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01.12.2016 | Review | Ausgabe 1/2016 Open Access

Journal of Hematology & Oncology 1/2016

Emerging therapeutic agents for lung cancer

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2016
Autoren:
Bhagirathbhai Dholaria, William Hammond, Amanda Shreders, Yanyan Lou
Abbreviations
ALK
Anaplastic lymphoma kinase
DCR
Disease control rate
EGFR
Epidermal growth factor receptor
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
PD
Progressive disease
PR
Partial response
SD
Stable disease

Background

Lung cancer is the second most commonly diagnosed cancer and is the leading cause of cancer-related death in both men and women. Implementation of tobacco control, low-dose spiral computed tomography screening programs, and advances in multidisciplinary treatments have resulted in the slow decline of both incidence and mortality. However, 52–58% of lung cancer patients present with advanced-stage disease, and a vast majority of these patients do not survive despite treatment. Similarly, the prognosis remains poor even in locally advanced disease because of the high relapse rate and early formation of micrometastases [1].
One of the most important therapeutic advances of lung cancer treatment in the last decade was identification of specific driver mutations and the development of small molecular tyrosine kinase inhibitors (TKIs) [2]. In 2009, erlotinib was the first selective epidermal growth factor receptor (EGFR) inhibitor approved by the US Food and Drug Administration (FDA) [3]. This was quickly followed by crizotinib, which was initially developed as a MET (mesenchymal-to-epithelial transition/hepatocyte growth factor receptor) inhibitor and was found to be highly active against small subset of non-small-cell lung cancer (NSCLC) cases harboring anaplastic lymphoma kinase (ALK) rearrangement [4]. These drugs promise around a 70% response rate; however, resistance development is almost universal, and second/third generation TKIs are being developed to overcome these issues. Novel targeted agents directed against EGFR, ALK, ROS1, MET, RET, BRAF, and many more are under investigation. Figure 1 provides summary of targets with specific focus on the drugs that currently in early-phase clinical trials in lung cancer. In addition to these drugs, next-generation sequencing and cell-free DNA (cfDNA) technologies have provided rapid and convenient tools for gene abnormality testing and the development of targeted therapies [5]. Additionally, personalized medicine has become part of daily practice, and tailoring treatment for individual patients is becoming a reality.
Immunotherapy in the form of checkpoint inhibitors represents a landmark success in NSCLC treatment, and patients have experienced durable responses with good tolerability. Pembrolizumab and nivolumab exert antitumor activity by blocking programmed death receptor-1 (PD-1) on T lymphocytes. These drugs are currently approved as second-line therapies for advanced NSCLC based on pilot studies that show improved and durable responses compared to docetaxel [68]. Most recently, the FDA approved pembrolizumab for the treatment of patients with metastatic NSCLC whose tumors express strong PD-L1 in the first-line setting based on significant improvement in progression-free survival (PFS) and overall survival (OS) [9]. Trials are underway to test using these agents as first-line therapies for patients with NSCLC either alone or in combination with chemotherapy, TKIs, radiation, and other immunotherapies [912]. For example, combinations of CTLA-4 and PD-1 inhibitors have been investigated in patients with NSCLC and small cell lung cancer (SCLC). Preliminary results from a phase I study demonstrated that ipilimumab and nivolumab can be effectively and safely combined as first-line treatment of advanced NSCLC [10]. This combination is currently being tested in ongoing phase III study. Similarly, increased antitumor activity was also seen in SCLC with this combination [11]. Multiple studies are underway to investigate the clinical activities of combined chemotherapy and checkpoint inhibitors. Studies to investigate the roles of checkpoint inhibitors in adjuvant and neoadjuvant settings in early-stage lung cancers are ongoing as well. These exciting developments have fuelled rapid progress in the field, and multiple molecules targeting different aspects of host-tumor immune interactions are currently being investigated. Figure 2 provides the summary of ongoing strategies and efforts in immunotherapy of lung cancer.
In this review, we have discussed recently published data on the first-in-human clinical trials and some of the most promising drugs in pipeline. Literature was searched for phase 1/2, first in human clinical trials in lung cancer by using PubMed, Google scholar, and the American Society of Clinical Oncology (ASCO) meeting abstracts. Each study was individually reviewed and data points have been summarized.

Targeted agents

EGFR inhibitors

EGFR is a member of the ErbB tyrosine kinase receptor (TKR) family and is referred to as ErbB1 or HER1. Gefitinib was first tested for EGFR-expressing NSCLC. It targets the ATP cleft within EGFR, which is overexpressed in 40–80% of NSCLC cases. Later, Lynch et al. demonstrated that only the tumors with somatic mutations in tyrosine kinase domain of the EGFR gene responded to gefitinib [13]. Testing for driver mutations in newly diagnosed, advanced NSCLC cases has become the standard of care. In patients who carry the targetable driver mutation, a first-line treatment with targeted agents is recommended over conventional chemotherapy. These drugs are well tolerated and give predictable objective response. A phase 2 trial in neo-adjuvant settings has shown an improved response rate compared to chemotherapy in EGFR+ NSCLC [14]. Driver mutations in EGFR (exon 19 deletion or exon 21 L858R substitution) are found in 15–20% of all lung adenocarcinomas (ACs) that account for the largest group of lung cancer patients. Erlotinib, gefitinib, and afatinib are approved as first-line treatments for targetable EGFR alterations. The median progression-free survival (PFS) from these agents is 9.2–13.1 months [1517]. Dacomitinib is a small molecule, irreversible inhibitor active against all HER family of tyrosine kinases. In randomized trials, it has comparable efficacy to erlotinib. The subgroup with EGFR exon 19 deletion has better PFS with dacomitinib compare to erlotinib (HR 0.585, P = 0.058) [18, 19]. A recent phase 3 trial (NCT01040780) comparing icotinib with gefitinib as the first-line EGFR TKI treatment showed similar results in Chinese patients [20].

T790M mutant-selective EGFR TKIs

After the initial response to EGFR TKI, resistance development through various mechanisms is inevitable. The EGFR T790M mutation causes acquired resistance to the first- and second-generation TKIs. T790M mutation-selective third-generation EGFR TKIs (osimertinib, rociletinib) have been developed with encouraging overall response rates up to 60% [21, 22]. Osimertinib was approved in 2015 by the FDA for confirmed EGFR T790M mutation-positive NSCLC. A first-line trial (NCT02296125) is underway to compare osimertinib vs erlotinib or gefitinib. This should give information on ideal sequencing on these agents. ASP8273 and olmutinib (BI1482694) are other third-generation T790M-selective EGFR TKIs. Early-phase studies (NCT02113813, NCT01588145) in T790M-positive NSCLC showed an overall response rate (ORR) of 31% and disease control rate (DCR) of 57% for ASP8273, as well as a 61% ORR and 90% DCR for BI1482694. The median PFS was 6.8 and 8.3 months, respectively [23, 24]. EGF816 is another agent that showed an ORR of 44% and DCR of 91% in a phase 1 study (NCT02108964) [25]. Typical EGFR TKI-related adverse events were observed with all three drugs.

CNS-penetrant EGFR TKIs

Central nervous system (CNS) metastasis is a common site of disease progression in EGFR+ NSCLC, leading to failure of the first-line TKIs. AZD3759 is a potent CNS-penetrant EGFR TKI currently being evaluated along with osimertinib in a phase 1 (BLOOM) study (NCT02228369) in patients with progressive CNS metastasis who have already had first-line treatment with EGFR TKI. AZD3759 showed activity in 20 patients with measurable brain metastasis evaluable for RECIST assessment; 8 had tumor shrinkage in the brain, 3 had confirmed partial response (PR), and 3 had unconfirmed PR [26]. In 12 patients taking osimertinib, 7 had radiological PR, 2 had stable disease, and 3 were not evaluable after 12 weeks [27].
Epitinib is another small-molecule TKI being developed for its favorable CNS penetration. In a dose-expansion phase, 12 patients with EGFR+ NSCLC and CNS metastasis received epitinib. Among those 12 evaluable patients, 5 reached PR (all treatment naïve) and showed dramatic shrinkage of brain lesions. The five prior-TKI-treated patients had stable disease (SD) in the brain [28] (NCT02590952).

ALK inhibitors

ALK fusion oncogene-associated NSCLC is a distinct subset of lung cancer amenable to targeted therapy. ALK rearrangement is found in 3–13% of NSCLC cases, with a higher prevalence among younger patients, never or light smokers, and adenocarcinoma with signet ring or acinar histology [29]. Crizotinib is a multi-targeted TKI that is active against ALK, ROS1, and MET [4]. It has been approved as a first-line treatment for ALK+ or ROS1+ NSCLC. Ceritinib and alectinib are second-generation ALK TKIs approved for crizotinib-resistant or intolerant cases [3032]. Resistance development and CNS progression are major issues, and the following ALK TKIs are currently under investigation.
Brigatinib was given to 222 patients with crizotinib-refractory, ALK+ NSCLC under a phase II study (ALTA, NCT02094573). A PFS of 8.8 and 11.1 months was noted among those receiving lower and higher doses of brigatinib, respectively. An encouraging intracranial ORR of 67% was seen in nine patients with measurable CNS metastasis. Early onset pulmonary toxicity was seen in 6% of the patients [33]. A phase III trial (NCT02737501) against crizotinib in a front-line setting for ALK+ NSCLC has been initiated.
Lorlatinib (PF-06463922) was tested in phase I/II study (NCT01970865) of ALK+/ROS+ NSCLC. A majority of the participants had a prior treatment with ≥2 ALK TKIs. Among 41 evaluable patients, an ORR 46% and median PFS of 11.4 months were seen. The intracranial ORR was 44%, including a few complete responses (CRs) [34]. Interestingly, the drug was active against diseases caused by the ALK G1202R mutation which confers resistance to ceritinib, alectinib, and brigatinib [35].
Ensartinib (X-396) is a novel ALK inhibitor with additional activity against ROS1, MET, SLK, Axl, LTK, ABL, and EPHA2. Partial responses were seen in 60% crizotinib-naïve (30 patients) and 88% crizotinib-resistant patients (12 patients) (NCT01625234). CNS responses were also observed in both groups [36]. A phase 3 study (NCT02767804) comparing ensartinib and crizotinib in a front-line setting is currently recruiting patients.

MET inhibitors

MET, a receptor tyrosine kinase after binding with hepatocyte growth factor (HGF), activates the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinases (MAPK) pathways. MET gene amplification and exon-14-skipping mutations are characteristic abnormalities causing increased MET signaling activation. Isolated MET exon 14 mutation is found in 3% of NSCLC; however, it is an acquired EGFR TKI resistance pathway in 15–20% of EGFR mutation-positive NSCLC cases [37, 38]. Crizotinib has shown some activity in selected MET-amplified and exon 14-skipping mutant NSCLC [39, 40] (NCT00585195). Cabozantinib, a multi-targeted MET inhibitor, was given to five patients with exon 14 mutations and had a stable disease for 5 months [40]. Capmatinib (INC280) is a selective MET inhibitor. In a phase I study (NCT01324479), relapsed NSCLC patients with high cMET expression were given capmatinib. In subgroup of patients with MET-amplified disease, the ORR was 63%, and the median PFS was 7.4 months [41]. Glesatinib (MGCD265) is another MET blocker currently being studied in NSCLC (NCT00697632).

Combined MET + EGFR inhibitors

Acquired EGFR TKI resistance is mediated by MET upregulation in a subset of NSCLC patients. One strategy to overcome this resistance is to combine a MET inhibitor with an EGFR TKI. A combination of capmatinib and gefitinib was tested in a phase 2 study (NCT01610336) in EGFR+ NSCLC patients after their disease progressed while using gefitinib. EGFR T790M NSCLCs were excluded and high cMET expression was required. An ORR of 18%, an SD of 62%, and a DCR of 80% were observed in 65 evaluable patients. More responses were seen in tumors with MET amplifications [42]. Tepotinib (MSC2156119J) with gefitinib was well tolerated in a phase 1 study (NCT01982955). Eighteen patients were treated, and five had a partial response [43]. A similar trial (NCT01900652) with emibetuzumab and an IgG4 anti-MET monoclonal antibody (mAb) with erlotinib in MET-expressing NSCLC with acquired erlotinib resistance showed some benefit in high cMET-expressing tumors [44].

RET inhibitors

The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family. RET rearrangements are found in 1–2% lung adenocarcinoma and are mutually exclusive with mutations involving EGFR, ALK, or KRAS. Vandetanib, sorafenib, sunitinib, lenvatinib, ponatinib, and cabozantinib are multi-targeted TKIs with RET-blocking activity. They are currently approved for other malignancies. In a phase 2 study with cabozantinib, 38% PR was seen among 16 evaluable patients, and there was a median PFS of 7 months [45].
Vandetanib in advanced RET-rearranged NSCLC showed an ORR 53%, a DCR 88%, and a median PFS of 4.7 months in 17 eligible patients. The CCDC6-RET subtype had an ORR of 83% and a median PFS of 8.3 months [46] (UMIN000010095). In a phase 1 study (NCT01582191), vandetanib was combined with everolimus (mTOR (mammalian target of rapamycin) inhibitor) to prevent resistance development based on in vitro studies. Among 13 stage IV NSCLC patients, PR was achieved in five patients with RET fusion. Good CNS activity was seen in three patients with intracranial metastasis [47].

BRAF/MEK inhibitors

BRAF is a downstream signaling mediator of KRAS, which activates the MAP kinase pathway. BRAF mutations are found in 1–2% of NSCLC cases and are usually smoking related [48]. It is also described as one of the resistance mechanisms associated with EGFR TKIs. Vemurafenib and dabrafenib are currently approved for BRAF V600E-positive malignant melanomas, but single-agent activity in BRAF V600E- positive NSCLC is limited. Dabrafenib had an ORR of 33% in platinum refractory cases with a median duration of response of 9.6 months in single study [49] (NCT01336634).

Combination BRAF + MEK inhibitors

Sequential inhibition of BRAF and downstream MEK is an active area of lung cancer research after encouraging results were seen in melanoma patients. Dabrafenib with trametinib (MEK inhibitor) was associated with ORR of 63% in 57 evaluable patients and the DCR was 79% [50].

Combination MEK inhibitor and immunotherapy

MEK inhibition can result intratumoral T cell accumulation and MHC-1 upregulation and synergizes with anti-PD-L1 agent leading to tumor regression [51]. Cobimetinib is a selective MEK1 and MEK2 inhibitor. In a phase 1b study (NCT01988896), cobimetinib with atezolizumab (anti-PD-L1) was given to advanced solid cancer patients. In colorectal cancer cohort (MSI-low), ORR was 17% and responses were durable. Increased PD-L1 and CD8 T lymphocyte infiltration was demonstrated in serial biopsies [52]. Results on NSCLC cohort are pending.

PI3K inhibitors

Phosphatidyl 3-kinase (PI3K) pathway is a central mediator of cell survival signals. PI3CA mutations are found in 4.4% of lung adenocarcinoma and 16% of squamous cell cancer. PI3CA amplifications are found in up to 40% of squamous cell lung cancer [53, 54]. PI3CA mutations also promote resistance to EGFR TKIs. PQR309 is a pan-PI3K, mTOR inhibitor. Its safety and maximum tolerated dose have been recently established in a phase 1 study (NCT02483858) with advance solid cancers. No response data are available for NSCLC cohort [55].

HER3 inhibitors

Patritumab is a fully human anti-HER3 mAb. HER3 is a member of the ErbB tyrosine kinase receptor family and is activated by heregulin. Preclinical studies with EGFR+ NSCLC cell lines have shown that increased heregulin level confers resistance to EGFR TKI. An initial phase 2 study (NCT01211483) failed to show the PFS benefit of adding patritumab to erlotinib compared to a placebo. However, the subgroup with increased soluble heregulin showed increased PFS (HR 0.41 [95% CI 0.18–0.90], P = 0.02) with patritumab [56]. A phase 3 placebo-controlled study (HER3-Lung, NCT02134015) in EGFR+ NSCLC is ongoing.

Aurora A kinase inhibitors

Aurora A is a member of a family of mitotic serine/threonine kinases which assist with cell proliferation. Alisertib (MLN-8237) is an aurora kinase A inhibitor. Based on in vitro synergism with EGFR TKIs, it was tested in 18 patients with EGFR+ NSCLC. The combination was well tolerated; one patient had a PR, while five other patients achieved SD [57]. Phase 2 recruitment is ongoing (NCT01471964).

FGFR inhibitors

The fibroblast growth factor receptor (FGFR) binds to members of the fibroblast growth factor family of proteins and promotes cell proliferation. BGJ398 is a potent, selective pan-FGFR (fibroblast growth factor receptor). FGFR1 amplification is found in around 21% of squamous NSCLC cases [58]. In a single phase 2 trial, 26 evaluable patients showed a PR of 15% and an SD if 35% in dose >100 mg [59]. Dovitinib is another FGFR inhibitor tested in squamous NSCLC. Among 26 patients, the ORR was 11.5%, the DCR was 50%, and the median PFS was 2.9 months [60].

PARP inhibitors

PARP (poly ADP ribose polymerase) plays an important role in DNA repair. PARP inhibitors have synergistic activity with platinum based chemotherapy (i.e., cisplatin) [61]. In a phase 2 study, veliparib in combination with carboplatin and paclitaxel was tested in first-line setting for advanced NSCLC. The combination was well tolerated, and there was a trend toward favorable PFS (HR 0.72 [95% CI 0.45–1.15, P = 0.17]) and OS (HR 0.80 [95% CI 0.54–1.18, P = 0.27]) in combination arm [62]. A phase 2 combining veliparib with chemoradiation in stage 3 NSCLC is recruiting (NCT02412371).

Immunotherapies

Immunotherapy has long been considered the holy grail of Oncology. Different attempts have been made to harness body’s immune system to eradicate malignancy. Lung cancer has the second highest mutation burden after melanoma, which increases its susceptibility to immunotherapy [63]. One of the key advantages of immunotherapy is the durability of responses. Where resistance development is universal with chemotherapy and targeted agents, memory function of the immune system can lead to lasting remission. Check point inhibitors target the PD1/PD-L1 axis to remove the inhibitory signals on T lymphocytes to eradicate malignancy. Pembrolizumab and nivolumab are currently approved as second-line therapies for both adenocarcinoma and squamous cell carcinoma of lung. Atezolizumab is the first anti-PD-L1 agent approved by the FDA for NSCLC in second-line setting after encouraging results from phase 3 OAK trial showing superior OS.(HR 0.73; P = 0.0003) [64]. A recent phase 3 study tested pembrolizumab vs platinum doublet chemotherapy in first-line NSCLC with at least 50% PD-L1expression in tumor cells. Pembrolizumab was associated with better PFS (10.3 vs 6 months) and response rate (44.8 vs 27.8%) compared to chemotherapy. Estimated survival at 6 months was also better in patients treated with pembrolizumab (HR = 0.60, P = 0.005) [9]. This had led to approval of pembrolizumab as first-line therapy in NSCLC with >50% PD-L1 expression in tumor cells. A combination of ipilimumab and nivolumab as first-line treatment in advanced NSCLC is feasible, safe, and has shown good ORR [10]. Durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA4) have been tested in phase 1b study and found to be safe with early evidence of clinical activity in relapsed NSCLC [65]. As these agents move quickly to treat early-stage lung cancers through clinical studies, other agents that target different aspects of the tumor-immune system milieu are being developed. Figure 2 demonstrates different strategies being utilized to enhance tumor recognition and elimination by the immune system [66].

OX40

OX40 (CD134) is a secondary costimulatory immune checkpoint receptor expressed on activated T cells that lead to expansion of effector and memory T cells after binding with OX40L (CD252) on antigen presenting cells. It is a part of tumor necrosis factor receptor (TNFR) superfamily and works in conjunction with B7 family members, such as PD1 and CTLA-4. GSK3174998 is a humanized IgG1 agonistic anti-OX40 monoclonal antibody (mAb) that promotes naïve CD4+ T- cells and suppresses their differentiation into immunosuppressive regulatory T cells (Treg) [67, 68]. ENGAGE-1 (NCT02528357) is a first-in-human study of GSK3174998 alone and in combination of pembrolizumab. Murine studies have shown synergistic activity between PD-1 blockade and OX40 agonist mAb [69]. No dose-limiting toxicity was found in the initial dose escalation cohort alone and in combination with a 200-mg fixed dose of pembrolizumab every 3 weeks. This study is still recruiting patients.
MEDI6383 (NCT02221960) is another OX40 agonist mAb currently being studied with durvalumab, an anti-PD-1 antibody. Lirilumab/BMS-986015 (NCT01714739) is anti-KIR mAb, which is a natural killer (NK)-cell checkpoint inhibitor that is being evaluated with nivolumab.

Lymphocyte activation gene 3

Lymphocyte activation gene 3 (LAG-3, CD223) is another checkpoint inhibitor on activated T lymphocytes that inhibits immune function after binding with major histocompatibility complex (MHC) II [70]. Urelumab is an anti-LAG3 mAb currently being studied for NSCLC in combination with anti-PD1 agents (NCT01968109, NCT02460224).

T cell immunoglobulin and mucin-domain containing-3

T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is Th1 (T helper-1)-specific regulator of macrophage responses. Recently, murine studies showed TIM-3 upregulation in the tumor microenvironment in an anti-PD1 resistant NSCLC model [71]. MBG453 and TSR-022 are anti-TIM3 mAbs currently being studied in two phase 1 trials (NCT02817633, NCT02608268).

B7-H3

B7-H3 is widely expressed among tumors and is associated with immune escape and metastasis. MGD009 is a humanized B7-H3 and CD3 dual-affinity re-targeting (DART) protein designed to engage T cells to B7-H3 expressing cells. Antitumor activity in multiple in vivo models has been demonstrated. A phase 1 trial (NCT02628535) in advanced B7-H3 expressing tumors, including NSCLC, is recruiting patients [72]. Prior anti-PD1 therapy is allowed.

MUC1

MUC1 is widely expressed in many malignancies, including NSCLC. TG4010 is a modified vaccinia Ankara expressing MUC1 and interleukin 2 (IL2). In a recent phase 2b study, TG4010 or placebo were given with chemotherapy as a first-line therapy for metastatic NSCLC (mNSCLC) without EFGR mutations and MUC1 expression in minimum 50% of tumor cells. Significant improvement in PFS (hazard ratio 0.74, 95% CI 0.55–0.98, P = 0.019) was noted. The phase 3 component is ongoing [73].

GM.CD40L

GM.CD40L is an allogeneic tumor cell vaccine developed from a human bystander cell line. Cells are transduced with granulocyte-macrophage colony-stimulating factor (GM-CSF) and CD40-ligand (CD40L) genes. In vivo, it stimulates dendritic cell-mediated immune response. CCL21 is a chemokine that helps with T cell responses. In a phase 1/2 study (NCT01433172), GM.CD40L + CCL21 did not improve PFS, and the median OS was comparable to single-agent chemotherapy in advanced adenoNSCLC. A combination study with anti-PD1 is underway [74].

Antibody drug conjugates

Antibody drug conjugates (ADCs) are an important class of biologics currently being investigated for range of malignancies. The chemotherapy molecule is attached to a target-specific antibody for tumor-directed cytotoxicity but sparing of normal tissue. Brentuximab vedotin (CD30 directed) and transtuzumab emtansine (HER2 directed) are ADCs currently available for relapsed Hodgkin lymphoma and metastatic HER2-positive breast cancer, respectively. The following ADCs are currently being studied in phase 1 trial for lung cancer.

Sacituzumab govitecan (IMMU-132)

Trop-2 is widely expressed among solid tumors. Sacituzumab govitecan is made from a humanized anti-Trop-2 monoclonal antibody (hRS7) that is conjugated with the active metabolite of irinotecan, SN-38. In a phase 1/2 study (NCT01631552), the single-agent sacituzumab govitecan was given to patients with advanced epithelial malignancies. In the NSCLC cohort, an objective response of 31% and median PFS of 3.9 months was observed. The SCLC cohort showed a similar response rate, a median PFS of 4.6 months, and a median OS of 8.3 months [75, 76]. Diarrhea and neutropenia were common adverse events. These are encouraging results in platinum refractory patients. It has received the FDA breakthrough therapy designation for triple-negative breast cancer.

Rovalpituzumab tesirine (SC16LD6.5)

Rovalpituzumab tesirine also known as Rova-T is an antibody (SC16) targeting delta-like protein 3 (DLL3) and is linked to pyrrolobenzodiazepine (PBD). DLL3, an inhibitory Notch ligand, is expressed in >80% of SCLCs. The first biomarker directed trial for advanced SCLC showed an objective response rate of 18% and a clinical benefit rate of 68% as a second or third line of therapy in evaluable patients. Interestingly, 27 patients with high DLL3-tumor expression had a response rate of 44 and 45% in the second- and third-line settings, respectively [77]. Thrombocytopenia, a skin rash, and serosal effusions were dose-limiting toxicities. A phase 2 study (TRINITY; NCT02674568) is recruiting patients with DLL3-expressing SCLC.

Cancer stemness inhibitors

Cancer stem cells are highly resistant to traditional therapies and cause disease relapse after initial response. Napabucasin (BBI608) is a first-in-class cancer stemness inhibitor that works through STAT3 pathway inhibition. It has shown activity in combination with paclitaxel. In a phase 2 study (NCT01325441), 27 heavily pretreated NSCLC patients were given a combination of napabucasin and weekly paclitaxel. Among 19 evaluable patients, there was a PR of 16%, a DCR of 79%, and a median PFS of 4 months [78].
Demcizumab (VS-6063) is a humanized IgG2 anti-DLL4 (delta-like ligand 4) antibody that inhibits tumor growth by suppressing the Notch pathway. A phase 1b study (NCT01189968) tested demcizumab with carboplatin and pemetrexate as first-line therapies for lung adenocarcinoma. Results showed complete responses in one (3%) of 40 patients and partial responses in 19 (47%) patients [79]. A randomized, placebo-controlled phase 2 trial (DENALI) (NCT02259582) has opened for first-line non-squamous NSCLC. Another study (NCT01859741) of first-line chemotherapy for SCLC is still recruiting patients.
Tarextumab (OMP-59R5) is a human anti-Notch 2/3 receptor mAb. In the phase 1b portion of the PINNACLE study, tarextumab was given with etoposide/platinum chemotherapy in the first-line extensive stage SCLC. The combination was well tolerated. The RECIST response was 77% with a median PFS and OS of 4.4 and 10.4 months, respectively, in 27 treated patients [80]. A randomized study (NCT01859741) is ongoing.

Future directions

We discussed results of first-in-human phase I/II clinical trials with novel agents in lung cancer in this article. There are many new molecules which are currently being studied for a variety of targets. Histone deacetylase (HDAC) inhibitors and DNA hypomethylating agents target epigenetics for tumor growth suppression. In immunotherapy, new peptide vaccines targeting novel tumor antigens, alternative checkpoint inhibitors, and chimeric antigen receptor T cells (CAR-T) are being developed for the patients who have failed or intolerant to anti-PD1/anti-PD-L1 therapy. Novel small molecular inhibitors directed to inhibit variety of signaling pathways are being developed to overcome resistance to currently available targeted therapies. Table 1 summarizes currently open phase I/II clinical trials for lung cancer patients with pending results. The information in this table was collected from Clinicaltrils.gov (accessed on September, 2016). It can serve as a guide for clinicians who treat relapsed refractory lung cancer.
Table 1
Currently open phase I/II clinical trials for lung cancer
Drug class
Drug
Mechanism of action
Clinical trials (phase)
Study design
Disease
Tumor epigenetics
Entinostat
Histone deacetylase (HDAC) inhibitor
NCT02437136 (1/2)
Combination
NSCLC
HBI-8000
NCT02718066 (1/2)
Combination
NSCLC
ACY 241
NCT02635061 (1)
Combination
NSCLC
Epacadostat
Combination
NSCLC
Mocentinostat
NCT02805660 (1/2)
Combination
NSCLC
CC-486
DNA hypomethylation
NCT02250326 (2)
Combination
NSCLC
Azacitidine
Monotherapy
NSCLC
RRX-001
DNA methylation, histone deacetylation, and lysine demethylation
Monotherapy
NSCLC
Tumor metabolism
Ethaselen
Thioredoxin reductase
Monotherapy
NSCLC
TAS-114
dUTPase
NCT02855125 (2)
Combination
NSCLC
ADI-PEG 20
Pegylated arginine deiminase
NCT02029690 (1)
Combination
NSCLC
CCT245737
Checkpoint kinase 1
NCT02797977 (1)
Combination
NSCLC/SCLC
LY2606368
NCT02860780 (1)
Combination
NSCLC/SCLC
CB-839
Glutaminase
NCT02771626 (1/2)
Combination
NSCLC
Immunotherapy
Cancer vaccines
CV301
Tumor peptide vaccine
NCT02840994 (1/2)
Combination
NSCLC
TG4010
Combination
NSCLC
Gemogenovatucel-T
NCT02639234 (2)
Combination
NSCLC
CMB305
NCT02387125 (1)
Monotherapy
NSCLC
DC-CIK
Dendritic cell vaccine
NCT02688686 (1/2)
Monotherapy
NSCLC
DCVAC/LUCA
NCT02470468 (1/2)
Monotherapy
NSCLC
AGS-003-LNG
Monotherapy
NSCLC
JNJ-64041757
Listeria vaccine
NCT02592967 (1)
Monotherapy
NSCLC
ADXS11-001
NCT02531854 (2)
Combination
NSCLC
DSP-7888
WT1 vaccine
NCT02498665 (1)
Monotherapy
NSCLC
S-588410
(HLA)-a*2402-restricted epitope peptides
Monotherapy
NSCLC
AD-MAGEA3 and MG1-MAGEA3
MAGE-A3-expressing maraba virus
NCT02879760 (1/2)
Monotherapy
NSCLC
L-DOS47
Immunoconjugate
NCT02340208 (1/2)
Monotherapy
NSCLC
NCT02309892 (1)
Monotherapy
NSCLC
DRibbles
NCT01909752 (2)
Monotherapy
NSCLC
Checkpoint inhibitors
Enoblituzumab (MGA271)
B7-H3 antibody
NCT02475213 (1)
Combination
NSCLC
NCT01391143 (1)
Monotherapy
NSCLC
MGD009
NCT02628535 (1)
Monotherapy
NSCLC
CM-24
CEACAM1 antibody
NCT02346955 (1)
Combination
NSCLC
Indoximod
Indoleamine 2,3-dioxygenase (IDO) inhibitor
NCT02460367 (1/2)
Combination
NSCLC
AMG 820
Colony-stimulating factor 1 receptor (CSF1R)
NCT02713529 (1/2)
Combination
NSCLC
PF-05082566
4-1BB agonist
NCT02315066 (1)
Combination
NSCLC/SCLC
PBF-509
Adenosine A2a
NCT02403193 (1/2)
Combination
NSCLC
CPI-444
NCT02655822 (1)
Combination
NSCLC
PF-04518600
Anti-OX40 mAb
NCT02315066 (1)
Combination
NSCLC/SCLC
JNJ-61610588
Anti-VISTA
NCT02671955 (1)
Monotherapy
NSCLC/SCLC
PDR001
Anti-PD1
NCT02460224 (1/2)
Combination
NSCLC/SCLC
CA-170
Oral PDL1/PDL2/VISTA inhibitor
NCT02812875 (1)
Monotherapy
NSCLC/SCLC
Avelumab
PD- L1 inhibitor
Combination
NSCLC
Varlilumab
Anti-CR27 mAb
NCT02335918 (1)
Combination
NSCLC
JNJ-64457107
Anti- CD40
NCT02829099 (1)
Monotherapy
NSCLC/SCLC
Modified T cell therapy
TIL
Tumor infiltrating lymphocytes
Monotherapy
NSCLC
DC-CTL
Combined dendritic cells- cytotoxic t lymphocyte
NCT02766348 (2)
Monotherapy
NSCLC
NCT02886897 (1/2)
Combination
NSCLC
IMMUNICELL®
Autologous γδ- T lymphocytes
NCT02459067 (2/3)
Monotherapy
NSCLC
MAGE A10c796T
Chimeric antigen receptor T lymphocytes
NCT02592577 (1/2)
Monotherapy
NSCLC
NY-ESO-1c259T
NCT02588612 (1/2)
Monotherapy
NSCLC
ANTI-MUC1 CAR T
NCT02587689 (1/2)
Monotherapy
NSCLC
PD1 knockout cells
Modified T cell therapy
Monotherapy
NSCLC
Targeted NK cells
Modified NK cell therapy
NCT02118415 (2)
Monotherapy
NSCLC
NCT02845856 (1/2)
Combination
NSCLC
WT1-TCRC4-T cells
WT1 targeted t cells
NCT02408016 (1/2)
Monotherapy
NSCLC
Cytokines
rSIFN-co
Recombinant interferon
NCT02387307 (1)
Monotherapy
NSCLC
ALT-803
IL- 15 agonist
NCT02523469 (1/2)
Combination
NSCLC
AM0010
Pegylated IL-10
NCT02009449 (1)
Monotherapy
NSCLC
AAT-007
Prostaglandin E receptor subtype 4
NCT02538432 (2)
Monotherapy
NSCLC
Poly-ICL
Toll-like receptor agonist
NCT02661100 (1/2)
Combination
NSCLC/SCLC
VTX-2337
NCT02650635 (1)
Monotherapy
NSCLC
L19-IL2
Antibody cytokine fusion protein
NCT02735850 (2)
Combination
NSCLC
CDX-1401
DEC-205/NY-eso-1 fusion protein
NCT02661100 (1/2)
Combination
NSCLC/SCLC
Targeted therapy
EGFR inhibitors
ABBV-221
EGFR
NCT02365662 (1)
Monotherapy
NSCLC
AC0010MA
EGFR T790M
NCT02448251 (1/2)
Monotherapy
NSCLC
Tesevatinib
EGFR (CNS penetrant)
NCT02616393 (2)
Monotherapy
NSCLC
JNJ-61186372
EGFR/MET bispecific mAb
NCT02609776 (1)
Monotherapy
NSCLC
AP32788
EGFR exon 20
NCT02716116 (1/2)
Monotherapy
NSCLC
MM-151 and MM-121
EGFR mAb
NCT02538627 (1)
Monotherapy
NSCLC
TargomiRs
EGFR ab bound mir-16
Monotherapy
NSCLC
Multi-kinase inhibitors
Navitoclax
Bcl-2, Bcl-x, Bcl-w
NCT02520778 (1)
Combination
NSCLC
CT-707
ALK, FAK, Pyk2
NCT02695550 (1)
Monotherapy
NSCLC
Famitinib
c-Kit, VEGFR2, PDGFR, VEGFR3, FLT1, FLT3
NCT02356991 (2)
Monotherapy
NSCLC
NCT02364362 (1)
Combination
NSCLC
MGCD516
VEGFR, PDGFR, DDR2, TRK and Eph families
NCT02219711 (1)
Monotherapy
NSCLC/SCLC
Pexidartinib
Kit, FLT3, CAF1r
NCT02452424 (1/2)
Combination
NSCLC
Anlotinib
VEGF1/2/3, FGFR2
NCT02388919 (2/3)
Monotherapy
NSCLC
Entrectinib
NTRK1/2/3, ROS1, ALK
Monotherapy
NSCLC
ASP2215
Axl, FLT3
NCT02495233 (1/2)
Combination
NSCLC/SCLC
PI3K/mTOR pathway inhibitors
MLN1117
PI3K
NCT02393209 (1/2)
Combination
NSCLC
AZD8186
Monotherapy
NSCLC
LY3023414
PI3K, mTOR
NCT02443337 (2)
Combination
NSCLC
Other miscellaneous target inhibitors
LEE011
CDK 4/6
NCT02292550 (1/2)
Combination
NSCLC
Abemaciclib
NCT02308020 (2)
Monotherapy
NSCLC
NCT02779751 (2)
Monotherapy
NSCLC
NCT02079636 (1)
Combination
NSCLC
INK128
TORC1/2
Combination
NSCLC
Alisertib
Aurora kinase inhibitor
NCT01471964 (1/2)
Combination
NSCLC
Ibrutinib
BTK
NCT02321540 (1/2)
Monotherapy
NSCLC
TAK-659
Syk
NCT02834247 (1)
Combination
NSCLC
Pyrotinib
HER2
NCT02535507 (2)
Monotherapy
NSCLC
EphB4-HSA
sEphB4
Combination
NSCLC
Ficlatuzumab
Hepatocyte growth factor (HGF)
NCT02318368 (2)
Combination
NSCLC
AMG 479
IGFR-1
NCT01061788 (1)
Combination
NSCLC/SCLC
MM-121
HER3
Combination
NSCLC
Defactinib
Focal adhesion kinase (FAK)
NCT02758587 (1/2)
Combination
NSCLC
JNJ-42756493
FGFR
Monotherapy
NSCLC
INCB054828
NCT02393248 (1/2)
Monotherapy
NSCLC/SCLC
LOXO-101
NTRK1/2/3
NCT02576431 (2)
Monotherapy
NSCLC/SCLC
RXDX-101
NCT02097810 (1)
Monotherapy
NSCLC/SCLC
Rh-endostatin
NCT02375022 (2)
Combination
NSCLC
Cediranib
NCT02498613 (2)
Combination
NSCLC/SCLC
GSK3052230
FGF ligand trap
NCT01868022 (1)
Combination
NSCLC/SCLC
TRC105
Endoglin (CD105)
NCT02429843 (1)
Combination
NSCLC
MEK162
MEK
NCT01859026 (1)
Combination
NSCLC
PD-0325901
NCT02022982 (1/2)
Combination
NSCLC
Selumetinib
RAS/RAF/MEK/ERK
NCT01586624 (1)
Combination
NSCLC
Pacritnib
JAK2
NCT02342353 (1/2)
Monotherapy
NSCLC
AT13387
Heat shock protein 90
NCT02535338 (1/2)
Combination
NSCLC
AUY922
NCT01922583 (2)
Monotherapy
NSCLC
NCT01854034 (2)
Monotherapy
NSCLC
Galunisertib
TGFβ signaling
NCT02423343 (1/2)
Combination
NSCLC/SCLC
MSC2156119J
MET
NCT01982955 (1/2)
Combination
NSCLC
Ralimetinib
MAPK
NCT02860780 (1)
Combination
NSCLC/SCLC
LTT462
NCT02711345 (1)
Monotherapy
NSCLC
PF-06671008
P-cadherin
NCT02659631 (1)
Monotherapy
NSCLC/SCLC
BGB324
Axl
NCT02424617 (1/2)
Combination
NSCLC
DNA repair
VX790
ATR
NCT02487095 (1/2)
Combination
SCLC
Veliparib
PARP
NCT01386385 (1/2)
Combination
NSCLC
Olaparib
NCT02498613 (2)
Combination
NSCLC/SCLC
Chemotherapy
Plinabulin
Tubulin-depolymerization
NCT02846792 (1/2)
Combination
NSCLC
Combination
NSCLC
PT-112
Platinum based
NCT02884479 (1/2)
Combination
NSCLC/SCLC
NC-6004
Micellar nanoparticle-encapsulated cisplatin
NCT02240238 (1/2)
Combination
NSCLC
EC1456
Folic acid-tubulysin conjugate
NCT01999738 (1)
Monotherapy
NSCLC/SCLC
Oncolytic virus
CVA21
Coxsackievirus A21
Monotherapy
NSCLC
NCT02824965 (1)
Combination
NSCLC
ALK anaplastic lymphoma kinase, ATR ataxia telangiectasia and Rad3-related protein, AXL AXL receptor tyrosine kinase, BTK Bruton’s tyrosine kinase, CDK 4/6 cyclin-dependent kinase 4/6, CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1, dUTPase deoxyuridine triphophatase, FAK focal adhesion kinase, FGF fibroblast growth factor, FLT1/3 fms-like tyrosine kinase 1/3, c-Kit proto-oncogene c-Kit, Her2 human epidermal growth factor receptor 2, HLA human leukocyte antigen, IGFR insulin-like growth factor receptor, JAK2 Janus kinase 2, MAGEA3 melanoma-associated antigen 3, MAPK mitogen-activated protein kinase, MEK mitogen-activated protein kinase kinase, mTOR mammalian target of rapamycin, NTRK3 neurotrophic tyrosine kinase, PARP poly ADP ribose polymerase, PDGFR platelet-derived growth factor receptor, PI3K phosphatidylinositide 3-kinases, sEphB4 soluble extracellular domain of EphB4, Syk spleen tyrosine kinase, VEGFR vascular endothelial growth factor receptor, VISTA V-domain Ig suppressor of T cell activation, WT1 Wilms’ tumor protein

Conclusions

Oncology is changing at a fast pace, and improved outcomes are being observed in most human malignancies. Until now, lung cancer has lagged behind, but novel targeted agents and immunotherapies have shown promising results for this common and aggressive cancer. The rapid development of novel agents targeting those molecular driver alterations in lung cancer will likely further improve the clinical outcomes. The combination of agents that target non-overlap pathways will likely provide additive or synergistic activities. Many studies are ongoing to test new targets for immunotherapy such as inhibitory molecules TIM-3, LAG-3, IDO (Indoleamine-pyrrole 2,3-dioxygenase), BTLA (B- and T-lymphocyte attenuator), adenosine, VISTA (V-domain immunoglobulin containing suppressor of T cell activation), and stimulatory molecules such as 4-1BB, OX40, CD40, and CD27. A great number of clinical studies are underway to test the clinical activities of various immunotherapy combination strategies in different settings. However, there are challenges to conquer. Treatment with target agents inevitably leads to drug resistance. Understanding the resistance mechanisms and developing novel agents or strategies targeting the resistant tumors are largely need. Although immunotherapy has shown durable response in some patients, the majority of patients do not benefit. Immunohistochemistry staining of PD-L1 on tumor cells is extensively studied but still remains as unperfect biomarker. Discovery of new biomarkers or combination of biomarkers are required to guide the selection of patients who most likely benefit from treatment to avoid unnecessary costs and toxicities. Many pre-clinical and clinical studies are ongoing to address these needs.

Acknowledgements

None.

Funding

None applicable.

Availability of data and materials

The material supporting the conclusion of this review has been included within the article.

Authors’ contributions

YL designed the study. BD and YL drafted the manuscript. WH and AS participated in the manuscript preparation and revisions. BD and YL designed and finalized the figure. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

This is not applicable for this review.

Ethics approval and consent to participate

This is not applicable for this review.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

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