Expert Opinion on Pharmacotherapy
ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20
New drugs in sarcomas Juan Martin-Liberal, Charlotte Benson & Ian Judson To cite this article: Juan Martin-Liberal, Charlotte Benson & Ian Judson (2014) New drugs in sarcomas, Expert Opinion on Pharmacotherapy, 15:2, 221-229 To link to this article: http://dx.doi.org/10.1517/14656566.2014.865015
Published online: 25 Nov 2013.
Submit your article to this journal
Article views: 336
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieop20 Download by: [Monash University Library]
Date: 10 November 2015, At: 16:57
Review
New drugs in sarcomas Juan Martin-Liberal†, Charlotte Benson & Ian Judson
Downloaded by [Monash University Library] at 16:57 10 November 2015
The Royal Marsden Hospital, Sarcoma Unit, London, UK 1.
Introduction
2.
Pazopanib in soft-tissue sarcomas
3.
Regorafenib in GIST
4.
Muramyl tripeptide in osteosarcoma
5.
Ridaforolimus as maintenance treatment
6.
Other active drugs
7.
Conclusions
8.
Expert opinion
Introduction: Adult sarcomas are rare tumors characterized, in general, by their poor prognosis and the paucity of effective treatments. However, the deeper understanding of their underlying molecular pathology, signaling pathways and key effectors has permitted the development of a number of drugs able to inhibit important processes in sarcoma pathogenesis. Some of these novel compounds have been assessed in clinical trials with successful results. Areas covered: The latest reported trials are comprehensively reviewed. Thus, the Phase III studies with pazopanib, regorafenib, muramyl tripeptide (MTP) and ridaforolimus are extensively discussed as well as the biological rationale for the use of these compounds. In addition, the most promising drugs that still are in earlier stages of development such as CDK4 and MDM2 inhibitors, cediranib, eribulin and crizotinib are also discussed. Expert opinion: It is crucial for the correct identification of active drugs in sarcomas that new clinical trials are focused on specific subtypes and/or molecular alterations. The results of these studies should improve the prognosis of the patients affected by sarcoma in forthcoming years. Keywords: CDK4, cediranib, crizotinib, eribulin, GIST, MDM2, muramyl tripeptide, osteosarcoma, pazopanib, ridaforolimus, soft-tissue sarcoma Expert Opin. Pharmacother. (2014) 15(2):221-229
1.
Introduction
Sarcomas are a rare group of malignancies of mesenchymal origin. In spite of this common feature, the name ‘sarcoma’ encompasses > 50 different entities with differing molecular biology, clinical behavior, responsiveness to treatment and prognosis. They can affect patients of all ages, although certain specific subtypes are more frequent in children and young adults. Almost every part of the body may be involved, either bone or soft tissue. In spite of this heterogeneity, in the majority of cases adult sarcomas are characterized by the lack of effective treatments in the metastatic setting. Thus, with the exception of a few histologies, the most active drugs in adult sarcomas only achieve a response rate (RR) of 20 -- 30% or even lower depending on the series [1,2]. Moreover, nearly half of all patients diagnosed with adult sarcomas will develop metastases even if they are diagnosed at an early stage [3]. As a result of the low efficacy of the drugs currently available, the median overall survival (OS) of an advanced adult sarcoma patient is just 1 year [4]. Therefore, it is necessary to identify new active drugs to improve the outcome of patients affected by this disease. In the past two decades, a number of novel drugs have been developed in oncology. Unfortunately, only a few of these new compounds have achieved successful results in sarcomas with imatinib for gastro-intestinal stromal tumor (GIST) being the most important example [5,6]. However, great advances have recently been made in the understanding of the molecular biology of sarcoma [7]. The deeper understanding of some relevant pathways and their key effectors has permitted the development of a number of drugs able to inhibit important processes in sarcoma pathogenesis. Consequently, some of these novel compounds have been assessed in clinical trials with successful results. Thus, anti-angiogenic drugs, inhibitors of 10.1517/14656566.2014.865015 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
221
J. Martin-Liberal et al.
Article highlights. . .
.
.
Downloaded by [Monash University Library] at 16:57 10 November 2015
.
.
Adult sarcomas are rare tumors with generally bad prognosis and lack of effective treatments. There are > 50 different subtypes of sarcoma, each of them with its own molecular characteristics, clinical behavior and responsiveness to treatment. The increasing understanding of the biology of sarcomas has permitted the development of a series of new active drugs. Pazopanib, regorafenib, muramyl tripeptide and ridaforolimus have demonstrated activity in sarcoma in Phase III trials. CDK4 and MDM2 inhibitors, cediranib, eribulin and crizotinib have shown promising results that deserve further investigation. It is crucial for the correct identification of active drugs in sarcomas the development of new clinical trials focused on specific subtypes and/or molecular alterations.
This box summarizes key points contained in the article.
the mammalian target of rapamycin (mTOR), multi-tyrosine kinase inhibitors (TKIs) or immune system modulators, among others, have been recently found to be active drugs against sarcomas [8]. The aim of this article is to perform an extensive review of the most recent drugs that have shown clinically relevant positive results in sarcomas (except carcinosarcoma). Also, we will provide a view of the future therapeutic strategies that will hopefully have an impact on the survival of patients affected by these malignancies.
2.
Pazopanib in soft-tissue sarcomas
Rationale Angiogenesis is one of the most relevant processes in cancer. It is driven by a series of complex interactions among the different factors in charge of its regulation. The formation of new blood vessels is necessary for the growth of every tumor, without which small metastatic tumors cannot progress beyond about 200 µm. Sarcomas are no exception to these general principles. Some of the key effectors of these mechanisms are well-described pro-angiogenic substances, such as vascular endothelial growth factor 1 (VEGF) and the VEGF receptor isoforms (VEGFR-1, VEGFR-2 and VEGFR-3). Several studies have assessed the role of VEGF in sarcomas in recent years. Thus, a study by Potti et al. correlated serum levels of VEGF with clinical outcome. Significant overexpression of VEGF was found in 68 of 273 patients (24.9%). Higher expression of VEGF was detected in pleomorphic undifferentiated sarcoma (previously known as malignant fibrous histiocytoma) (30%), carcinosarcoma (30%), leiomyosarcoma (25%) and dermatofibrosarcoma (20%). Interestingly, overexpression of VEGF had prognostic value only in
leiomyosarcoma and these patients were found to have a significantly shorter survival [9]. Another study determined VEGF serum levels preoperatively in 85 patients affected by soft-tissue sarcomas (STS). This examined the relationship between VEGF and tumor grade. It was found that the least well-differentiated tumors had the highest VEGF levels, proposing VEGF in serum as a biomarker of tumor aggressiveness [10]. Similar results were observed in a larger prospective series of 144 patients in which serum levels of VEGF were found to have significant correlation not only with grade, but also with response to treatment [11]. One additional study supported these findings in tumor samples. Thus, in a 2001 paper by Chao et al., VEGF overexpression in paraffin-embedded tissue of surgical specimens from 79 patients with STS also correlated with high tumor grade. Furthermore, 78% of patients who died of disease (29 out of 37) had high VEGF expression [12]. In addition, another study analyzed the expression of VEGF by immunohistochemistry (IHC) in tissue from 27 cases of thoracic sarcomas. The results showed that disease-free survival (DFS) in patients with strong tumor VEGF expression was significantly poorer compared with those with lower VEGF expression [13]. But VEGF is not the only important factor controlling angiogenesis. It is well known that its interaction with VEGFR-2 is the most crucial step in the process [14]. In addition, a recent study also proposed VEGFR-3 as a prognostic factor in STS. Thus, Kilvaer et al. constructed tissue microarrays from tumor samples of 249 patients with STS in which the expression of several angiogenesis effectors was determined by IHC. High expression of VEGFR-3 was found to be an independent significant negative prognostic marker for disease-specific survival [15]. These data suggested the inhibition of the VEGF-VEGFR interaction as a potential therapeutic target in sarcomas.
2.1
222
Clinical experience Pazopanib is a new TKI with potent anti-angiogenic effects due to its affinity for the key effectors VEGFR-1, VEGFR-2 and VEGFR-3. In addition, it is also able to inhibit other relevant tyrosine kinases such as KIT or the platelet-derived growth factor receptors a and b (PDGFRA and PDGFRB) [16]. Pazopanib is the first anti-angiogenic drug that has proven to be effective in a large randomized Phase III trial in sarcoma [17]. The first encouraging clinical results were reported in a Phase II trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC). A total of 142 patients with intermediate or high-risk advanced STS who had received up to 2 prior lines of treatment were enrolled. They were stratified in four different groups: adipocytic STS, leiomyosarcomas, synovial sarcomas and other STS types. Pazopanib failed to show convincing activity in the adipocytic STS cohort but achieved encouraging results in the remaining groups. Progressionfree survival (PFS) rates at 12 weeks were 44% in the 2.2
Expert Opin. Pharmacother. (2014) 15(2)
Downloaded by [Monash University Library] at 16:57 10 November 2015
New drugs in sarcomas
leiomyosarcoma cohort, 49% in synovial sarcomas and 39% in the other STS types [18]. Following this, a randomized, double-blind, placebocontrolled Phase III trial in patients with metastatic nonadipocytic STS was conducted. In total, 369 patients were treated with either pazopanib or placebo in a 2:1 randomization. In terms of efficacy, median PFS was 4.6 months for pazopanib compared with 1.6 months for placebo, with p < 0.0001. OS was also higher in the pazopanib arm although it failed to reach statistical significance. However, the real impact of pazopanib on survival may have been affected by subsequent treatment as many patients received further lines of chemotherapy after progression. As with other anti-angiogenic agents, there were some concerns about cardiotoxicity. Sixteen pazopanib-treated patients had a fall in cardiac ejection fraction compared with only three in the placebo group. Currently it is unclear to what extent uncontrolled hypertension or prior treatment with anthracyclines contributed to this toxicity but it did appear to be reversible in a proportion of patients. Other toxicities highlighted were venous thromboembolic disease and pneumothorax. Interestingly, global health and quality of life scores did not differ significantly between groups [17]. The results of this trial have established pazopanib as a new therapeutic option in non-adipocytic STS and it has been licensed by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
3.
Regorafenib in GIST
Rationale GISTs are the most frequent sarcomas of the gastro-intestinal tract [19]. Surgery is the mainstay of treatment for localized disease. However, nearly 40% of these patients will relapse [20]. When advanced disease is diagnosed, systemic treatment is required. Historically GIST was considered a chemo- and radiotherapy insensitive tumor [21]. It was not until its molecular biology began to be understood that effective therapies were developed. About 80% of all GISTs are driven by gain-of-function mutations in the proto-oncogene KIT, which encodes a tyrosine kinase receptor [22]. Less frequently, mutations in the PDGFRA gene are also responsible [23]. Following the identification of gain-of-function mutations in KIT, imatinib was tested successfully and subsequently a number of other inhibitors have been developed for the treatment of GIST. Imatinib, a TKI with activity against KIT and PDGFRA, has dramatically improved the survival of GIST patients from a median of 18 months to 5 years for patients with advanced disease [24,25]. Unfortunately, development of resistance to imatinib is a frequent occurrence owing to secondary mutations that affect its binding to KIT [26]. Sunitinib, another multi-targeted TKI, has proven clinical activity in the second-line setting after imatinib failure, although some secondary mutations generate resistance to both agents [27]. The 3.1
development of other TKIs capable of inhibiting these mutant isoforms has been an active area of research. Clinical experience Regorafenib is a novel multi-TKI, a close analog of sorafenib that blocks several pathways involved in GIST pathogenesis [28]. A single-arm Phase II trial in 34 patients previously treated with imatinib and sunitinib showed significant signs of activity. Thus, 4 and 22 patients achieved partial response (PR) and stable disease (SD) ‡ 16 weeks, respectively. In total, the clinical benefit rate (defined as PR + SD ‡ 16 weeks) was 79% and the median PFS was 10 months [29]. These promising results were confirmed in a randomized, double-blind, placebo-controlled Phase III trial. Participants were randomized to treatment with either regorafenib or placebo following failure of at least imatinib and sunitinib. On progression, patients receiving placebo were allowed to crossover to open-label regorafenib. In total, 240 patients were screened and 199 were randomized in 57 institutions. Median PFS per independent blinded central review was 4.8 and 0.9 months for regorafenib and placebo, respectively (Hazard ratio (HR) 0.27; p < 0.0001). PFS at 3 and 6 months was 60 and 38%, respectively, for regorafenib, and 11 and 0%, for placebo. In terms of response, 6 out of the 133 patients (4.5%) treated with regorafenib achieved PR. In this same group of patients, SD as best response was reported in 95 cases (71.4%). The total rate of disease control lasting for at least 12 weeks in the active treatment cohort was 52.6%. With respect to toxicity, the most common clinically significant regorafenib-related adverse events were hypertension (23%), hand-foot skin reaction (20%) and diarrhea (5%). Although dose modifications were frequent in the regorafenib group (72%), the occurrence of adverse events that led to permanent discontinuation of treatment was low (6%). In general, adverse events were manageable by dose modification without the need to discontinue treatment in the majority of cases [30]. This trial has led to the acceptance of regorafenib by the FDA and the EMA as third-line therapy in advanced GIST. 3.2
4.
Muramyl tripeptide in osteosarcoma
Rationale Osteosarcoma is the most common sarcoma of the bone. It is characterized by the production of osteoid or immature bone by proliferating spindle cells [31]. Unfortunately, nearly 20% of all patients are diagnosed with advanced disease at presentation and without adjuvant systemic treatment the majority of patients would eventually succumb to metastatic disease. However, it is generally a chemo-sensitive tumor and the RRs are higher compared with other sarcomas [32]. Moreover, adjuvant treatment has a major positive impact on survival and its use is widely accepted [33]. Muramyl tripeptide (MTP) is a synthetic analog of a component of the cell wall of bacteria, specifically Bacille 4.1
Expert Opin. Pharmacother. (2014) 15(2)
223
J. Martin-Liberal et al.
Calmette--Guerin. MTP is encapsulated in liposomes and it is delivered to monocytes and macrophages causing their activation and inducing anti-tumor activity in osteosarcoma [34,35]. It has been reported that when used concomitantly with particular chemotherapy agents such as ifosfamide there is no increase in toxicity. Also, combined therapy does not affect the stimulation of cytokines caused by MTP [36]. Therefore, there was a clear clinical rationale for the assessment of MTP-containing chemotherapy regimens in osteosarcoma. Clinical experience A large, randomized, Phase III trial to assess the activity of MTP in combination with chemotherapy in the localized setting was conducted. The study had a 2 2 factorial design and tried to answer two different questions: first, whether the addition of ifosfamide to doxorubicin, cisplatin and high-dose methotrexate (HDMTX) had any benefit in survival and, second, whether the addition of MTP to chemotherapy improved the outcome of the patients. Results showed that ifosfamide did not enhance the activity of standard chemotherapy. However, the addition of MTP proved to be beneficial, mainly in the ifosfamide arm. Thus, 662 patients without metastases and resectable primary tumors received treatment within the study. Event-free survival (EFS) rates for patients treated with chemotherapy alone were 63 and 61% at 4 and 6 years, respectively. However, EFS for the patients treated with MTP and chemotherapy was 69 and 67% at 4 and 6 years, respectively, although this improvement failed to reach statistical significance. Furthermore, the addition of MTP to chemotherapy improved OS at 6 years from 70 to 78%. This difference was statistically significant (p = 0.03) [37]. Interestingly, MTP did not improve the outcome when patients were treated in the presence of metastases [38]. The toxicity observed was consistent with the already known safety profile of the chemotherapy agents used. However, administration of MTP was associated with fever and chills. The protocol of the trial called for dose escalation of MTP until these effects were observed to assure biologic activity but most patients did not need dose escalation. Reactions to MTP decreased with time and premedication with paracetamol or ibuprofen for most patients, but fever and chills continued in some cases with each administration of MTP [39]. In spite of the statistically significant improvement in OS, MTP was denied approval by the FDA. However, it was licensed by the EMA in 2009 although it is not widely used in Europe, mainly due to its high cost.
Downloaded by [Monash University Library] at 16:57 10 November 2015
4.2
5.
Ridaforolimus as maintenance treatment
Rationale The mTOR is a serine/threonine kinase integrated in the phosphatidyl-inositol 3-kinase (PI3K) complex network of signaling. It forms part of two multiprotein complexes named mTOR complex 1 and mTOR complex 2 (mTORC1 and
mTORC2) and plays a key role in cell growth, proliferation, angiogenesis and survival. The upregulation of growth factors or mutations in tyrosine kinase receptors that belong to the mTOR network has been reported to be involved in the development of various sarcomas [40]. Furthermore, deletions of some mTOR pathway tumor suppressors such as tuberous sclerosis complex 1 and 2 (TSC1 and TSC2) and neurofibromatosis type 1 (NF1) are associated with both benign and malignant mesenchymal tumors [41,42]. A number of mTOR inhibitors derived from the parent compound rapamycin (sirolimus) have been tested both clinically and pre-clinically in sarcomas [43-47]. One of these compounds, ridaforolimus, had been confirmed to be active in cell lines and xenograft models of sarcoma. Moreover, additive inhibitory effects when combined with cytotoxic agents had also been reported [48]. These encouraging data warranted its assessment in clinical trials. Clinical experience The initial reports of the activity of ridaforolimus in sarcomas showed promising results. Thus, in a single-arm Phase II trial by Chawla et al. the clinical benefit rate in heavily pre-treated patients with advanced sarcoma was 28.8% and the median OS was 40 weeks [49]. Such interesting results led to the only Phase III trial to date with an mTOR inhibitor in sarcomas: the SUCCEED trial. This double-blind, placebo-controlled Phase III trial randomized sarcoma patients who had achieved complete response (CR), PR or SD after 1, 2 or 3 lines of chemotherapy to receive placebo or ridaforolimus as maintenance treatment. A total of 702 patients received blinded study drug. Ridaforolimus showed some signs of activity, inducing a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo. In addition, it achieved a statistically significant improvement in PFS compared with placebo in both independent and per investigator assessment. However, the magnitude of that improvement was very modest (median PFS 17.7 weeks versus 14.6 weeks per independent review), making its clinical relevance arguable. The difference in OS observed in favor of ridaforolimus (90.6 weeks versus 85.3 weeks) was not statistically significant. As expected, toxicity was more common in the ridaforolimus cohort. The most frequent adverse events observed included stomatitis 77.8%, infections 51.6%, fatigue 35.6% and thrombocytopenia 33.5%. Overall, the percentage of patients treated with ridaforolimus that had to discontinue treatment due to adverse events was 14.6% [50]. Although the clinical benefit observed in this study was modest, maintenance treatment in sarcomas is a therapeutic strategy that deserves further investigation given the short PFS achieved with the majority of conventional cytotoxic agents. 5.2
5.1
224
6.
Other active drugs
A number of other drugs in early clinical development have been reported to have promising activity in sarcomas recently.
Expert Opin. Pharmacother. (2014) 15(2)
New drugs in sarcomas
The positive results observed in several Phase II and Phase I trials need to be confirmed but these novel drugs may well represent valid therapeutic strategies in the near future. Here, we outline some of the most clinically relevant drugs currently in development. Cyclin-dependent kinase 4 and mouse double minute 2 homolog inhibitors in well-differentiated/ dedifferentiated liposarcoma
Downloaded by [Monash University Library] at 16:57 10 November 2015
6.1
Liposarcomas are one of the most frequently occurring STS. One specific subtype, well-differentiated/dedifferentiated liposarcoma (WD/DDLPS) is considered to be less sensitive to conventional chemotherapy. The genes coding for cyclindependent kinase 4 (CDK4) P16 and mouse double minute 2 homolog (MDM2) are co-amplified on 12q13-15 in nearly 90% of all WD/DDLPS [51]. Therefore, CDK4 targeting has been proposed as a therapeutic option in this subtype of liposarcoma. The CDK4 inhibitor PD0332991 has been assessed in a Phase II clinical trial in patients with progressive advanced WD/DDLPS. A total of 30 patients were enrolled and PR was seen in only 1 patient. Nevertheless, the PFS rate at 12 weeks of treatment was 66% and the median PFS was 18 weeks [52]. In another study, 20 patients received up to three cycles of neoadjuvant treatment with RG7112, an MDM2 inhibitor. PR was reported in 1 patient and 14 patients achieved SD. Moreover, RG7112 was generally well tolerated although all patients experienced at least one adverse event [53]. Cediranib in alveolar soft-part sarcoma Alveolar soft-part sarcoma (ASPS) is one of the rarest subtypes of STS. It is usually an indolent disease, with median OS of around 40 months and 5-year survival rate of 20% even in the presence of unresectable metastases [54]. Studies performed on surgical samples of ASPS have revealed upregulation of several transcripts associated with angiogenesis, which correlates with its high vascularization [55,56]. Cediranib is a TKI with high affinity for the three isoforms of VEGFR, as well as PDGFRB and to a somewhat less extent PDGFRA and fibroblast growth factor receptor 1 (FGFR1), which makes it a potent inhibitor of angiogenesis [57]. It also inhibits KIT and colony stimulating factor 1 receptor (CSF-1R). A Phase II trial with cediranib in ASPS showed that 15 out of 46 patients enrolled (35%) achieved PR and 26 patients (60%) had SD. In total, the disease control rate at 24 weeks was 84% [58]. At least two clinical trials that further assess the activity of cediranib in ASPS are currently ongoing (ClinicalTrials.gov identifiers NCT01391962 and NCT01337401). 6.2
Eribulin in liposarcoma and leiomyosarcoma Eribulin is one of the most recent drugs to have demonstrated activity against sarcomas. It is a synthetic compound originally extracted from marine sponges with anti6.3
microtubule properties. However, its mechanism of action seems to be different from other anti-microtubule drugs such as taxanes [59-61]. Promising results of its activity in STS have recently been reported. Thus, 128 patients with progressive high-grade STS who had received no more than one previous combination chemotherapy or a maximum of two single drugs for advanced disease were treated with eribulin in a Phase II trial. Interestingly, liposarcoma and leiomyosarcoma were the two cohorts that showed the best results, whereas synovial sarcomas and other sarcomas did not reach the required threshold for evidence of activity. Thus, 46.9, 31.6, 21.1 and 19.2% of patients with liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcomas, respectively, were progression-free at 3 months of treatment [62]. Hopefully, the efficacy of eribulin will be more clearly defined with the results of a randomized Phase III trial comparing it with dacarbazine in the thirdline setting in both adipocytic sarcoma and leiomyosarcoma (ClinicalTrials.gov identifier NCT01327885). Crizotinib in inflammatory myofibroblastic tumor Inflammatory myofibroblastic tumor (IMT) is a rare type of STS characterized by a spindle-cell proliferation with an inflammatory infiltrate [63]. In nearly 50% of cases, IMTs exhibit rearrangements in the anaplastic lymphoma kinase (ALK) gene, which is associated with a higher frequency of recurrence [64]. ALK expression reliably correlates with ALK rearrangement; therefore, the subgroup of inflammatory myofibroblastic tumors that present an ALK rearrangement may be sensitive to targeted kinase inhibition [65]. This suggestion has been supported by the outcomes of two patients with advanced inflammatory myofibroblastic tumor treated with crizotinib (an ALK inhibitor) within a Phase I study. One patient had translocation in ALK and the other was ALKtranslocation negative. After treatment with crizotinib, the ALK-translocated patient achieved a dramatic and sustained response, whereas no activity was observed in the patient without the translocation [66]. Further investigation is ongoing and a study that assesses the activity of crizotinib in a variety of tumors with alterations in ALK and/or MET pathways, including IMT, the CREATE study, is currently recruiting patients (ClinicalTrials.gov identifier NCT01524926). 6.4
7.
Conclusions
Sarcomas are, in general, challenging tumors with few highly effective treatment options. However, up to four new drugs have demonstrated significant activity in Phase III trials in recent years [17,30,37,50]. A number of other drugs have not yet reached mature clinical development but their initial promising results reported so far deserve further investigation [52,53,58,62,66]. In conclusion, in spite of being a group of diseases with historically limited therapeutic alternatives, the prognosis of patients affected by sarcomas should improve
Expert Opin. Pharmacother. (2014) 15(2)
225
J. Martin-Liberal et al.
in forthcoming years thanks to the slow but constant addition of new drugs to the list of active therapeutic options.
Downloaded by [Monash University Library] at 16:57 10 November 2015
8.
Expert opinion
The treatment of adult sarcomas has been historically characterized by the lack of effective treatments, with no improvement in OS in the past few decades. Several reasons have contributed to this. First of all, sarcomas are rare accounting for only 1% of all cancers in adults [67]. Thus, to enroll sufficient number of patients to reach statistically significant results, the classical design of the trials allowed a broad spectrum of different histologies. There have been described > 50 different subtypes of sarcoma, each of them with their own specific characteristics. The broad heterogeneity of sarcomas in terms of responsiveness and prognosis has made such trials difficult to interpret and has resulted in wide differences in outcome for standard treatments, such as doxorubicin from one such trial to another. It is highly probable that some of the trials conducted in the last decades that have been reported as negative, might have been positive if they had been limited to the most suitable selected population. Unfortunately, a high number of sarcoma patients have been enrolled for years in clinical trials with no stratification by histological subtype without achieving any improvement in outcome. A recent illustrative example of this is the abovementioned maintenance trial with the mTOR inhibitor ridaforolimus [50]. Paradoxically, the study is positive because it meets the pre-specified primary endpoint but the scarce clinical benefit observed (just an improvement of 3 weeks in PFS) leaves questions regarding its clinical relevance. It is quite possible that, if the patients had been treated with ridaforolimus based on their mTOR pathway activation, that is, patients with upregulation of p-AKT, p-S6K1, p-4EBP1, the results might have been better. The paradigm of treatment in sarcomas is currently changing thanks to the deeper understanding of their molecular biology. The association with chimeric proteins derived from specific chromosomal translocations has been known for over 20 years [68], but the mechanisms by which the fusion
226
proteins drive cancer have, in some cases, only recently been identified [69-71]. Others have complex karyotypes where the driver or drivers are unknown, which makes them very difficult to treat due to the lack of a relevant target, and there are other subtypes in which a specific gene mutation is responsible for driving the uncontrolled growth and resistance to death of the sarcoma cells [70]. This valuable information has led to major achievements in certain tumors such as GIST, in which the finding of a specific gene mutation (KIT) responsible for its malignant behavior made possible the development of effective drugs with dramatically positive impact in survival [5,6]. Following this example, other specific targeted treatments have been recently assessed such as the aforementioned inhibitors of the overexpressed CDK4 and MDM2 in WD/DDLP [52,53]. Although they still are in an early stage of their clinical development, the results observed are encouraging and these drugs are a welcome addition to therapeutic options in this sarcoma subtype. They are a good example of the close relationship between translational and clinical research that should further guide the development of new drugs in sarcoma. Fortunately, current clinical trials in sarcoma are increasingly focused on specific subtypes. It is important in such trials to incorporate predictive and prognostic biomarkers and functional imaging [72]. Consideration should also be given to assessment of tumor response, and there are instances where RECIST criteria have been superseded by Choi as a meaningful endpoint. It is hoped that these strategies will provide more meaningful results in the future compared with historical studies, although recruitment will always prove challenging. International collaboration is a key driver in this process through bodies such as EORTC, Sarcoma Alliance for Research through Collaboration (SARC) and World Sarcoma Network (WSN). The future of the treatment of sarcomas depends very much on the success of this approach.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.
Expert Opin. Pharmacother. (2014) 15(2)
New drugs in sarcomas
Bibliography
overexpression in leiomyosarcoma. J Cancer Res Clin Oncol 2004;130(1):52-6
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Downloaded by [Monash University Library] at 16:57 10 November 2015
2.
3.
4.
5.
van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens--a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 1999;17(1):150-7
10.
van Oosterom AT, Mouridsen HT, Nielsen OS, et al. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer 2002;38(18):2397-406
12.
Italiano A, Mathoulin-Pelissier S, Le Cesne A, et al. Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer 2011;117(5):1049-54 Leahy M, Garcia Del Muro X, Reichardt P, et al. Chemotherapy treatment patterns and clinical outcomes in patients with metastatic soft tissue sarcoma. TheSArcoma treatment and Burden of Illness in North America and Europe (SABINE) study. Ann Oncol 2012;23(10):2763-70 Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279(5350):577-80
6.
Demetri GD. Differential properties of current tyrosine kinase inhibitors in gastrointestinal stromal tumors. Semin Oncol 2011;38(Suppl 1):S10-19
7.
Wardelmann E, Schildhaus HU, Merkelbach-Bruse S, et al. Soft tissue sarcoma: from molecular diagnosis to selection of treatment. Pathological diagnosis of soft tissue sarcoma amid molecular biology and targeted therapies. Ann Oncol 2010;21(Suppl 7):vii265-9
8.
Martı´n Liberal J, Lagares-Tena L, Sa´inz-Jaspeado M, et al. Targeted therapies in sarcomas: challenging the challenge. Sarcoma 2012;2012:626094
9.
Potti A, Ganti AK, Tendulkar K, et al. Determination of vascular endothelial growth factor (VEGF) overexpression in soft tissue sarcomas and the role of
11.
13.
Graeven U, Andre N, Achilles E, et al. Serum levels of vascular endothelial growth factor and basic fibroblast growth factor inpatients with soft-tissue sarcoma. J Cancer Res Clin Oncol 1999;125(10):577-81 Hayes AJ, Mostyn-Jones A, Koban MU, et al. Serum vascular endothelial growth factor as a tumour marker in soft tissue sarcoma. Br J Surg 2004;91(2):242-7 Chao C, Al-Saleem T, Brooks JJ, et al. Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade. Ann Surg Oncol 2001;8(3):260-7 Iyoda A, Hiroshima K, Baba M, et al. Expression of vascular endothelial growth factor in thoracic sarcomas. Ann Thorac Surg 2001;71(5):1635-9
14.
Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25(4):581-611
15.
Kilvaer TK, Valkov A, Sorbye S, et al. Profiling of VEGFs and VEGFRs as prognostic factors in soft tissue sarcoma: VEGFR-3 is an independent predictor of poor prognosis. PLoS One 2010;5(12):e15368
16.
Hamberg P, Verweij J, Sleijfer S. (Pre-) clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. Oncologist 2010;15(6):539-47
17.
van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet 2012;379(9829):1879-86 First positive Phase III trial with an anti-angiogenic drug in sarcomas.
..
18.
19.
Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 2009;27(19):3126-32 Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the management of
Expert Opin. Pharmacother. (2014) 15(2)
patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw 2010;8:S1-41 20.
Joensuu H. Adjuvant treatment of GIST: patient selection and treatment strategies. Nat Rev Clin Oncol 2012;9:351-8
21.
Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 2002;33:466-77
22.
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342-9
23.
Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer 2011;11:865-78
24.
Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-80
25.
Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 2012;307:1265-72
26.
Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005;11:4182-90
27.
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329-38
28.
Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011;129:245-55
29.
George S, Wang Q, Heinrich MC, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol 2012;30(19):2401-7
30.
Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib
227
J. Martin-Liberal et al.
Downloaded by [Monash University Library] at 16:57 10 November 2015
..
for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebocontrolled, phase 3 trial. Lancet 2013;381(9863):295-302 Positive Phase III trial in third-line setting in GIST.
31.
Meyers PA, Gorlick R. Osteosarcoma. Pediatr Clin North Am 44:973-89.1997
32.
Kung FH, Pratt CB, Vega RA, et al. Ifosfamide/etoposide combination in the treatment of recurrent malignant solid tumors of childhood. A Pediatric Oncology Group Phase II study. Cancer 1993;71(5):1898-903
33.
34.
35.
36.
37.
..
38.
39.
228
cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 2005;23(9):2004-11 40.
Wan X, Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist 2007;12(8):1007-18
41.
Sampson JR. Therapeutic targeting of mTOR in tuberous sclerosis. Biochem Soc Trans 2009;37(Pt 1):259-64
42.
Katz D, Lazar A, Lev D. Malignant peripheral nerve sheath tumour (MPNST): the clinical implications of cellular signalling pathways. Expert Rev Mol Med 2009;11:e30
43.
Endo M, Yamamoto H, Setsu N, et al. Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors. Clin Cancer Res 2013;19(2):450-61
Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314(25):1600-6 Fidler IJ, Sone S, Fogler WE, Barnes ZL. Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci USA 1981;78(3):1680-4
44.
Houghton PJ, Morton CL, Gorlick R, et al. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther 2010;9(1):101-12
50.
..
Demetri GD, Chawla SP, Ray-Coquard I, et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol 2013;31(19):2485-92 Phase III trial in maintenance in sarcomas with positive results but limited clinical benefit.
51.
Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 2005;29(10):1340-7
52.
Dickson MA, Tap WD, Keohan ML, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified welldifferentiated or dedifferentiated liposarcoma. J Clin Oncol 2013;31(16):2024-8 Successful Phase II trial with a targeted agent in well-differentiated/dedifferentiated liposarcoma.
.
MacEwen EG, Kurzman ID, Rosenthal RC, et al. Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J Natl Cancer Inst 1989;81(12):935-8
45.
Kleinerman ES, Meyers PA, Raymond AK, et al. Combination therapy with ifosfamide and liposomeencapsulated muramyl tripeptide: tolerability, toxicity, and immune stimulation. J Immunother Emphasis Tumor Immunol 1995;17(3):181-93
46.
Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children’s Oncology Group. J Clin Oncol 2008;26(4):633-8 First drug in decades that improves overall survival in sarcomas.
47.
Cohen EE, Wu K, Hartford C, et al. Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients. Clin Cancer Res 2012;18(17):4785-93
54.
Portera CA Jr, Ho V, Patel SR, et al. Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution. Cancer 2001;91(3):585-91
48.
Squillace RM, Miller D, Cookson M, et al. Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models. Mol Cancer Ther 2011;10(10):1959-68
55.
Lazar AJ, Das P, Tuvin D, et al. Angiogenesis-promoting gene patterns in alveolar soft part sarcoma. Clin Cancer Res 2007;13(24):7314-21
56.
Lorigan JG, O’Keeffe FN, Evans HL, Wallace S. The radiologic manifestations of alveolar soft-part sarcoma. AJR Am J Roentgenol 1989;153(2):335-9
57.
Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor
Chou AJ, Kleinerman ES, Krailo MD, et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Cancer 2009;115(22):5339-48 Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to
49.
Okuno S, Bailey H, Mahoney MR, et al. A phase 2 study of temsirolimus (CCI779) in patients with soft tissue sarcomas: a study of the Mayo phase 2 consortium (P2C). Cancer 2011;117(15):3468-75 Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol 2010;28(5):835-40
Chawla SP, Staddon AP, Baker LH, et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol 2012;30(1):78-84
Expert Opin. Pharmacother. (2014) 15(2)
53.
.
Ray-Coquard I, Blay JY, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, welldifferentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 2012;13(11):1133-40 Positive proof-of-concept Phase II trial in well-differentiated/dedifferentiated liposarcoma.
New drugs in sarcomas
for the treatment of cancer. Cancer Res 2005;65(10):4389-400 58.
.
59.
Downloaded by [Monash University Library] at 16:57 10 November 2015
60.
61.
62.
.
Kummar S, Allen D, Monks A, et al. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol 2013;31(18):2296-302 Successful Phase II trial in a subtype of sarcoma especially resistant to treatment. Towle MJ, Salvato KA, Budrow J, et al. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 2001;61:1013-21 Jordan MA, Kamath K, Manna T, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther 2005;4:1086-95 Okouneva T, Azarenko O, Wilson L, et al. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther 2008;7:2003-11 Sch€offski P, Ray-Coquard IL, Cioffi A, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol 2011;12(11):1045-52 Positive Phase II study in two histologies: leiomyosarcoma and liposarcoma.
63.
64.
65.
66.
.
Coffin CM, Watterson J, Priest JR, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor): a clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol 1995;19:859-72 Coffin CM, Patel A, Perkins S, et al. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol 2001;14(6):569-76 Cook JR, Dehner LP, Collins MH, et al. Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol 2001;25:1364-71 Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALKrearranged inflammatory myofibroblastic tumor. N Engl J Med 2010;363(18):1727-33 Dramatic response with a drug active against ALK chromosomal rearrangement.
67.
Amankwah EK, Conley AP, Reed DR. Epidemiology and therapies for metastatic sarcoma. Clin Epidemiol 2013;5:147-62
68.
Reeves BR, Smith S, Fisher C, et al. Characterization of the translocation between chromosomes X and 18 in
Expert Opin. Pharmacother. (2014) 15(2)
human synovial sarcomas. Oncogene 1989;4(3):373-8 69.
de Alava E. Molecular pathology in sarcomas. Clin Transl Oncol 2007;9:130-44
70.
Jain S, Xu R, Prieto VG, Lee P. Molecular classification of soft tissue sarcomas and its clinical applications. Int J Clin Expert Pathol 2010;3(4):416-28
71.
Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 2013;153(1):71-85
72.
Casali PG. Histology- and non-histology-driven therapy for treatment of soft tissue sarcomas. Ann Oncol 2012;23(Suppl 10):x167-9
Affiliation
Juan Martin-Liberal†, Charlotte Benson & Ian Judson † Author for correspondence The Royal Marsden Hospital, Sarcoma Unit, Fulham Road SW3 6JJ, London, UK Tel: +44 20 7808 2200; Fax: +44 20 7808 2113; E-mail: [email protected]
229
ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20
New drugs in sarcomas Juan Martin-Liberal, Charlotte Benson & Ian Judson To cite this article: Juan Martin-Liberal, Charlotte Benson & Ian Judson (2014) New drugs in sarcomas, Expert Opinion on Pharmacotherapy, 15:2, 221-229 To link to this article: http://dx.doi.org/10.1517/14656566.2014.865015
Published online: 25 Nov 2013.
Submit your article to this journal
Article views: 336
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieop20 Download by: [Monash University Library]
Date: 10 November 2015, At: 16:57
Review
New drugs in sarcomas Juan Martin-Liberal†, Charlotte Benson & Ian Judson
Downloaded by [Monash University Library] at 16:57 10 November 2015
The Royal Marsden Hospital, Sarcoma Unit, London, UK 1.
Introduction
2.
Pazopanib in soft-tissue sarcomas
3.
Regorafenib in GIST
4.
Muramyl tripeptide in osteosarcoma
5.
Ridaforolimus as maintenance treatment
6.
Other active drugs
7.
Conclusions
8.
Expert opinion
Introduction: Adult sarcomas are rare tumors characterized, in general, by their poor prognosis and the paucity of effective treatments. However, the deeper understanding of their underlying molecular pathology, signaling pathways and key effectors has permitted the development of a number of drugs able to inhibit important processes in sarcoma pathogenesis. Some of these novel compounds have been assessed in clinical trials with successful results. Areas covered: The latest reported trials are comprehensively reviewed. Thus, the Phase III studies with pazopanib, regorafenib, muramyl tripeptide (MTP) and ridaforolimus are extensively discussed as well as the biological rationale for the use of these compounds. In addition, the most promising drugs that still are in earlier stages of development such as CDK4 and MDM2 inhibitors, cediranib, eribulin and crizotinib are also discussed. Expert opinion: It is crucial for the correct identification of active drugs in sarcomas that new clinical trials are focused on specific subtypes and/or molecular alterations. The results of these studies should improve the prognosis of the patients affected by sarcoma in forthcoming years. Keywords: CDK4, cediranib, crizotinib, eribulin, GIST, MDM2, muramyl tripeptide, osteosarcoma, pazopanib, ridaforolimus, soft-tissue sarcoma Expert Opin. Pharmacother. (2014) 15(2):221-229
1.
Introduction
Sarcomas are a rare group of malignancies of mesenchymal origin. In spite of this common feature, the name ‘sarcoma’ encompasses > 50 different entities with differing molecular biology, clinical behavior, responsiveness to treatment and prognosis. They can affect patients of all ages, although certain specific subtypes are more frequent in children and young adults. Almost every part of the body may be involved, either bone or soft tissue. In spite of this heterogeneity, in the majority of cases adult sarcomas are characterized by the lack of effective treatments in the metastatic setting. Thus, with the exception of a few histologies, the most active drugs in adult sarcomas only achieve a response rate (RR) of 20 -- 30% or even lower depending on the series [1,2]. Moreover, nearly half of all patients diagnosed with adult sarcomas will develop metastases even if they are diagnosed at an early stage [3]. As a result of the low efficacy of the drugs currently available, the median overall survival (OS) of an advanced adult sarcoma patient is just 1 year [4]. Therefore, it is necessary to identify new active drugs to improve the outcome of patients affected by this disease. In the past two decades, a number of novel drugs have been developed in oncology. Unfortunately, only a few of these new compounds have achieved successful results in sarcomas with imatinib for gastro-intestinal stromal tumor (GIST) being the most important example [5,6]. However, great advances have recently been made in the understanding of the molecular biology of sarcoma [7]. The deeper understanding of some relevant pathways and their key effectors has permitted the development of a number of drugs able to inhibit important processes in sarcoma pathogenesis. Consequently, some of these novel compounds have been assessed in clinical trials with successful results. Thus, anti-angiogenic drugs, inhibitors of 10.1517/14656566.2014.865015 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
221
J. Martin-Liberal et al.
Article highlights. . .
.
.
Downloaded by [Monash University Library] at 16:57 10 November 2015
.
.
Adult sarcomas are rare tumors with generally bad prognosis and lack of effective treatments. There are > 50 different subtypes of sarcoma, each of them with its own molecular characteristics, clinical behavior and responsiveness to treatment. The increasing understanding of the biology of sarcomas has permitted the development of a series of new active drugs. Pazopanib, regorafenib, muramyl tripeptide and ridaforolimus have demonstrated activity in sarcoma in Phase III trials. CDK4 and MDM2 inhibitors, cediranib, eribulin and crizotinib have shown promising results that deserve further investigation. It is crucial for the correct identification of active drugs in sarcomas the development of new clinical trials focused on specific subtypes and/or molecular alterations.
This box summarizes key points contained in the article.
the mammalian target of rapamycin (mTOR), multi-tyrosine kinase inhibitors (TKIs) or immune system modulators, among others, have been recently found to be active drugs against sarcomas [8]. The aim of this article is to perform an extensive review of the most recent drugs that have shown clinically relevant positive results in sarcomas (except carcinosarcoma). Also, we will provide a view of the future therapeutic strategies that will hopefully have an impact on the survival of patients affected by these malignancies.
2.
Pazopanib in soft-tissue sarcomas
Rationale Angiogenesis is one of the most relevant processes in cancer. It is driven by a series of complex interactions among the different factors in charge of its regulation. The formation of new blood vessels is necessary for the growth of every tumor, without which small metastatic tumors cannot progress beyond about 200 µm. Sarcomas are no exception to these general principles. Some of the key effectors of these mechanisms are well-described pro-angiogenic substances, such as vascular endothelial growth factor 1 (VEGF) and the VEGF receptor isoforms (VEGFR-1, VEGFR-2 and VEGFR-3). Several studies have assessed the role of VEGF in sarcomas in recent years. Thus, a study by Potti et al. correlated serum levels of VEGF with clinical outcome. Significant overexpression of VEGF was found in 68 of 273 patients (24.9%). Higher expression of VEGF was detected in pleomorphic undifferentiated sarcoma (previously known as malignant fibrous histiocytoma) (30%), carcinosarcoma (30%), leiomyosarcoma (25%) and dermatofibrosarcoma (20%). Interestingly, overexpression of VEGF had prognostic value only in
leiomyosarcoma and these patients were found to have a significantly shorter survival [9]. Another study determined VEGF serum levels preoperatively in 85 patients affected by soft-tissue sarcomas (STS). This examined the relationship between VEGF and tumor grade. It was found that the least well-differentiated tumors had the highest VEGF levels, proposing VEGF in serum as a biomarker of tumor aggressiveness [10]. Similar results were observed in a larger prospective series of 144 patients in which serum levels of VEGF were found to have significant correlation not only with grade, but also with response to treatment [11]. One additional study supported these findings in tumor samples. Thus, in a 2001 paper by Chao et al., VEGF overexpression in paraffin-embedded tissue of surgical specimens from 79 patients with STS also correlated with high tumor grade. Furthermore, 78% of patients who died of disease (29 out of 37) had high VEGF expression [12]. In addition, another study analyzed the expression of VEGF by immunohistochemistry (IHC) in tissue from 27 cases of thoracic sarcomas. The results showed that disease-free survival (DFS) in patients with strong tumor VEGF expression was significantly poorer compared with those with lower VEGF expression [13]. But VEGF is not the only important factor controlling angiogenesis. It is well known that its interaction with VEGFR-2 is the most crucial step in the process [14]. In addition, a recent study also proposed VEGFR-3 as a prognostic factor in STS. Thus, Kilvaer et al. constructed tissue microarrays from tumor samples of 249 patients with STS in which the expression of several angiogenesis effectors was determined by IHC. High expression of VEGFR-3 was found to be an independent significant negative prognostic marker for disease-specific survival [15]. These data suggested the inhibition of the VEGF-VEGFR interaction as a potential therapeutic target in sarcomas.
2.1
222
Clinical experience Pazopanib is a new TKI with potent anti-angiogenic effects due to its affinity for the key effectors VEGFR-1, VEGFR-2 and VEGFR-3. In addition, it is also able to inhibit other relevant tyrosine kinases such as KIT or the platelet-derived growth factor receptors a and b (PDGFRA and PDGFRB) [16]. Pazopanib is the first anti-angiogenic drug that has proven to be effective in a large randomized Phase III trial in sarcoma [17]. The first encouraging clinical results were reported in a Phase II trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC). A total of 142 patients with intermediate or high-risk advanced STS who had received up to 2 prior lines of treatment were enrolled. They were stratified in four different groups: adipocytic STS, leiomyosarcomas, synovial sarcomas and other STS types. Pazopanib failed to show convincing activity in the adipocytic STS cohort but achieved encouraging results in the remaining groups. Progressionfree survival (PFS) rates at 12 weeks were 44% in the 2.2
Expert Opin. Pharmacother. (2014) 15(2)
Downloaded by [Monash University Library] at 16:57 10 November 2015
New drugs in sarcomas
leiomyosarcoma cohort, 49% in synovial sarcomas and 39% in the other STS types [18]. Following this, a randomized, double-blind, placebocontrolled Phase III trial in patients with metastatic nonadipocytic STS was conducted. In total, 369 patients were treated with either pazopanib or placebo in a 2:1 randomization. In terms of efficacy, median PFS was 4.6 months for pazopanib compared with 1.6 months for placebo, with p < 0.0001. OS was also higher in the pazopanib arm although it failed to reach statistical significance. However, the real impact of pazopanib on survival may have been affected by subsequent treatment as many patients received further lines of chemotherapy after progression. As with other anti-angiogenic agents, there were some concerns about cardiotoxicity. Sixteen pazopanib-treated patients had a fall in cardiac ejection fraction compared with only three in the placebo group. Currently it is unclear to what extent uncontrolled hypertension or prior treatment with anthracyclines contributed to this toxicity but it did appear to be reversible in a proportion of patients. Other toxicities highlighted were venous thromboembolic disease and pneumothorax. Interestingly, global health and quality of life scores did not differ significantly between groups [17]. The results of this trial have established pazopanib as a new therapeutic option in non-adipocytic STS and it has been licensed by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
3.
Regorafenib in GIST
Rationale GISTs are the most frequent sarcomas of the gastro-intestinal tract [19]. Surgery is the mainstay of treatment for localized disease. However, nearly 40% of these patients will relapse [20]. When advanced disease is diagnosed, systemic treatment is required. Historically GIST was considered a chemo- and radiotherapy insensitive tumor [21]. It was not until its molecular biology began to be understood that effective therapies were developed. About 80% of all GISTs are driven by gain-of-function mutations in the proto-oncogene KIT, which encodes a tyrosine kinase receptor [22]. Less frequently, mutations in the PDGFRA gene are also responsible [23]. Following the identification of gain-of-function mutations in KIT, imatinib was tested successfully and subsequently a number of other inhibitors have been developed for the treatment of GIST. Imatinib, a TKI with activity against KIT and PDGFRA, has dramatically improved the survival of GIST patients from a median of 18 months to 5 years for patients with advanced disease [24,25]. Unfortunately, development of resistance to imatinib is a frequent occurrence owing to secondary mutations that affect its binding to KIT [26]. Sunitinib, another multi-targeted TKI, has proven clinical activity in the second-line setting after imatinib failure, although some secondary mutations generate resistance to both agents [27]. The 3.1
development of other TKIs capable of inhibiting these mutant isoforms has been an active area of research. Clinical experience Regorafenib is a novel multi-TKI, a close analog of sorafenib that blocks several pathways involved in GIST pathogenesis [28]. A single-arm Phase II trial in 34 patients previously treated with imatinib and sunitinib showed significant signs of activity. Thus, 4 and 22 patients achieved partial response (PR) and stable disease (SD) ‡ 16 weeks, respectively. In total, the clinical benefit rate (defined as PR + SD ‡ 16 weeks) was 79% and the median PFS was 10 months [29]. These promising results were confirmed in a randomized, double-blind, placebo-controlled Phase III trial. Participants were randomized to treatment with either regorafenib or placebo following failure of at least imatinib and sunitinib. On progression, patients receiving placebo were allowed to crossover to open-label regorafenib. In total, 240 patients were screened and 199 were randomized in 57 institutions. Median PFS per independent blinded central review was 4.8 and 0.9 months for regorafenib and placebo, respectively (Hazard ratio (HR) 0.27; p < 0.0001). PFS at 3 and 6 months was 60 and 38%, respectively, for regorafenib, and 11 and 0%, for placebo. In terms of response, 6 out of the 133 patients (4.5%) treated with regorafenib achieved PR. In this same group of patients, SD as best response was reported in 95 cases (71.4%). The total rate of disease control lasting for at least 12 weeks in the active treatment cohort was 52.6%. With respect to toxicity, the most common clinically significant regorafenib-related adverse events were hypertension (23%), hand-foot skin reaction (20%) and diarrhea (5%). Although dose modifications were frequent in the regorafenib group (72%), the occurrence of adverse events that led to permanent discontinuation of treatment was low (6%). In general, adverse events were manageable by dose modification without the need to discontinue treatment in the majority of cases [30]. This trial has led to the acceptance of regorafenib by the FDA and the EMA as third-line therapy in advanced GIST. 3.2
4.
Muramyl tripeptide in osteosarcoma
Rationale Osteosarcoma is the most common sarcoma of the bone. It is characterized by the production of osteoid or immature bone by proliferating spindle cells [31]. Unfortunately, nearly 20% of all patients are diagnosed with advanced disease at presentation and without adjuvant systemic treatment the majority of patients would eventually succumb to metastatic disease. However, it is generally a chemo-sensitive tumor and the RRs are higher compared with other sarcomas [32]. Moreover, adjuvant treatment has a major positive impact on survival and its use is widely accepted [33]. Muramyl tripeptide (MTP) is a synthetic analog of a component of the cell wall of bacteria, specifically Bacille 4.1
Expert Opin. Pharmacother. (2014) 15(2)
223
J. Martin-Liberal et al.
Calmette--Guerin. MTP is encapsulated in liposomes and it is delivered to monocytes and macrophages causing their activation and inducing anti-tumor activity in osteosarcoma [34,35]. It has been reported that when used concomitantly with particular chemotherapy agents such as ifosfamide there is no increase in toxicity. Also, combined therapy does not affect the stimulation of cytokines caused by MTP [36]. Therefore, there was a clear clinical rationale for the assessment of MTP-containing chemotherapy regimens in osteosarcoma. Clinical experience A large, randomized, Phase III trial to assess the activity of MTP in combination with chemotherapy in the localized setting was conducted. The study had a 2 2 factorial design and tried to answer two different questions: first, whether the addition of ifosfamide to doxorubicin, cisplatin and high-dose methotrexate (HDMTX) had any benefit in survival and, second, whether the addition of MTP to chemotherapy improved the outcome of the patients. Results showed that ifosfamide did not enhance the activity of standard chemotherapy. However, the addition of MTP proved to be beneficial, mainly in the ifosfamide arm. Thus, 662 patients without metastases and resectable primary tumors received treatment within the study. Event-free survival (EFS) rates for patients treated with chemotherapy alone were 63 and 61% at 4 and 6 years, respectively. However, EFS for the patients treated with MTP and chemotherapy was 69 and 67% at 4 and 6 years, respectively, although this improvement failed to reach statistical significance. Furthermore, the addition of MTP to chemotherapy improved OS at 6 years from 70 to 78%. This difference was statistically significant (p = 0.03) [37]. Interestingly, MTP did not improve the outcome when patients were treated in the presence of metastases [38]. The toxicity observed was consistent with the already known safety profile of the chemotherapy agents used. However, administration of MTP was associated with fever and chills. The protocol of the trial called for dose escalation of MTP until these effects were observed to assure biologic activity but most patients did not need dose escalation. Reactions to MTP decreased with time and premedication with paracetamol or ibuprofen for most patients, but fever and chills continued in some cases with each administration of MTP [39]. In spite of the statistically significant improvement in OS, MTP was denied approval by the FDA. However, it was licensed by the EMA in 2009 although it is not widely used in Europe, mainly due to its high cost.
Downloaded by [Monash University Library] at 16:57 10 November 2015
4.2
5.
Ridaforolimus as maintenance treatment
Rationale The mTOR is a serine/threonine kinase integrated in the phosphatidyl-inositol 3-kinase (PI3K) complex network of signaling. It forms part of two multiprotein complexes named mTOR complex 1 and mTOR complex 2 (mTORC1 and
mTORC2) and plays a key role in cell growth, proliferation, angiogenesis and survival. The upregulation of growth factors or mutations in tyrosine kinase receptors that belong to the mTOR network has been reported to be involved in the development of various sarcomas [40]. Furthermore, deletions of some mTOR pathway tumor suppressors such as tuberous sclerosis complex 1 and 2 (TSC1 and TSC2) and neurofibromatosis type 1 (NF1) are associated with both benign and malignant mesenchymal tumors [41,42]. A number of mTOR inhibitors derived from the parent compound rapamycin (sirolimus) have been tested both clinically and pre-clinically in sarcomas [43-47]. One of these compounds, ridaforolimus, had been confirmed to be active in cell lines and xenograft models of sarcoma. Moreover, additive inhibitory effects when combined with cytotoxic agents had also been reported [48]. These encouraging data warranted its assessment in clinical trials. Clinical experience The initial reports of the activity of ridaforolimus in sarcomas showed promising results. Thus, in a single-arm Phase II trial by Chawla et al. the clinical benefit rate in heavily pre-treated patients with advanced sarcoma was 28.8% and the median OS was 40 weeks [49]. Such interesting results led to the only Phase III trial to date with an mTOR inhibitor in sarcomas: the SUCCEED trial. This double-blind, placebo-controlled Phase III trial randomized sarcoma patients who had achieved complete response (CR), PR or SD after 1, 2 or 3 lines of chemotherapy to receive placebo or ridaforolimus as maintenance treatment. A total of 702 patients received blinded study drug. Ridaforolimus showed some signs of activity, inducing a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo. In addition, it achieved a statistically significant improvement in PFS compared with placebo in both independent and per investigator assessment. However, the magnitude of that improvement was very modest (median PFS 17.7 weeks versus 14.6 weeks per independent review), making its clinical relevance arguable. The difference in OS observed in favor of ridaforolimus (90.6 weeks versus 85.3 weeks) was not statistically significant. As expected, toxicity was more common in the ridaforolimus cohort. The most frequent adverse events observed included stomatitis 77.8%, infections 51.6%, fatigue 35.6% and thrombocytopenia 33.5%. Overall, the percentage of patients treated with ridaforolimus that had to discontinue treatment due to adverse events was 14.6% [50]. Although the clinical benefit observed in this study was modest, maintenance treatment in sarcomas is a therapeutic strategy that deserves further investigation given the short PFS achieved with the majority of conventional cytotoxic agents. 5.2
5.1
224
6.
Other active drugs
A number of other drugs in early clinical development have been reported to have promising activity in sarcomas recently.
Expert Opin. Pharmacother. (2014) 15(2)
New drugs in sarcomas
The positive results observed in several Phase II and Phase I trials need to be confirmed but these novel drugs may well represent valid therapeutic strategies in the near future. Here, we outline some of the most clinically relevant drugs currently in development. Cyclin-dependent kinase 4 and mouse double minute 2 homolog inhibitors in well-differentiated/ dedifferentiated liposarcoma
Downloaded by [Monash University Library] at 16:57 10 November 2015
6.1
Liposarcomas are one of the most frequently occurring STS. One specific subtype, well-differentiated/dedifferentiated liposarcoma (WD/DDLPS) is considered to be less sensitive to conventional chemotherapy. The genes coding for cyclindependent kinase 4 (CDK4) P16 and mouse double minute 2 homolog (MDM2) are co-amplified on 12q13-15 in nearly 90% of all WD/DDLPS [51]. Therefore, CDK4 targeting has been proposed as a therapeutic option in this subtype of liposarcoma. The CDK4 inhibitor PD0332991 has been assessed in a Phase II clinical trial in patients with progressive advanced WD/DDLPS. A total of 30 patients were enrolled and PR was seen in only 1 patient. Nevertheless, the PFS rate at 12 weeks of treatment was 66% and the median PFS was 18 weeks [52]. In another study, 20 patients received up to three cycles of neoadjuvant treatment with RG7112, an MDM2 inhibitor. PR was reported in 1 patient and 14 patients achieved SD. Moreover, RG7112 was generally well tolerated although all patients experienced at least one adverse event [53]. Cediranib in alveolar soft-part sarcoma Alveolar soft-part sarcoma (ASPS) is one of the rarest subtypes of STS. It is usually an indolent disease, with median OS of around 40 months and 5-year survival rate of 20% even in the presence of unresectable metastases [54]. Studies performed on surgical samples of ASPS have revealed upregulation of several transcripts associated with angiogenesis, which correlates with its high vascularization [55,56]. Cediranib is a TKI with high affinity for the three isoforms of VEGFR, as well as PDGFRB and to a somewhat less extent PDGFRA and fibroblast growth factor receptor 1 (FGFR1), which makes it a potent inhibitor of angiogenesis [57]. It also inhibits KIT and colony stimulating factor 1 receptor (CSF-1R). A Phase II trial with cediranib in ASPS showed that 15 out of 46 patients enrolled (35%) achieved PR and 26 patients (60%) had SD. In total, the disease control rate at 24 weeks was 84% [58]. At least two clinical trials that further assess the activity of cediranib in ASPS are currently ongoing (ClinicalTrials.gov identifiers NCT01391962 and NCT01337401). 6.2
Eribulin in liposarcoma and leiomyosarcoma Eribulin is one of the most recent drugs to have demonstrated activity against sarcomas. It is a synthetic compound originally extracted from marine sponges with anti6.3
microtubule properties. However, its mechanism of action seems to be different from other anti-microtubule drugs such as taxanes [59-61]. Promising results of its activity in STS have recently been reported. Thus, 128 patients with progressive high-grade STS who had received no more than one previous combination chemotherapy or a maximum of two single drugs for advanced disease were treated with eribulin in a Phase II trial. Interestingly, liposarcoma and leiomyosarcoma were the two cohorts that showed the best results, whereas synovial sarcomas and other sarcomas did not reach the required threshold for evidence of activity. Thus, 46.9, 31.6, 21.1 and 19.2% of patients with liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcomas, respectively, were progression-free at 3 months of treatment [62]. Hopefully, the efficacy of eribulin will be more clearly defined with the results of a randomized Phase III trial comparing it with dacarbazine in the thirdline setting in both adipocytic sarcoma and leiomyosarcoma (ClinicalTrials.gov identifier NCT01327885). Crizotinib in inflammatory myofibroblastic tumor Inflammatory myofibroblastic tumor (IMT) is a rare type of STS characterized by a spindle-cell proliferation with an inflammatory infiltrate [63]. In nearly 50% of cases, IMTs exhibit rearrangements in the anaplastic lymphoma kinase (ALK) gene, which is associated with a higher frequency of recurrence [64]. ALK expression reliably correlates with ALK rearrangement; therefore, the subgroup of inflammatory myofibroblastic tumors that present an ALK rearrangement may be sensitive to targeted kinase inhibition [65]. This suggestion has been supported by the outcomes of two patients with advanced inflammatory myofibroblastic tumor treated with crizotinib (an ALK inhibitor) within a Phase I study. One patient had translocation in ALK and the other was ALKtranslocation negative. After treatment with crizotinib, the ALK-translocated patient achieved a dramatic and sustained response, whereas no activity was observed in the patient without the translocation [66]. Further investigation is ongoing and a study that assesses the activity of crizotinib in a variety of tumors with alterations in ALK and/or MET pathways, including IMT, the CREATE study, is currently recruiting patients (ClinicalTrials.gov identifier NCT01524926). 6.4
7.
Conclusions
Sarcomas are, in general, challenging tumors with few highly effective treatment options. However, up to four new drugs have demonstrated significant activity in Phase III trials in recent years [17,30,37,50]. A number of other drugs have not yet reached mature clinical development but their initial promising results reported so far deserve further investigation [52,53,58,62,66]. In conclusion, in spite of being a group of diseases with historically limited therapeutic alternatives, the prognosis of patients affected by sarcomas should improve
Expert Opin. Pharmacother. (2014) 15(2)
225
J. Martin-Liberal et al.
in forthcoming years thanks to the slow but constant addition of new drugs to the list of active therapeutic options.
Downloaded by [Monash University Library] at 16:57 10 November 2015
8.
Expert opinion
The treatment of adult sarcomas has been historically characterized by the lack of effective treatments, with no improvement in OS in the past few decades. Several reasons have contributed to this. First of all, sarcomas are rare accounting for only 1% of all cancers in adults [67]. Thus, to enroll sufficient number of patients to reach statistically significant results, the classical design of the trials allowed a broad spectrum of different histologies. There have been described > 50 different subtypes of sarcoma, each of them with their own specific characteristics. The broad heterogeneity of sarcomas in terms of responsiveness and prognosis has made such trials difficult to interpret and has resulted in wide differences in outcome for standard treatments, such as doxorubicin from one such trial to another. It is highly probable that some of the trials conducted in the last decades that have been reported as negative, might have been positive if they had been limited to the most suitable selected population. Unfortunately, a high number of sarcoma patients have been enrolled for years in clinical trials with no stratification by histological subtype without achieving any improvement in outcome. A recent illustrative example of this is the abovementioned maintenance trial with the mTOR inhibitor ridaforolimus [50]. Paradoxically, the study is positive because it meets the pre-specified primary endpoint but the scarce clinical benefit observed (just an improvement of 3 weeks in PFS) leaves questions regarding its clinical relevance. It is quite possible that, if the patients had been treated with ridaforolimus based on their mTOR pathway activation, that is, patients with upregulation of p-AKT, p-S6K1, p-4EBP1, the results might have been better. The paradigm of treatment in sarcomas is currently changing thanks to the deeper understanding of their molecular biology. The association with chimeric proteins derived from specific chromosomal translocations has been known for over 20 years [68], but the mechanisms by which the fusion
226
proteins drive cancer have, in some cases, only recently been identified [69-71]. Others have complex karyotypes where the driver or drivers are unknown, which makes them very difficult to treat due to the lack of a relevant target, and there are other subtypes in which a specific gene mutation is responsible for driving the uncontrolled growth and resistance to death of the sarcoma cells [70]. This valuable information has led to major achievements in certain tumors such as GIST, in which the finding of a specific gene mutation (KIT) responsible for its malignant behavior made possible the development of effective drugs with dramatically positive impact in survival [5,6]. Following this example, other specific targeted treatments have been recently assessed such as the aforementioned inhibitors of the overexpressed CDK4 and MDM2 in WD/DDLP [52,53]. Although they still are in an early stage of their clinical development, the results observed are encouraging and these drugs are a welcome addition to therapeutic options in this sarcoma subtype. They are a good example of the close relationship between translational and clinical research that should further guide the development of new drugs in sarcoma. Fortunately, current clinical trials in sarcoma are increasingly focused on specific subtypes. It is important in such trials to incorporate predictive and prognostic biomarkers and functional imaging [72]. Consideration should also be given to assessment of tumor response, and there are instances where RECIST criteria have been superseded by Choi as a meaningful endpoint. It is hoped that these strategies will provide more meaningful results in the future compared with historical studies, although recruitment will always prove challenging. International collaboration is a key driver in this process through bodies such as EORTC, Sarcoma Alliance for Research through Collaboration (SARC) and World Sarcoma Network (WSN). The future of the treatment of sarcomas depends very much on the success of this approach.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.
Expert Opin. Pharmacother. (2014) 15(2)
New drugs in sarcomas
Bibliography
overexpression in leiomyosarcoma. J Cancer Res Clin Oncol 2004;130(1):52-6
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Downloaded by [Monash University Library] at 16:57 10 November 2015
2.
3.
4.
5.
van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens--a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 1999;17(1):150-7
10.
van Oosterom AT, Mouridsen HT, Nielsen OS, et al. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer 2002;38(18):2397-406
12.
Italiano A, Mathoulin-Pelissier S, Le Cesne A, et al. Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer 2011;117(5):1049-54 Leahy M, Garcia Del Muro X, Reichardt P, et al. Chemotherapy treatment patterns and clinical outcomes in patients with metastatic soft tissue sarcoma. TheSArcoma treatment and Burden of Illness in North America and Europe (SABINE) study. Ann Oncol 2012;23(10):2763-70 Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279(5350):577-80
6.
Demetri GD. Differential properties of current tyrosine kinase inhibitors in gastrointestinal stromal tumors. Semin Oncol 2011;38(Suppl 1):S10-19
7.
Wardelmann E, Schildhaus HU, Merkelbach-Bruse S, et al. Soft tissue sarcoma: from molecular diagnosis to selection of treatment. Pathological diagnosis of soft tissue sarcoma amid molecular biology and targeted therapies. Ann Oncol 2010;21(Suppl 7):vii265-9
8.
Martı´n Liberal J, Lagares-Tena L, Sa´inz-Jaspeado M, et al. Targeted therapies in sarcomas: challenging the challenge. Sarcoma 2012;2012:626094
9.
Potti A, Ganti AK, Tendulkar K, et al. Determination of vascular endothelial growth factor (VEGF) overexpression in soft tissue sarcomas and the role of
11.
13.
Graeven U, Andre N, Achilles E, et al. Serum levels of vascular endothelial growth factor and basic fibroblast growth factor inpatients with soft-tissue sarcoma. J Cancer Res Clin Oncol 1999;125(10):577-81 Hayes AJ, Mostyn-Jones A, Koban MU, et al. Serum vascular endothelial growth factor as a tumour marker in soft tissue sarcoma. Br J Surg 2004;91(2):242-7 Chao C, Al-Saleem T, Brooks JJ, et al. Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade. Ann Surg Oncol 2001;8(3):260-7 Iyoda A, Hiroshima K, Baba M, et al. Expression of vascular endothelial growth factor in thoracic sarcomas. Ann Thorac Surg 2001;71(5):1635-9
14.
Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25(4):581-611
15.
Kilvaer TK, Valkov A, Sorbye S, et al. Profiling of VEGFs and VEGFRs as prognostic factors in soft tissue sarcoma: VEGFR-3 is an independent predictor of poor prognosis. PLoS One 2010;5(12):e15368
16.
Hamberg P, Verweij J, Sleijfer S. (Pre-) clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. Oncologist 2010;15(6):539-47
17.
van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet 2012;379(9829):1879-86 First positive Phase III trial with an anti-angiogenic drug in sarcomas.
..
18.
19.
Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 2009;27(19):3126-32 Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the management of
Expert Opin. Pharmacother. (2014) 15(2)
patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw 2010;8:S1-41 20.
Joensuu H. Adjuvant treatment of GIST: patient selection and treatment strategies. Nat Rev Clin Oncol 2012;9:351-8
21.
Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 2002;33:466-77
22.
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342-9
23.
Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer 2011;11:865-78
24.
Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-80
25.
Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 2012;307:1265-72
26.
Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005;11:4182-90
27.
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329-38
28.
Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011;129:245-55
29.
George S, Wang Q, Heinrich MC, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol 2012;30(19):2401-7
30.
Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib
227
J. Martin-Liberal et al.
Downloaded by [Monash University Library] at 16:57 10 November 2015
..
for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebocontrolled, phase 3 trial. Lancet 2013;381(9863):295-302 Positive Phase III trial in third-line setting in GIST.
31.
Meyers PA, Gorlick R. Osteosarcoma. Pediatr Clin North Am 44:973-89.1997
32.
Kung FH, Pratt CB, Vega RA, et al. Ifosfamide/etoposide combination in the treatment of recurrent malignant solid tumors of childhood. A Pediatric Oncology Group Phase II study. Cancer 1993;71(5):1898-903
33.
34.
35.
36.
37.
..
38.
39.
228
cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 2005;23(9):2004-11 40.
Wan X, Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist 2007;12(8):1007-18
41.
Sampson JR. Therapeutic targeting of mTOR in tuberous sclerosis. Biochem Soc Trans 2009;37(Pt 1):259-64
42.
Katz D, Lazar A, Lev D. Malignant peripheral nerve sheath tumour (MPNST): the clinical implications of cellular signalling pathways. Expert Rev Mol Med 2009;11:e30
43.
Endo M, Yamamoto H, Setsu N, et al. Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors. Clin Cancer Res 2013;19(2):450-61
Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314(25):1600-6 Fidler IJ, Sone S, Fogler WE, Barnes ZL. Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci USA 1981;78(3):1680-4
44.
Houghton PJ, Morton CL, Gorlick R, et al. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther 2010;9(1):101-12
50.
..
Demetri GD, Chawla SP, Ray-Coquard I, et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol 2013;31(19):2485-92 Phase III trial in maintenance in sarcomas with positive results but limited clinical benefit.
51.
Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 2005;29(10):1340-7
52.
Dickson MA, Tap WD, Keohan ML, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified welldifferentiated or dedifferentiated liposarcoma. J Clin Oncol 2013;31(16):2024-8 Successful Phase II trial with a targeted agent in well-differentiated/dedifferentiated liposarcoma.
.
MacEwen EG, Kurzman ID, Rosenthal RC, et al. Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J Natl Cancer Inst 1989;81(12):935-8
45.
Kleinerman ES, Meyers PA, Raymond AK, et al. Combination therapy with ifosfamide and liposomeencapsulated muramyl tripeptide: tolerability, toxicity, and immune stimulation. J Immunother Emphasis Tumor Immunol 1995;17(3):181-93
46.
Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children’s Oncology Group. J Clin Oncol 2008;26(4):633-8 First drug in decades that improves overall survival in sarcomas.
47.
Cohen EE, Wu K, Hartford C, et al. Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients. Clin Cancer Res 2012;18(17):4785-93
54.
Portera CA Jr, Ho V, Patel SR, et al. Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution. Cancer 2001;91(3):585-91
48.
Squillace RM, Miller D, Cookson M, et al. Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models. Mol Cancer Ther 2011;10(10):1959-68
55.
Lazar AJ, Das P, Tuvin D, et al. Angiogenesis-promoting gene patterns in alveolar soft part sarcoma. Clin Cancer Res 2007;13(24):7314-21
56.
Lorigan JG, O’Keeffe FN, Evans HL, Wallace S. The radiologic manifestations of alveolar soft-part sarcoma. AJR Am J Roentgenol 1989;153(2):335-9
57.
Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor
Chou AJ, Kleinerman ES, Krailo MD, et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Cancer 2009;115(22):5339-48 Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to
49.
Okuno S, Bailey H, Mahoney MR, et al. A phase 2 study of temsirolimus (CCI779) in patients with soft tissue sarcomas: a study of the Mayo phase 2 consortium (P2C). Cancer 2011;117(15):3468-75 Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol 2010;28(5):835-40
Chawla SP, Staddon AP, Baker LH, et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol 2012;30(1):78-84
Expert Opin. Pharmacother. (2014) 15(2)
53.
.
Ray-Coquard I, Blay JY, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, welldifferentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 2012;13(11):1133-40 Positive proof-of-concept Phase II trial in well-differentiated/dedifferentiated liposarcoma.
New drugs in sarcomas
for the treatment of cancer. Cancer Res 2005;65(10):4389-400 58.
.
59.
Downloaded by [Monash University Library] at 16:57 10 November 2015
60.
61.
62.
.
Kummar S, Allen D, Monks A, et al. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol 2013;31(18):2296-302 Successful Phase II trial in a subtype of sarcoma especially resistant to treatment. Towle MJ, Salvato KA, Budrow J, et al. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 2001;61:1013-21 Jordan MA, Kamath K, Manna T, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther 2005;4:1086-95 Okouneva T, Azarenko O, Wilson L, et al. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther 2008;7:2003-11 Sch€offski P, Ray-Coquard IL, Cioffi A, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol 2011;12(11):1045-52 Positive Phase II study in two histologies: leiomyosarcoma and liposarcoma.
63.
64.
65.
66.
.
Coffin CM, Watterson J, Priest JR, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor): a clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol 1995;19:859-72 Coffin CM, Patel A, Perkins S, et al. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol 2001;14(6):569-76 Cook JR, Dehner LP, Collins MH, et al. Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol 2001;25:1364-71 Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALKrearranged inflammatory myofibroblastic tumor. N Engl J Med 2010;363(18):1727-33 Dramatic response with a drug active against ALK chromosomal rearrangement.
67.
Amankwah EK, Conley AP, Reed DR. Epidemiology and therapies for metastatic sarcoma. Clin Epidemiol 2013;5:147-62
68.
Reeves BR, Smith S, Fisher C, et al. Characterization of the translocation between chromosomes X and 18 in
Expert Opin. Pharmacother. (2014) 15(2)
human synovial sarcomas. Oncogene 1989;4(3):373-8 69.
de Alava E. Molecular pathology in sarcomas. Clin Transl Oncol 2007;9:130-44
70.
Jain S, Xu R, Prieto VG, Lee P. Molecular classification of soft tissue sarcomas and its clinical applications. Int J Clin Expert Pathol 2010;3(4):416-28
71.
Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 2013;153(1):71-85
72.
Casali PG. Histology- and non-histology-driven therapy for treatment of soft tissue sarcomas. Ann Oncol 2012;23(Suppl 10):x167-9
Affiliation
Juan Martin-Liberal†, Charlotte Benson & Ian Judson † Author for correspondence The Royal Marsden Hospital, Sarcoma Unit, Fulham Road SW3 6JJ, London, UK Tel: +44 20 7808 2200; Fax: +44 20 7808 2113; E-mail: [email protected]
229
![[New drugs in rheumatology].](/assets/img/hold.png)
