Entinostat

Entinostat (SNDX-275) for the treatment of non-small cell lung cancer
1.Introduction

2.Overview of HDAC inhibition in treatment of malignancies/
lung cancer
3.Entinostat
4.Pre-clinical studies in lung cancer
5.Clinical efficacy
6.Safety and tolerability
7.Conclusion
8.Expert opinion
Rossana Ruiz†, Luis E Raez & Christian Rolfo
†Medical Oncologist, Instituto Nacional de Enfermedades Neopla´sicas (INEN), Lima, Perti

Introduction: Epigenetic aberrations play an important role in lung carcino- genesis. Chromatin deacetylation is a fundamental mechanism of gene silencing. Histone deacetylase (HDAC) inhibitors are an emerging class of antineoplastic agents that enable the accessibility of DNA to transcription fac- tors, therefore promoting gene expression. Entinostat is a selective HDAC inhibitor that has shown anti-neoplastic activity and tolerability in hemato- logic and solid tumors, including lung cancer.
Areas covered: This article summarizes the pharmacokinetics, pharmacody- namics, mechanisms of action, safety, tolerability, pre-clinical studies and clinical trials of the HDAC inhibitor entinostat, as a novel promissory agent for the treatment of NSCLC.
Expert opinion: The field of targeted therapy has increased in lung cancer. However, even now with the current FDA-approved agents, < 15% of patients benefit from these interventions and we are still far from curing lung cancer. New targets are needed. Either in combination with cytotoxic drugs, epige- netic therapy or other molecular targeted drugs, entinostat represents a new potential agent for the treatment of non-small cell carcinomas. However, the preliminary safety and efficacy results from several clinical trials still need to be validated in large Phase III trials. Keywords: entinostat, epigenetics, histone deacetylase, non-small cell lung cancer Expert Opin. Investig. Drugs [Early Online] 1.Introduction Lung cancer remains the leading cause of cancer-related mortality in men and women in the USA [1] and worldwide, accounting for more than a million deaths annually [2]. NSCLC is by far the most common type, accounting for ~ 85% of all lung cancer cases [2]. More than 60% of these patients are diagnosed with advanced and incurable disease [3], only amenable to palliation. In these cases, cytotoxic chemotherapy remains the mainstay of treatment, achieving an overall sur- vival (OS) of < 12 months [4]. In-depth study of cancer biology and molecular path- ways involved in oncogenesis has allowed further progress [5]. Molecular targeted therapy has importantly improved progression-free survival (PFS) in patients with specific genetic mutations [6-9]. Regardless of these advances, the prognosis of lung cancer remains dismal and new avenues are clearly warranted to improve current outcomes. Epigenetics is the study of heritable alterations in gene expression produced by mechanisms other than direct changes in the DNA sequence, in other words, on how chromatin structure modulates gene transcription [10]. Epigenetic mechanisms play important roles in both, physiological and pathological conditions, including carcinogenesis [11]. Indeed, these modifications can outnumber genetic alterations and usually occur early and in all the steps of cancer development [12]. 10.1517/13543784.2015.1056779 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted 1 Box 1. Drug summary. in the treatment of cutaneous T-cell lymphoma and are cur- rently FDA approved [20-23]. In advanced NSCLC, a random- Drug name Phase Indication Pharmacology description/ mechanism of action Entinostat (SNDX 275, MS-275) II NSCLC Class I HDAC inhibitor (HDAC1 and 3) ized Phase III trial associating vorinostat with first-line carboplatin and paclitaxel was precociously terminated, as it failed to show anticipated improvement in objective response rate (ORR), PFS or OS [24]. Yet, the clinical effect of other HDAC inhibitors remains to be established. Route of Oral administration 3. Entinostat Chemical O structure N O 3.1 Chemistry, pharmacokinetics and metabolism O H Entinostat, previously known as SNDX-275 and N MS-275 (Box 1) is a synthetic benzamide derivative [25] that Pivotal trials [54,55] NH NH2 inhibits only the class I enzymes HDAC1 to HDAC3 [16]. It is moderately lipophilic (LogD = 1.79), with moderate plasma protein binding (fraction unbound 0.188 in humans) [26]. It is an orally bioavailable agent (F ~ 85%) [27] with a var- iable absorption rate. After administration, time to maximal concentration (Tmax) ranges between 0.5 and 60 h [27-30], but decreased to 0.25 if administered 2 h after fasting [29]. The area under the plasma concentration versus time curve Epigenetic mechanisms include DNA methylation, histone tail modification and non-coding micro-RNA regulation. Being dynamic and potentially reversible, epigenetic altera- tions constitute attractive therapeutic targets [13]. Currently, epigenetic therapy is undergoing pre-clinical and clinical trials for the treatment of several solid tumors, including lung can- cer. This review outlines the pharmacological profile, mecha- nism of action, safety, tolerability and relevant clinical trials of the histone deacetylase (HDAC) inhibitor entinostat, as a novel agent for the treatment of NSCLC. 2.Overview of HDAC inhibition in treatment of malignancies/lung cancer Chromatin is formed by nucleosomes, the complex of DNA and histone proteins that enables packing the entire genome within a single cell. It is an octamer containing 2 molecules of each histones 2A, 2B; 3 and 4 and the DNA tightly coiled around them. The N-terminal tails protrude from nucleosomes and post-translational modifications of these lysine-rich tails determine the accessibility of the DNA to transcription factors [14]. Acetylation reduces the tails positive charge, therefore, decreasing their interaction with the nega- tively charged DNA backbone [15]. While acetylation of histones contributes to a relaxed and open chromatin struc- ture that enables transcriptional activation and gene expres- sion [16], deacetylation leads to gene silencing [17]. As HDA are frequently overexpressed in cancer cells [18], HDAC inhib- itors have emerged as promising anticancer agents. There are four types of HDAC inhibitors: hydroxamate, cyclic peptides, aliphatic acids and benzamides [19]. Two of them, vorinostat (hydroxamic acid class) and romidepsin (cyclic tetrapeptide), have demonstrated antitumor activity increases linearly with dose [27,30]. The relation between total drug exposure and apparent oral clearance was not uniform between Phase I trials, probably due to the reduced number of subjects evaluated at certain doses [31]. Entinostat has systemic distribution, but poor brain penetra- tion as demonstrated by a study using positron emission tomog- raphy and the radiolabelled drug [32]. The mean elimination half-life (t1/2) was 52 h and it was nearly 50-fold longer from what was expected from pre-clinical studies. Possible explana- tions for this finding were attributed to enterohepatic recircula- tion and higher binding to human plasma proteins [27]. The metabolic pathway of entinostat is mostly unknown. The drug was not accumulated in the two main liver-specific isoforms of the family of organic anion transporting polypep- tides. Furthermore, cytochrome P450-mediated metabolism in human liver microsomes or glucoronic acid conjugation was also excluded. These results strongly suggest that hepatic metabolism is a minor pathway of elimination in humans [33]. Metabolism of entinostat needs to be elucidated in subsequent clinical trials. 3.2 Pharmacodynamics Entinostat inhibition of HDAC has been determined through the analysis of histones H3 and H4 acetylation status in peripheral blood or bone marrow mononuclear cells, either through immunohistochemistry (IHC) [27-29] or flow cytome- try [30]. Phase I trials found that entinostat administration increases acetylation status, therefore, promoting the up- regulation of gene transcription. This drug has been shown to affect the expression of pro- teins involved in cellular proliferation in vitro in several differ- ent human cancer cell lines, including leukemia, lymphoma, breast, ovary, prostate, melanoma and NSCLC among others. 2 Expert Opin. Investig. Drugs (2015) 24 (8) Furthermore, in vivo antitumor activity has been demon- strated in human tumor models [31,34]. Entinostat apoptotic effects result from the generation of reactive oxygen species (ROS), which causes mitochondrial damage [35] and from the induction of caspase-dependent apoptosis [25,36,37]. Additionally, entinostat increases cellular sensitivity to TNF-related apoptosis inducing ligand [38] and down-regulates the expression of the anti-apoptotic genes Bcl-2 and XIAP [35]. This HDA inhibitor also exhibits antiproliferative activity decreasing S-phase cells and increasing G-phase cells [25]. These events are mediated by the transcriptional activation of the tumor suppressors cyclin-dependent kinase inhibitor transcriptionally repressive chromatin, which is characterized by the presence of underacetylated histones [45]. In fact, although re-expression of epigenetically silenced genes can be restored with inhibition of DNA methyltransferase alone, synergy with complimentary inhibition of histone deacetyla- tion leads to more pronounced changes in gene expres- sion [45,46]. In 2011, Belinsky et al. [39] evaluated the strategy of associating two epigenetic drugs: entinostat and the demethylating agent, azacitidine in lung adenocarcinomas engrafted orthotopically in nude rats. They reported that this combination suppressed tumor growth and reprog- rammed the epigenome. The tumor burden of K-ras/p53 or EGFR-mutant lung cancer-derived cell lines was significantly (CDKI) p21WAF1/CIP1 [25,35,39-41] and gelsolin [25,34]. The reduced and the expression of proapoptotic genes, CDKI down-regulation of cyclin D1 secondary to entinostat also aids in growth arrest [35] [41]. Additionally, entinostat has been shown to increase the lev- els of the TGF-b type 2 receptor mRNA levels [36] and E-cadherin expression [42,43]. Also, anti-angiogenic properties due to decreased expression of pro-angiogenic genes have been attributed to entinostat [44]. 4.Pre-clinical studies in lung cancer In 2006, Witta et al. [42] demonstrated that restoring the expression of the cell adhesion molecule E-cadherin increased sensitivity to EGFR inhibitors in lung cancer cell lines. The zinc finger transcriptional repressor, ZEB1, inhibits E-cadherin through the recruitment of HDAC and this process might be involved in epithelial to mesenchymal tran- sition (EMT). Pretreating resistant cell lines with entinostat has been proved to induce E-cadherin expression, therefore, decreasing tumoral growth. Moreover, this apoptotic effect was further enhanced by gefitinib. Other drug combinations have been explored following the same rationale. The effect of entinostat either alone or in association with cetuximab, or erlotinib in EGFR inhibitor- resistant NSCLC cell lines in athymic mice, was assessed by the same investigator [43]. The three potential mechanisms of resistance were RAS mutation according to E-cadherin expression, T790M EGFR mutation and amplified MET. The combination of entinostat and cetuximab in RAS-mutant E-cadherin-positive lines achieved a higher tumor growth inhibition (88%) than cetuximab (65%) or entinostat (70%) alone, and greater than the responses observed in the E-cadherin-negative lines (cetuximab + entinostat 75%, cetuximab 3%, entinostat 64%). Also, entinostat enhanced the activity of erlotinib in cell lines harboring the EGFR-L858R/T790M mutation or MET amplification. These pre-clinical studies provided the rationale for designing clinical trials in patients with NSCLC with tumors resistant to EGFR inhibitors. Pre-clinical data showed that the epigenetic processes of DNA methylation and chromatin deacetylation are actively related. Highly methylated DNA associates p21 and p16 increased. Moreover, several modifications were seen in the expression of genes within the cell cycle, DNA damage, apoptosis, tissue remodeling, inflammatory and immune response, cell differentiation and angiogenesis. Later on, the combination of entinostat with the second- generation DNA methyltransferase inhibitor, SGI-110, was tested in the same orthotopic lung cancer model. SGI-110 is a derivative of decitabine, resistant to deamination by cytidine deaminase in the liver that shows an improved pharmacoki- netic profile, characterized by an extended plasma half-life and exposure window. This epigenetic combination also affected profoundly the growth of K-ras/p53 mutant lung adenocarcinoma cell lines, caused widespread demethylation of gene promoters and produced gene expression changes in key cancer regulatory pathways [47]. Recently, a pre-clinical study assessed chemosensitivity to different agents, following treatment with azacitidine and entinostat, as epigenetic priming. In in vivo assays using cell lines and patient-derived xenografts, significantly different responses were observed, but only in select models and specifically with irinotecan [48]. Certainly, these results are not conclusive to support or discard epigenetic priming to chemotherapy and further studies are warranted. Currently, a Phase II trial addressing this issue is recruiting participants [49]. 5.Clinical efficacy 5.1Phase I studies Based on pre-clinical studies, Konduri et al, conducted in 2009, a Phase I trial to evaluate the feasibility of associating entinostat with erlotinib, and to determine safe dosage ranges [50]. Nine NSCLC previously treated patients were included; they all received erlotinib 150 mg daily and entino- stat either at 5 mg (n = 3) or 10 mg (n = 6) orally every 2 weeks. Clinical benefit was observed; one patient had a confirmed partial response (PR) and had received more than 5 cycles of treatment at the time of publication, and another patient had stable disease (SD) for 8 months. The most common adverse events were anorexia and asthenia, including dose-limiting toxicity (DLT) of grade 3 asthenia in the 10 mg dose cohort. The combination of entinostat 10 mg once every Expert Opin. Investig. Drugs (2015) 24 (8) 3 Table 1. Completed entinostat clinical trials in NSCLC. n Study population Study design Treatment ORR (%) Median PFS Median OS Relevant findings Ref. Combination with targeted therapy 132 Stage III/IV previously treated NSCLC Phase II Erlotinib + entinostast Erlotinib + placebo 3.vs 9.2%, p = 0.13 1.97 vs 1.88 months, p = 0.98 8.9 vs 6.7 months, p = 0.39 Subset of patients with high E-cadherin levels: OS 9.4 vs 5.4 months; p < 0.03 [54] Combination of epigenetic therapy 45 Recurrent or metastatic previously treated NSCLC Phase I/II Azacitidine + entinostat 4% 1.9 months 6.4 months 23% of patients achieved SD for ‡ 12 weeks [55] OS: Overall survival; ORR: Overall response rate; PFS: Progression-free survival; SD: Stable disease. 2 weeks and erlotinib 150 mg daily in a 28-day cycle was established as the recommended Phase II dose in patients with advanced NSCLC. Table 1 shows the summary of com- pleted entinostat clinical trials in NSCLC. 5.2Phase II studies EMT plays a fundamental role in tumor progression and metastasis [51]. Most interestingly, pre-clinical studies suggest a direct correlation between activity of EGFR-tyrosine kinase inhibitor (TKI) and the degree to which cancer cells have undergone an EMT [42,52,53]. High E-cadherin expression, characteristic of an epithelial phenotype, implies sensitivity to EGFR-TKI, while high levels of vimentin, fibronectin and ZEB-1, all mesenchymal markers, suggest resistance [52,53]. Entinostat is capable of resensitizing cellular lines with mesen- chymal phenotype to EGFR-TKI, through reversion to an epithelial phenotype [42]. In concordance with these findings, a randomized multicenter Phase II study evaluated erlotinib (150 mg daily) with and without entinostat (10 mg each 15 days) in 132 previously treated (but not exposed to EGFR inhibitors) with stage III or IV NSCLC [54]. Primary end point was 4-month PFS rate. Secondary objectives were 6-month PFS rate, PFS, OS and ORR. Molecular analysis was performed for EGFR exon 19 mutations, KRAS mutations and E-cadherin expression by IHC and H-score. In both groups, patients received a median of 2 cycles of study treatment. The most common reason for study discontinua- tion was disease progression. In the intention-to-treat population (ITT), PFS rate at 4 months was 18% for erlotinib-entinostat (E-E) and 20% for erlotinib-placebo (E-P). The difference did not reach statistical significance in this unselected population (p = 0.70). Secondary end points, PFS rate at 6 months (E-E 11.9 vs E-P 10.8%, p = 0.92), median PFS (E-E 1.97 vs E-P 1.88 months, p = 0.98), median OS (E-E 8.9 vs E-P 6.7 months, p = 0.39) and ORR (E-E 3 vs E-P 9.2%, p = 0.13), were likewise not significantly different. However, in a preplanned analysis of the subset of patients with high E-cadherin levels (3 + o > 150), OS was longer in the experimental arm (E-E 9.4 vs E-P 5.4 months; hazard ratio: 0.35; 95% CI: 0.13 — 0.92; p < 0.03). Even after exclud- ing the three patients with activating EGFR mutations, who were all allocated to the experimental arm, OS remained significantly greater for the E-E group (p = 0.03). As the authors state, the difference in OS could be driven by the delay or avoidance of emergence of EGFR-TKI drug tolerance or resistance. Even more important, E-cadherin expression arises as a new biomarker predicting clinical activity of the EGFR inhibitor erlotinib in NSCLC patients. The successful combination of azacitidine and entinostat in pre-clinical models [39] was tested in a Phase I -- II study that included 45 pretreated patients with metastatic or recurrent NSCLC [55]. In the Phase I portion of the study, three patients received subcutaneous azacitidine 30 mg/m2/day and seven received 40 mg/m2/day on days 1 -- 6 and 8 -- 10, respectively. All patients were administered entinostat at a fixed dose of 7 mg on days 3 and 10 of each cycle. The Phase II part of the protocol was a single arm, open-label study designed to assess the ORR, PFS and OS of the combination, at the 40 mg/m2/day dose of azacitidine. In total, 42 patients, including the 7 patients from the Phase I component were evaluated. The cohort was extensively pretreated as 50% of them had received three previous therapies. The median number of experimental treatment cycles was 2. ORRs were observed in two patients, including a complete response that lasted 14 months and a PR that lasted 8 months. Interestingly, the clinical responses were sustained even after ceasing the epi- genetic therapy. Twenty-three percent of the patients (n = 10) achieved SD of at least 12 weeks. More than a half of patients, 52.3% (n = 22) had progressive disease after 2 cycles of ther- apy. For the whole group, the median OS was 6.4 months, which is comparable to the median survival achieved with approved therapies [56-58], for this extensively pretreated population. Forty-five percent (n = 19) were able to undergo immediate salvage therapy and, intriguingly four of them 4 Expert Opin. Investig. Drugs (2015) 24 (8) experimented major ORRs. This observation brought up the possibility of an epigenetically conducted priming effect that could alter cancer cell responsiveness to cytotoxic therapy. Additionally, the authors investigated whether this combi- nation could revert the methylation of the promoter region of four silenced genes (APC, RASSF1a, DH13 and CDKN2a), which had been previously associated with early recurrence in patients with stage I NSCLC [59]. Analysis of free-circulating DNA in serum of 26 of the patients, before and after cycle 1 of epigenetic therapy, was performed. The pre-treatment serum of 10 patients showed promoter hyper- methylation of at least two of these genes that decreased by day 29 and were classified as ‘methylation signature’ positive. Eighty percent of them had SD or ORRs after epigenetic therapy. Conversely, only 25% of the 16 patients without methylation of the promoters before treatment achieved SD and there were no ORRs. The investigators also reported significant differences in median OS (10.4 vs 6.5 months for the methylation signature positive and negative, respec- tively; p = 0.035) and PFS (3.3 vs 1.7 months, p = 0.035). 5.3Current trials The effect of the combination of subcutaneous azacitidine (days 1 -- 6) and entinostat (days 8 -- 10) in reversing aberrant genome-wide promoter methylation and prompting gene re- expression will be determined in treatment-naı¨ve, surgically resectable stage IA to IIIA NSCLC. Tumor tissue pairs will be evaluated before and after receiving 1 cycle of this preoper- ative epigenetic treatment. This study has temporarily sus- pended participant recruitment. The final data collection date for primary outcome measure is expected in April 2016 [60]. A Phase II trial of cytotoxic chemotherapy with and with- out epigenetic priming in stage III, IV or recurrent NSCLC is recruiting participants [49]. Patients are being randomized to receive entinostat on days 3 and 10 associated with subcu- taneous (days 1 -- 6 and 8 -- 10) or oral (days 1 -- 21) azaciti- dine for two courses followed by chemotherapy of the treating oncologist’s choice (irinotecan, docetaxel, pemetrexed or gem- citabine) or chemotherapy of the treating oncologist’s choice without epigenetic priming. The estimated primary comple- tion date was January 2015. The already explored association of entinostat and erlotinib is being tested in a different context, with NSCLC patients who are progressing on the TKI inhibitor. This Phase II clin- ical trial divided patients into two groups, according to previ- ous response to erlotinib (those progressing following a complete response or PR to erlotinib or a period of SD lasting at least 3 months vs those who progressed immediately during treatment with erlotinib or had an ORR or period of SD of < 3 months). The primary outcome measure was disease control rate in terms of response or SD. Secondarily, PFS at 2 and 4 months will be assessed too [61]. This study has com- pleted accrual and the results are still expected. Restraining immune tolerance to cancer cells by blocking inhibitory immune checkpoint molecules and therefore allow- ing T-cell-mediated antitumor activity to progress is a brand- new field of investigation. The anti-programmed death 1(PD-1) agent, nivolumab as monotherapy in NSCLC has been shown to achieve an outstanding 17% of ORR with median PFS and OS of 2.3 and 9.9 months, respectively [62]. This compound is currently undergoing a Phase III study, head-to-head, against docetaxel in previously treated meta- static NSCLC [63]. Likewise, a Phase II trial of nivolumab preceded by epigenetic priming with oral/subcutaneous azaci- tidine with or without entinostat is currently recruiting partic- ipants [64]. The estimated study completion date is August 2015. A summary of ongoing clinical trials with entinostat for NSCLC can be found in Table 2. 6. Safety and tolerability Entinostat has been proved to be a safe and well-tolerated agent when given weekly or every 2 weeks. With the initial daily administration schedule, DLT was reported; specifically supraventricular tachycardia, elevated transaminases, hypo- tension, hypoalbuminemia and hypophosphatemia, before the completion of the first cycle. This was attributed to a pro- longed elimination, not predicted by pre-clinical studies. Consequently, the dosing schedule was changed to once every 2weeks. With this regimen, first course grade 3 DLT included anorexia, nausea, vomiting and fatigue. No grade 4 toxicity was observed. Adverse events (AEs) observed during or after course 2 represented accumulated toxicity. They included fatigue, nausea, anorexia and headache. All of these developed in > 50% of the subjects. Other frequent AEs were hypoalbuminemia, taste disturbance, hypocalcaemia, diarrhea, hyponatremia, hypophosphatemia, neutropenia and anemia. Most of these events were mild. Grade 4 events were only reported for neutropenia. Toxicity increased with dose escalation as > 50% of patients required a reduction of the dose at the 6 — 10 mg/m2 dose level [27].
Another Phase I study conducted in patients with refractory solid tumors and lymphomas, which used doses from 2 to 6 mg/m2 on twice weekly, weekly or every other week regimens, reported a similar toxicity profile. Out of 149 cycles, grade 3 anemia occurred in 3% and grade 3 or 4 neutropenia in 4%. No grade 3 or 4 thrombocytopenia was reported. The most common non-hematologic adverse events were nausea (32%), asthenia (32%) and anorexia (15%). Grade 3/4 asthe- nia and hypoalbuminemia were observed in 5 and 2% of the cycles, respectively. Asymptomatic grade 3 or 4 hypophospha- temia was commonly seen (16%). It constituted a DLT in two patients. Unlike other HDAC inhibitors, no significant electrocardiograms or MUGA abnormalities were noted in this study [29,65].
Conversely, in the Phase I study that assessed entinostat in refractory leukemias, several infectious complications were

Expert Opin. Investig. Drugs (2015) 24 (8) 5

Table 2. Ongoing entinostat clinical trials in NSCLC.

Status
Population Study design
Treatment
Primary endpoint
Secondary endpoints
Ref.

Epigenetic therapy before surgery
Temporarily closed to accrual and treatment
Stage
IA — IIIA NSCLC patients undergoing surgery
Phase I/II SC azacitidine + entinostat followed by surgery
Changes in aberrant genome-wide promoter methylation and in gene
expression between pre- and post-treatment tumors
DFS Toxicity profiling
[60]

Epigenetic priming to chemotherapy
Currently recruiting patients
Stage III, IV or recurrent NSCLC
Phase II SC azacitidine + entinostat followed by chemotherapy (irinotecan, docetaxel, pemetrexed or gemcitabine)
Oral azacitidine + entinostat followed by chemotherapy Chemotherapy
PFS at 6 m
PFS
OS
[49]

Combination with targeted therapy
Completed. Pending results
NSCLC patients who are progressing on erlotinib
Phase II Entinostat + erlotinib in ‘erlotinib-responsive’ patients
Entinostat + erlotinib in ‘erlotinib-non-responsive’ patients
Disease control rate (CR, PR or SD)
PFS at 2 m PFS at 4 m
[61]

Epigenetic priming to immunotherapy
Currently recruiting patients
Recurrent or metastatic NSCLC
Phase II Oral azacitidine followed by nivolumab
SC azacitidine + entinostat followed by nivolumab
ORR
PFS
TTP (on nivolumab) OS
Safety and tolerability
[64]

CR: Complete response; m: Months; OS: Overall survival; ORR: Overall response rate, PFS: Progression-free survival; PR: Partial response; SD: Stable disease; SC: Subcutaneous; TTP: Time to progression.

seen [28]; however, they were generally considered as being a consequence of the underlying disease.

7.Conclusion

There are no HDAC inhibitors approved for NSCLC. Enti- nostat as single agent or in combination with cytotoxic ther- apy or other molecular targeted therapies represents a viable option for the treatment of NSCLC patients. Ongoing studies will further define the potential utility of this new class of agents. From the Phase I and Phase II data published, we can get an idea of the toxicity profile expected with these compounds.

8.Expert opinion

The field of molecular therapy for NSCLC is filling fast, how- ever, the approved targeted agents like: crizotinib, cetirinib and afatinib, only benefit < 15% of all NSCLC patients benefit of these new targeted therapies. Despite the availability of these therapies, we have been unable to cure lung cancer yet. It is very clear that there is a great need of more agents in the field. One of the reasons why we cannot cure lung cancer even with targeted therapy is that all of the approved agents eventually fail as tumor resistance emerges. HDAC inhibitors represent a new type of targeted therapy which will hopefully that there will be show no cross-resistance with existing agents, bringing one more line of therapy for the patients. In the literature, there is plenty of information about the importance of epigenetic changes in the presence and develop- ment of cancers. Indeed, we already have for two agents that have proved to have a role in anticancer therapy and are already FDA approved for other tumors. Much has been pub- lished about epigenetic changes in lung cancer, now it’s time to find agents that are more effective than those HDAC inhibitors that have failed to fulfill the expectations. Like most of the anticancer agents, there is no cancer drug that can successfully treat all cases. Indeed, if there is a role for a certain drug it might not be as single agent (i.e., bevacizumab for adenocarcinomas of the lung) or if there is a role for these agents, we need to find it. This is why it is very important to elucidate if the combination with other HDAC inhibitors, TKI, chemotherapeutic agents or immunotherapy (anti- PD-1 or anti-programmed death-ligand 1) can give the answer. All of these agents have shown efficacy in NSCLC is that, as most of the therapies including targeted therapies or with 6 Expert Opin. Investig. Drugs (2015) 24 (8) chemotherapy. We are eager to see the results for the combina- tion of entinostat with erlotinib or nivolumab. It is too early to make a prediction of the impact of entinostat due to the lack of information coming from randomized Phase III trials but cer- tainly it’s a compound worth to follow. Another important concern in NSCLC is that, as most of the therapies including targeted therapy agents are palliative, it is of major importance that the new compounds exhibit an adequate toxicity profile and an improvement of quality of life. Most of the documented entinostat side effects: anorexia, nausea, vomiting and fatigue, hypoalbuminemia, taste disturbance, hypocalcaemia, diarrhea, hyponatremia, hypophosphatemia, neutropenia and anemia, are unfrequent and mild. 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2013 American Society of Clinical Oncology Annual Meeting; 31-June
4 May 2013; Chicago, Illinois. Abstract 8030
63.Bristol-Myers Squibb. Study of BMS- 936558 (Nivolumab) compared to docetaxel in previously treated metastatic
Luis E Raez2 MD FACP FCCP &
Christian Rolfo3
†Author for correspondence
1Universidad Peruana Cayetano Heredia, Instituto Nacional de Enfermedades Neopla´sicas (INEN), Angamos Este 2520 Surquilllo, Lima, Pertiu
Tel: +519 889 662 44;
E-mail: [email protected] 2Director, Clinical Associate Professor of Medicine,
Florida International University, Memorial Cancer Institute, Memorial Health Care System, Herbert Wertheim College of Medicine, Miami, USA
3Head of Phase I – Early Clinical Trials Unit, Antwerp University Hospital, Oncology Department, Wilrijkstraat 10, 2650 Edegem, Belgium

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