HMA-naïve status, low leukemia burden, ASXL1 mutation, and high number of pre-treatment CD3⁺ and CD8⁺ cells evaluated by mass cytometry (CyTOF) and immunohistochemistry (IHC) [145]. Herbrich et al. [159] analyzed the baseline immune landscape using single-cell CyTOF profiling of serial samples collected from R/R AML patients receiving AZA and avelumab (NCT02953561). The CD4/CD8 ratio and residual T cell profiles were found to predict the response following HMA/PD-L1 inhibition. Importantly, immune landscape studies revealed that AML cells also express other immune checkpoints, in particular, PD-L2, TNF receptor superfamily member 4 (TNFRSF4) and TIM3 could be potential targets for novel epi-immunotherapy [159]. In a recent phase II trial (NCT03066648), sabatolimab (MBG453), an anti-TIM3 antibody, plus DAC or AZA led to an ORR of 58%-70% for HR-MDS, 27%-41% for newly-diagnosed AML, and 24% for R/R AML [160, 161]. The study also showed that combining HMAs with TIM3 inhibition was safe with a relatively durable response in MDS and AML [160, 161]. Based on these data, the STIMULUS MDS-US trial will further assess the feasibility and clinical efficacy of sabatolimab in combination with an oral HMA in patients with advanced MDS [162].

3.2.1 Breast cancer

A phase II clinical trial was designed to combine CC-486, an oral HMA, and durvalumab to treat selected immunologically cold tumors, including breast cancer (BC), resulting in marginal clinical response [163]. When combined with anti-PD-1, anti-CTLA4, or both, ENT can significantly prolong tumor-free survival in a HER2/neu transgenic BC model [164]. In ENCORE 602 trial (NCT02708680) [165], 81 patients with refractory triple-negative breast cancer (TNBC) were randomized to receive atezolizumab plus ENT or atezolizumab alone. Unfortunately, no significant differences in ORR, PFS and median OS were observed between the two arms, while more AEs were seen in the combination arm. Similarly, Terranova-Barberio et al. [166] presented the data from a randomized phase II trial (NCT02395627) using triple combination of vorinostat, pembrolizumab, and tamoxifen. In 34 heavily pretreated patients with estrogen receptor (ER)-positive BC, this combination treatment showed limited efficacy. However, comprehensive correlative analysis revealed that an exhausted CD8⁺ T-cell (PD-1⁺/CTLA4⁺) immune signature and an HDACi-dependent decrease in Tregs (CD4⁺ Foxp3⁺/CTLA4⁺) might predict response to epi-immunotherapy. Recently, another HDACi, romidepsin, was combined with cisplatin and nivolumab in a phase I/II study (NCT02393794) [167], in which 51 patients with metastatic TNBC were enrolled. Among 34 evaluable patients, the ORR was 44%, median PFS was 4.4 months, and 1-year PFS rate was 23%; the median OS was 10.3 months, and 1-year OS rate was 43%. The triple combination had safe profiles and impressive efficacy in refractory metastatic TNBC, including PD-L1-negative diseases and those with liver metastasis [167].

3.2.2 Non-small cell lung cancer

Juergens et al. [168] from Johns Hopkins University first reported durable clinical responses to immune checkpoint therapy in advanced NSCLC patients who received prior epi-drug therapy, and later they suggested that AZA-induced PD-L1 upregulation may account for the beneficial effect observed in the combination of epi-drugs and anti-PD-1 [169]. Recently, a Bayesian network meta-analysis revealed that PD-1/PD-L1 inhibitors were more efficacious than control treatment in patients with solid tumors, including non-small cell lung cancer (NSCLC) [170]. However, it is unclear whether the combined use of PD-1/PD-L1 inhibitor and HMA would benefit NSCLC patients [171]. In a phase II trial (NCT02546986), 100 patients with a previous line of platinum-based therapy were assigned to receive pembrolizumab combined with either oral AZA or placebo, and PFS was not improved (median, 2.9 and 4.0 months) [172]. We recently reported an unexpectedly good outcome for 3 advanced NSCLC patients carrying unfavorable ICI biomarkers, such as low tumor mutation load, low microsatellite instability and HLA loss of heterozygosity [173]. Surprisingly, all 3 patients responded well to low-dose DAC in combination with camrelizumab, with mild AEs, suggesting that low-dose DAC sensitized PD-1/PD-L1 inhibitors in NSCLC. High expression of the enzyme cytidine deaminase (CDA) that catabolizes DAC within minutes was reported in NSCLC [174]. The combination of HMA with tetrahydrouridine (THU), a CDA inhibitor, was found to cause > 2-fold DNMT1 depletion and > 5-fold increase in TILs, as well as destruction of NSCLC in vivo. Based on these data, the PRECISE trial (NCT02664181) has been conducted to compare the efficacy of nivolumab alone or in combination with THU and DAC in patients with R/R NSCLC [175]. To investigate the effect of guadecitabine, a second-generation DNA methylation inhibitor, on solid cancers, a phase II dose-escalation trial (NCT02998567) was initiated [176]. Overall, 34 patients were enrolled, of whom 10 of 15 patients with NSCLC (13 patients were resistant/refractory to PD-1/PD-L1 targeting agents) were evaluable, with a DCR of 80% and 5 patients having DCR > 6 months.

Recent clinical trials suggest that the combination of anti-PD-1/PD-L1 and HDACi is a promising option for treating NSCLC patients. A phase Ib study (NCT02635061) assessed the clinical efficacy of ACY-241, a selective HDAC6 inhibitor, plus nivolumab on metastatic NSCLC [177]. Eighteen patients received the treatment. Eight of 13 evaluable patients showed clinical benefit, including 1 CR, 4 PRs and 3 SDs. Immune cell profiling revealed a trend of increased infiltrating cytotoxic T and NK cells following the combined treatment [177]. Two clinical trials (NCT01928576 and NCT02437136) are evaluating the combination of pembrolizumab with HDACis such as vorinostat and ENT on anti-PD-1/PD-L1-naïve or refractory NSCLCs [178]. In a phase I/Ib trial, 33 patients were given pembrolizumab plus vorinostat [179]. Among 30 evaluable patients, 20 had SD or PR. In the subsequent open-label, phase II randomized trial (NCT02638090), patients with metastatic NSCLC were randomized to receive pembrolizumab alone (arm A) or pembrolizumab plus vorinostat (arm B) [180]. Among 47 of 49 patients evaluable for response, the ORR of patients with low pre-treatment TIL count (score = 1) in arm B (66.7%) was obviously higher than that in arm A (33.3%), suggesting that the combination strategy may favor NSCLC patients with a low-TIL count.

3.2.3 Metastatic melanoma

ICIs, including nivolumab, pembrolizumab and ipilimumab, have significantly improved the clinical outcomes of metastatic melanoma and are now in routine use [181-183]. However, more than half of patients experience either primary or acquired resistance [184]. To date, some preclinical studies have shown the therapeutic value of CTLA4 inhibitor combined with HMA [185]. In a phase Ib NIBIT-M4 study (NCT02608437), guadecitabine combined with ipilimumab resulted in immune-related DCR of 42% and ORR of 26% [186]. The interim results of a phase II study (NCT02816021) reported that, in anti-PD-1-naive patients with metastatic melanoma, oral AZA plus pembrolizumab led to a PR 55%, while the anti-PD-1 pretreated patients did not show any response [187].

Epi-immunotherapies using HDACi also have been investigated in metastatic melanoma patients. The ENCORE-601 (NCT02437136), an open-label study, enrolled melanoma patients in which 70% had prior pembrolizumab treatment [188, 189]. With ENT plus pembrolizumab, 10 of 53 patients achieved CR or PR (ORR = 19%). Efficacy results in patients receiving prior PD-1 therapy were consistent with the overall population. Preliminary biomarker analysis suggests that the addition of ENT restores inflammation in the TME necessary for successful re-treatment with anti-PD-1/PD-L1 [188, 189]. An early clinical study (NCT02032810) determined the safety and efficacy of panobinostat, a pan inhibitor of class I, II, and IV HDAC, combined with ipilimumab in advanced melanoma [190]. However, the results with this combination treatment were disappointing. Mocetinostat, an investigational class I and IV HDACi, has demonstrated anticancer activity in patients with hematological malignancies and solid tumor [191]. Preclinical studies showed that mocetinostat promotes the accumulation of central memory CD8 and CD4 T cells and inhibits Treg cell and MDSC functions [192]. In the phase Ib trial (NCT03565406), the efficacy of mocetinostat in combination with ipilimumab was evaluated in 10 patients with unresectable melanoma [193]. At a median follow-up of 16 months, the ORR was 70%, including 2 CRs and 5 PRs; 7 patients developed grade 3-4 immune-related AEs.

3.2.4 Renal and bladder carcinoma

Preclinical and clinical studies have provided a rationale for PD-1, PD-L1 or CTLA4 blockade for the treatment of renal cell carcinoma [194]. Recently, several studies had evaluated the safety and efficacy of epi-immunotherapies using HMA, HDACi, and EZH2 inhibitors. In a phase Ib/II study (NCT03308396), 42 patients with advanced renal cancer were treated with durvalumab and guadecitabine [195]. At a median follow-up of 20.1 months, 66% of patients achieved clinical benefit defined as either PR of SD that lasted ≥6 months. Mechanistically, decreased Tregs and MDSCs might be associated with favorable outcomes, and increased Th17 subpopulations of T cells were associated with immune-related AEs [195]. The results from another phase Ib study showed that vorinostat and pembrolizumab combination was tolerable and active in a subset of ICI-resistant urothelial and renal carcinoma patients [196]. A phase I/II study with pembrolizumab in combination with tazemetostat is ongoing (NCT03854474).

3.2.5 Epithelial ovarian cancer and cervical cancer

To date, most ICI-containing clinical trials for advanced recurrent ovarian cancer (OC) have focused on anti-PD-1/PD-L1 therapy, but the results were disappointing [197]. The combination of ICI with HMA is being explored. In a phase II trial (NCT02901899), guadecitabine plus pembrolizumab brought clinical benefit in 27% of patients with R/R OC. Epic arrays were used to measure global tumor methylation, and showed 0.05% CpG sites being differentially methylated after the treatment [198]. The combination of oral AZA and durvalumab produced a median PFS of 1.9 months and a median OS of 5 months in 28 anti-PD-1-naive patients with platinum-resistant OC in the open-label, phase II multicohort study (NCT02811497) [163]. The biomarker studies did not detect any significant tumor DNA hypomethylation. A phase II randomized study (NCT02915523) recruited 126 advanced OC patients who received avelumab plus either ENT or placebo but found no significant difference in ORR (6% vs. 5%) or OS (NE vs. 11.3 months) [199]. Toripalimab, a humanized PD-1 antibody, in combination with chidamide is being explored in a phase Ib/II, single-arm, multi-center study (NCT04651127), in patients with R/R metastatic cervical cancer.

3.2.6 Colorectal cancer

A recent real-world analysis showed that the earlier use of ICIs resulted in better tumor response in a subset of CRC patients [200]. Since either DMNTi or HDACi combined with ICIs markedly improved treatment outcomes in CRC-bearing mice and DAC-based TME reprogramming could enhance the effect of the PD-1 blockade on CRC with microsatellite stability (MSS) [40], epi-immunotherapies also have been evaluated in a few clinical settings for CRC. Unfortunately, PD-1 blockade (pembrolizumab) combined with AZA appears to have modest activity against metastatic CRC with MSS [201].

3.2.7 Head and neck squamous cell carcinoma

In a phase II trial (NCT02538510), the combination of pembrolizumab and vorinostat was evaluated for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and salivary gland cancer (SGC) [202]. Among 25 patients with HNSCC, 8 (32%) achieved PR, and 5 (20%) had SD; the median OS was 12.6 months, and the median PFS was 4.5 months. Four (16%) of 25 patients with SGC had PR and 14 (56%) had SD; the median OS was 14 months and median PFS was 6.9 months [202]. In addition, a phase Ib study (NCT03019003) is investigating the safety and efficacy of oral DAC (ASTX727) combined with durvalumab in recurrent or metastatic HNSCC patients who were resistant to ICI monotherapy.