Introduction
Trabectedin in soft tissue sarcomas
Thomas Brodowicz*
ABSTRACT Trabectedin (Yondelis®; PharmaMar, Madrid, Spain), a synthetic anticancer agent originally isolated from the Caribbean tunicate, Ecteinascidia turbinata, is currently approved in more than 70 countries worldwide for the treatment of soft tissue sarcoma (STS). Trabectedin is an isoquinoline alkylating agent that, unlike other alkylating agents, binds in the DNA minor groove to initiate cytotoxic activity. Other multitarget mechanisms of action of trabectedin include important effects within the tumor microenvironment; in particular, trabectedin possesses indirect anti-inflammatory and anti-angiogenic activity via tumorassociated macrophages and high-specificity modulation of various transcription factors. The clinical efficacy of trabectedin, administered intravenously over 24 h every 3 weeks, has been demonstrated in several studies in patients with STS. In the Phase II STS-201 trial, 270 patients with liposarcoma or leiomyosarcoma were randomized to receive trabectedin 1.5 mg/m2 given as a 24-h intravenous (iv.) infusion every 3 weeks or as a weekly regimen (0.58 mg/m2; 3-h iv. infusion for three consecutive weeks in a 4-week cycle). There was a statistically significant and clinically relevant 27% reduction in the risk of disease progression (primary end point) with trabectedin given as a 24-h infusion q3w (p = 0.0302) with an overall survival rate at 12 months of 60%. Trabectedin was generally well tolerated; the most frequently reported severe adverse events were neutropenia (47% of patients) and elevated transaminases (47%). Overall, the majority of adverse events were mild to moderate and, despite a long duration of exposure to trabectedin in some patients, no cumulative toxicities were experienced. Trabectedin (Yondelis®; PharmaMar, Madrid, Spain) is a synthetic marine-derived anticancer agent originally isolated from the Caribbean tunicate, Ecteinascidia turbinata [1] . Currently approved in 70 countries worldwide, trabectedin was first approved by the EMA in 2007 for the treatment of advanced soft tissue sarcoma (STS) and, in September 2009, for use in combination with pegylated liposomal doxorubicin for relapsed platinum-sensitive ovarian cancer.
Keywords
• cytotoxic drugs
• trabectedin • tumorassociated macrophages • tumor micro-environment
Trabectedin is a multitarget agent Trabectedin, an isoquinoline, is an atypical alkylating agent. Unlike classical alkylating anticancer agents (e.g., cisplatin, melphalan, mechlorethamine, busulfan, chlorambucil, cyclophosphamide and nitrosoureas), which bind to the major DNA groove, trabectedin binds to the guanine-N2 position in the DNA minor groove, inducing a distortion of the double helix structure and causing double-strand breaks, which result in tumor cell apoptosis. A part of the molecule protrudes from the DNA, which is likely to be important for interaction with DNA binding proteins [2] . In addition to binding to the DNA minor groove, trabectedin has a *Clinical Division of Oncology, Department of Medicine 1, Comprehensive Cancer Center – MusculoSkeletal Tumors, Medical University Vienna – General Hospital, Vienna, Austria; Tel.: +43 140 400 4466; [email protected]
10.2217/FON.14.117 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(8 Suppl.) 1–5
part of
ISSN 1479-6694
1
Introduction Brodowicz unique mechanism of action via various molecular actions in tumor cells and in the tumor microenvironment [3] . DNA repair mechanisms are important for sensitivity to drugs that interact with DNA. In the case of trabectedin, nucleotide excisional repair (NER) and homologous recombination repair (HRR) are of importance. In contrast to other DNA-damaging agents, NER-deficient cells are two to ten-times less sensitive to trabectedin, indicating that its effects are at least partly facilitated by the cell repair system itself. The portion of the trabectedin molecule that protrudes after binding to DNA is able to bind to the XPG protein which is recruited to the damaged site of the DNA when recognized Aerobic glycolysis inhibitors
by NER. Cells with HRR deficiencies, such as BRCA1 or BRCA2 mutations, are more sensitive to trabectedin [3] . As a consequence of trabectedin covalently binding to the DNA minor groove, structural changes occur in the molecule that block the binding targets of transcription factors, altering the transcription profile of cells. Oncogenes in cancer cells are particularly sensitive to the effect of trabectedin. Displacement of transcription factors also leads to changes in processes, such as differentiation of adipocytes, which is abnormally interrupted in liposarcoma cells. Displacement of the fusion protein from its target in the DNA restores the differentiation process and normalizes the tissue. Thus, trabectedin causes
Cyclin-dependent kinase inhibitors
Trabectedin Aerobic glycolysis inhibitors
Sustaining proliferative signaling
Evading growth suppressors
Immune activating anti-CTLA4 mAb
Deregulating cellular energetics
Proapoptotic BH3 mimetics
Avoiding immune destruction
Enabling replicative immortality
Resisting cell death
Tumorpromoting inflammation
Genome instability & mutation Inducing angiogenesis
PARP inhibitors
Activating invasion & metastasis
Telomerase inhibitors
Trabectedin
Selective antiinflammatory drugs
Trabectedin
Inhibitors of VEGF signaling
Inhibitors of HGF/c-Met
Figure 1. Trabectedin is a multi-target antitumor agent. Redrawn with permission from [10].
2
Future Oncol. (2014) 10(8 Suppl.)
future science group
Trabectedin in soft-tissue sarcomas DNA breakage, displaces transcription factors and fusion proteins from their targets, and modulates gene transcription. This is a unique mechanism for a DNA interacting agent that results in cell cycle block, inhibition of growth and cell death [3] . Trabectedin demonstrates in vitro and in vivo effects on the tumor microenvironment that are mediated mainly by tumor-associated macrophages (TAMs) and monocytes. A recent publication by Germano et al. provided experimental evidence that the in vivo therapeutic effect of trabectedin results partially from targeting TAMs [4] . TAMs have limited cytotoxic activity against neoplastic cells but, rather, influence fundamental aspects of tumor biology. Some well-documented pro-tumoral functions of TAMs include the production of numerous growth factors (EGF, FGF and VEGF) for tumor cells and nascent blood and lymphatic vessels that are essential for neo-angiogenesis and tumor proliferation [5] . TAMs also produce proteolytic enzymes that degrade the extracellular matrix, thus facilitating neoplastic cell invasion, and contribute to the ability of tumors to evade immune control by producing immunosuppressive cytokines, such as IL-10 and TGF-b. In line with such evidence, a high density of TAMs in the tumor microenvironment corresponds directly with poor prognosis for the majority of tumors [5] . Trabectedin is cytotoxic for macrophages and selectively downregulates anti-inflammatory/ protumoral cytokines. In fact, it has shown a strong cytotoxic effect on monocytes, but not on lymphocytes or thymocytes. This selective effect on the monocytic lineage has been confirmed with macrophages from human ovarian tumors; importantly, this effect is not shared by other conventional chemotherapeutic agents, such as paclitaxel, cisplatin or doxorubicin, at therapeutic doses [6,7] . Treatment with trabectedin below cytotoxic concentrations significantly decreases the production of inflammatory mediators, cytokines and growth factors by monocytes and macrophages. Mediators include CCL2 (a chemokine that attracts monocytes and macrophages within tumor cells), IL-6 (a primary inflammatory cytokine that increases tumor cell survival and locally counteracts the immunological response against the tumor), VEGF and angiopoietin 1 (both of which are important angiogenic mediators). Trabectedin
future science group
Introduction
demonstrates a selective effect for mediators as not all mediators (e.g., TNF) are inhibited [8,9] . Results from a recent study have shown that the in vivo anti-tumor response to trabectedin is mediated by TAMs [4] . Tumors were generated in mice using stable trabectedin-resistant cells lines. Unexpectedly, treatment with trabectedin led to a significant reduction in tumor growth, as compared with untreated mice. It was also observed that macrophages in the tumor microenvironment were significantly reduced. Perfusion of macrophages following each trabectedin dose led to a partial loss of response, further demonstrating the mediation of macrophages in the antitumor response to trabectedin. Tumors were explanted after treatment, and investigators confirmed that tumor cells remained resistant to trabectedin. As a result, investigators concluded that trabectedin triggers an indirect antitumor response and that this response is mediated by TAM in the tumor microenvironment [4] . Taking all the evidence into account, trabectedin can be classed as a multitarget agent. Based on the recent ‘hallmarks of cancer’ scheme by Hanahan and Weinberg [10] , trabectedin is known to induce DNA damage leading to cell cycle arrest and, eventually, to tumor cell apoptosis. Trabectedin also modulates the transcription of oncogenic fusion proteins in translocation-related sarcoma. In addition, trabectedin targets tumor inflammation and angiogenesis by means of monocytes and TAMs (Figure 1) . Trabectedin therefore represents a Table 1. Safety summary from the STS-201 trial of trabectedin at the recommended regimen†. Toxicity
Patients affected (%)
Hematological toxicity (grade 3/4) Neutropenia Thrombocytopenia Anemia Febrile neutropenia
47 11 8 0.8
Nonhematological toxicity (grade 3/4) Transaminase increase Fatigue Nausea Vomiting Creatine phosphokinase increase
47 8 5 5 5
Trabectedin (n = 130). † 1.5 mg/m2 every 3 weeks over 24 h. Data taken from [14].
www.futuremedicine.com
3
Introduction Brodowicz
Quick onset and transient
Noncumulative 6
16 15 14
5
13 12 4
10
×UNL
×UNL
11
9
3
8 7 6
2
5 4 3
1
2 1 0 Treatment [2-4] day
[5-7]
[8-10] [11-13] [14-16] [17-19] [20-22] [23-25] [26-28] [29-31]
0
1
2
Cycle day Every 3 weeks; 24 h
3
4
5
6
7
8
9
10
Cycle Every 3 weeks; 3 h (1.5 mg/m2)
Every week; 3 h
Figure 2. Pattern of transaminase elevation with trabectedin at the recommended regimen (1.5 mg/m2 every 3 weeks over 24 h). UNL: Upper normal limit. Reproduced with permission from [16].
prototype of a new class of antitumor agent that targets cancer cells as well as the tumor microenvironment. Clinical evidence in soft tissue sarcoma The clinical efficacy of trabectedin in STS has been demonstrated in numerous Phase II clinical trials [11–14] . Approval of trabectedin in the EU was based on the randomized, multicenter, open-label STS-201 study of Demetri and colleagues. The STS-201 study compared two different trabectedin dosing regimens (1.5 mg/m 2 intravenous [iv.] over 24 h every 3 weeks (q3w 24-h) or 0.58 mg/m 2 iv. over 3 h every week for 3 out of 4 weeks) in 270 adult patients (aged ≥18 years) with liposarcoma or leiomyosarcoma [14] . Eligible patients were to have documented disease progression after failure of prior anthracycline and ifosfamide treatment. The study achieved the primary end point, showing a statistically significant (p = 0.0302) and clinically relevant 27% reduction in the risk of disease progression with trabectedin 1.5 mg/
4
Future Oncol. (2014) 10(8 Suppl.)
m 2 q3w 24-h. Although survival did not differ significantly between the dosage groups, the overall survival rate after 1 year with trabectedin in the q3w 24-h arm was 60%. The benefits in patients treated with trabectedin q3w 24-h were highlighted by progression-free survival (PFS) rates of 51.5% at 3 months and 35.5% at 6-months, which largely surpassed the threshold criteria established by the European Organization for Research and Treatment of Cancer (EORTC) to define drug activity in pretreated STS (i.e., 39% at 3 months and 14% at 6 months) [15] . As shown in Table 1, trabectedin was generally well tolerated in the STS-201 trial [14] . The most frequently reported grade 3/4 adverse events were neutropenia (47% of patients) and elevated transaminases (47%). Febrile neutropenia was rare, occurring in
Trabectedin in soft tissue sarcomas
Thomas Brodowicz*
ABSTRACT Trabectedin (Yondelis®; PharmaMar, Madrid, Spain), a synthetic anticancer agent originally isolated from the Caribbean tunicate, Ecteinascidia turbinata, is currently approved in more than 70 countries worldwide for the treatment of soft tissue sarcoma (STS). Trabectedin is an isoquinoline alkylating agent that, unlike other alkylating agents, binds in the DNA minor groove to initiate cytotoxic activity. Other multitarget mechanisms of action of trabectedin include important effects within the tumor microenvironment; in particular, trabectedin possesses indirect anti-inflammatory and anti-angiogenic activity via tumorassociated macrophages and high-specificity modulation of various transcription factors. The clinical efficacy of trabectedin, administered intravenously over 24 h every 3 weeks, has been demonstrated in several studies in patients with STS. In the Phase II STS-201 trial, 270 patients with liposarcoma or leiomyosarcoma were randomized to receive trabectedin 1.5 mg/m2 given as a 24-h intravenous (iv.) infusion every 3 weeks or as a weekly regimen (0.58 mg/m2; 3-h iv. infusion for three consecutive weeks in a 4-week cycle). There was a statistically significant and clinically relevant 27% reduction in the risk of disease progression (primary end point) with trabectedin given as a 24-h infusion q3w (p = 0.0302) with an overall survival rate at 12 months of 60%. Trabectedin was generally well tolerated; the most frequently reported severe adverse events were neutropenia (47% of patients) and elevated transaminases (47%). Overall, the majority of adverse events were mild to moderate and, despite a long duration of exposure to trabectedin in some patients, no cumulative toxicities were experienced. Trabectedin (Yondelis®; PharmaMar, Madrid, Spain) is a synthetic marine-derived anticancer agent originally isolated from the Caribbean tunicate, Ecteinascidia turbinata [1] . Currently approved in 70 countries worldwide, trabectedin was first approved by the EMA in 2007 for the treatment of advanced soft tissue sarcoma (STS) and, in September 2009, for use in combination with pegylated liposomal doxorubicin for relapsed platinum-sensitive ovarian cancer.
Keywords
• cytotoxic drugs
• trabectedin • tumorassociated macrophages • tumor micro-environment
Trabectedin is a multitarget agent Trabectedin, an isoquinoline, is an atypical alkylating agent. Unlike classical alkylating anticancer agents (e.g., cisplatin, melphalan, mechlorethamine, busulfan, chlorambucil, cyclophosphamide and nitrosoureas), which bind to the major DNA groove, trabectedin binds to the guanine-N2 position in the DNA minor groove, inducing a distortion of the double helix structure and causing double-strand breaks, which result in tumor cell apoptosis. A part of the molecule protrudes from the DNA, which is likely to be important for interaction with DNA binding proteins [2] . In addition to binding to the DNA minor groove, trabectedin has a *Clinical Division of Oncology, Department of Medicine 1, Comprehensive Cancer Center – MusculoSkeletal Tumors, Medical University Vienna – General Hospital, Vienna, Austria; Tel.: +43 140 400 4466; [email protected]
10.2217/FON.14.117 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(8 Suppl.) 1–5
part of
ISSN 1479-6694
1
Introduction Brodowicz unique mechanism of action via various molecular actions in tumor cells and in the tumor microenvironment [3] . DNA repair mechanisms are important for sensitivity to drugs that interact with DNA. In the case of trabectedin, nucleotide excisional repair (NER) and homologous recombination repair (HRR) are of importance. In contrast to other DNA-damaging agents, NER-deficient cells are two to ten-times less sensitive to trabectedin, indicating that its effects are at least partly facilitated by the cell repair system itself. The portion of the trabectedin molecule that protrudes after binding to DNA is able to bind to the XPG protein which is recruited to the damaged site of the DNA when recognized Aerobic glycolysis inhibitors
by NER. Cells with HRR deficiencies, such as BRCA1 or BRCA2 mutations, are more sensitive to trabectedin [3] . As a consequence of trabectedin covalently binding to the DNA minor groove, structural changes occur in the molecule that block the binding targets of transcription factors, altering the transcription profile of cells. Oncogenes in cancer cells are particularly sensitive to the effect of trabectedin. Displacement of transcription factors also leads to changes in processes, such as differentiation of adipocytes, which is abnormally interrupted in liposarcoma cells. Displacement of the fusion protein from its target in the DNA restores the differentiation process and normalizes the tissue. Thus, trabectedin causes
Cyclin-dependent kinase inhibitors
Trabectedin Aerobic glycolysis inhibitors
Sustaining proliferative signaling
Evading growth suppressors
Immune activating anti-CTLA4 mAb
Deregulating cellular energetics
Proapoptotic BH3 mimetics
Avoiding immune destruction
Enabling replicative immortality
Resisting cell death
Tumorpromoting inflammation
Genome instability & mutation Inducing angiogenesis
PARP inhibitors
Activating invasion & metastasis
Telomerase inhibitors
Trabectedin
Selective antiinflammatory drugs
Trabectedin
Inhibitors of VEGF signaling
Inhibitors of HGF/c-Met
Figure 1. Trabectedin is a multi-target antitumor agent. Redrawn with permission from [10].
2
Future Oncol. (2014) 10(8 Suppl.)
future science group
Trabectedin in soft-tissue sarcomas DNA breakage, displaces transcription factors and fusion proteins from their targets, and modulates gene transcription. This is a unique mechanism for a DNA interacting agent that results in cell cycle block, inhibition of growth and cell death [3] . Trabectedin demonstrates in vitro and in vivo effects on the tumor microenvironment that are mediated mainly by tumor-associated macrophages (TAMs) and monocytes. A recent publication by Germano et al. provided experimental evidence that the in vivo therapeutic effect of trabectedin results partially from targeting TAMs [4] . TAMs have limited cytotoxic activity against neoplastic cells but, rather, influence fundamental aspects of tumor biology. Some well-documented pro-tumoral functions of TAMs include the production of numerous growth factors (EGF, FGF and VEGF) for tumor cells and nascent blood and lymphatic vessels that are essential for neo-angiogenesis and tumor proliferation [5] . TAMs also produce proteolytic enzymes that degrade the extracellular matrix, thus facilitating neoplastic cell invasion, and contribute to the ability of tumors to evade immune control by producing immunosuppressive cytokines, such as IL-10 and TGF-b. In line with such evidence, a high density of TAMs in the tumor microenvironment corresponds directly with poor prognosis for the majority of tumors [5] . Trabectedin is cytotoxic for macrophages and selectively downregulates anti-inflammatory/ protumoral cytokines. In fact, it has shown a strong cytotoxic effect on monocytes, but not on lymphocytes or thymocytes. This selective effect on the monocytic lineage has been confirmed with macrophages from human ovarian tumors; importantly, this effect is not shared by other conventional chemotherapeutic agents, such as paclitaxel, cisplatin or doxorubicin, at therapeutic doses [6,7] . Treatment with trabectedin below cytotoxic concentrations significantly decreases the production of inflammatory mediators, cytokines and growth factors by monocytes and macrophages. Mediators include CCL2 (a chemokine that attracts monocytes and macrophages within tumor cells), IL-6 (a primary inflammatory cytokine that increases tumor cell survival and locally counteracts the immunological response against the tumor), VEGF and angiopoietin 1 (both of which are important angiogenic mediators). Trabectedin
future science group
Introduction
demonstrates a selective effect for mediators as not all mediators (e.g., TNF) are inhibited [8,9] . Results from a recent study have shown that the in vivo anti-tumor response to trabectedin is mediated by TAMs [4] . Tumors were generated in mice using stable trabectedin-resistant cells lines. Unexpectedly, treatment with trabectedin led to a significant reduction in tumor growth, as compared with untreated mice. It was also observed that macrophages in the tumor microenvironment were significantly reduced. Perfusion of macrophages following each trabectedin dose led to a partial loss of response, further demonstrating the mediation of macrophages in the antitumor response to trabectedin. Tumors were explanted after treatment, and investigators confirmed that tumor cells remained resistant to trabectedin. As a result, investigators concluded that trabectedin triggers an indirect antitumor response and that this response is mediated by TAM in the tumor microenvironment [4] . Taking all the evidence into account, trabectedin can be classed as a multitarget agent. Based on the recent ‘hallmarks of cancer’ scheme by Hanahan and Weinberg [10] , trabectedin is known to induce DNA damage leading to cell cycle arrest and, eventually, to tumor cell apoptosis. Trabectedin also modulates the transcription of oncogenic fusion proteins in translocation-related sarcoma. In addition, trabectedin targets tumor inflammation and angiogenesis by means of monocytes and TAMs (Figure 1) . Trabectedin therefore represents a Table 1. Safety summary from the STS-201 trial of trabectedin at the recommended regimen†. Toxicity
Patients affected (%)
Hematological toxicity (grade 3/4) Neutropenia Thrombocytopenia Anemia Febrile neutropenia
47 11 8 0.8
Nonhematological toxicity (grade 3/4) Transaminase increase Fatigue Nausea Vomiting Creatine phosphokinase increase
47 8 5 5 5
Trabectedin (n = 130). † 1.5 mg/m2 every 3 weeks over 24 h. Data taken from [14].
www.futuremedicine.com
3
Introduction Brodowicz
Quick onset and transient
Noncumulative 6
16 15 14
5
13 12 4
10
×UNL
×UNL
11
9
3
8 7 6
2
5 4 3
1
2 1 0 Treatment [2-4] day
[5-7]
[8-10] [11-13] [14-16] [17-19] [20-22] [23-25] [26-28] [29-31]
0
1
2
Cycle day Every 3 weeks; 24 h
3
4
5
6
7
8
9
10
Cycle Every 3 weeks; 3 h (1.5 mg/m2)
Every week; 3 h
Figure 2. Pattern of transaminase elevation with trabectedin at the recommended regimen (1.5 mg/m2 every 3 weeks over 24 h). UNL: Upper normal limit. Reproduced with permission from [16].
prototype of a new class of antitumor agent that targets cancer cells as well as the tumor microenvironment. Clinical evidence in soft tissue sarcoma The clinical efficacy of trabectedin in STS has been demonstrated in numerous Phase II clinical trials [11–14] . Approval of trabectedin in the EU was based on the randomized, multicenter, open-label STS-201 study of Demetri and colleagues. The STS-201 study compared two different trabectedin dosing regimens (1.5 mg/m 2 intravenous [iv.] over 24 h every 3 weeks (q3w 24-h) or 0.58 mg/m 2 iv. over 3 h every week for 3 out of 4 weeks) in 270 adult patients (aged ≥18 years) with liposarcoma or leiomyosarcoma [14] . Eligible patients were to have documented disease progression after failure of prior anthracycline and ifosfamide treatment. The study achieved the primary end point, showing a statistically significant (p = 0.0302) and clinically relevant 27% reduction in the risk of disease progression with trabectedin 1.5 mg/
4
Future Oncol. (2014) 10(8 Suppl.)
m 2 q3w 24-h. Although survival did not differ significantly between the dosage groups, the overall survival rate after 1 year with trabectedin in the q3w 24-h arm was 60%. The benefits in patients treated with trabectedin q3w 24-h were highlighted by progression-free survival (PFS) rates of 51.5% at 3 months and 35.5% at 6-months, which largely surpassed the threshold criteria established by the European Organization for Research and Treatment of Cancer (EORTC) to define drug activity in pretreated STS (i.e., 39% at 3 months and 14% at 6 months) [15] . As shown in Table 1, trabectedin was generally well tolerated in the STS-201 trial [14] . The most frequently reported grade 3/4 adverse events were neutropenia (47% of patients) and elevated transaminases (47%). Febrile neutropenia was rare, occurring in
