|Year : 2017 | Volume
| Issue : 1 | Page : 20-28
Current and future systemic treatment options for advanced soft-tissue sarcoma beyond anthracyclines and ifosfamide
Nadia Hindi, Javier Martin-Broto
Instituto de Biomedicina de Sevilla (IBIS); Department of Medical Oncology, Hospital Universitario Virgen del Rocio, CSIC, Universidad de Sevilla, Seville, Spain
|Date of Submission||06-Nov-2016|
|Date of Acceptance||04-Jan-2017|
|Date of Web Publication||23-Feb-2017|
Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, CSIC, Universidad de Sevilla, C/Manuel Siurot s/n, 41013 Seville
Source of Support: None, Conflict of Interest: None
Sarcomas are rare, life-threatening, malignant tumors. Surgery is the cornerstone of therapy in the localized setting. About one-third of patients develop distant metastasis. In the metastatic setting, systemic therapy is the mainstay of treatment, and several second-line options are available, proving a modest survival increase for these patients. Trabectedin is an active drug with several described mechanisms of action. Although the objective response rate is low, about one-third of patients achieve disease stabilizations and a prolonged disease control. Interestingly, it has no accumulative toxicities. Pazopanib is the only targeted therapy approved for soft-tissue sarcoma (STS), with the exception of adipocytic sarcoma. Eribulin represents a recently approved therapeutic option for liposarcoma. Other drugs such as gemcitabine combinations, dacarbazine, and taxanes have also shown activity in second lines in advanced STS. The selection should be based on histologic subtype, patient characteristics, and toxicity profile among other factors. This review will summarize clinical development of the current and future therapeutic options for this heterogeneous group of diseases.
Keywords: Metastatic disease, sarcoma, systemic therapy, targeted therapy, translational research
|How to cite this article:|
Hindi N, Martin-Broto J. Current and future systemic treatment options for advanced soft-tissue sarcoma beyond anthracyclines and ifosfamide. Cancer Transl Med 2017;3:20-8
|How to cite this URL:|
Hindi N, Martin-Broto J. Current and future systemic treatment options for advanced soft-tissue sarcoma beyond anthracyclines and ifosfamide. Cancer Transl Med [serial online] 2017 [cited 2017 Dec 17];3:20-8. Available from: http://www.cancertm.com/text.asp?2017/3/1/20/200858
| Introduction|| |
Soft-tissue sarcoma (STS) is a heterogeneous group of more than fifty different subtypes, accounting for < 2% of all solid tumors in adults, with an estimated incidence of 5 new cases per 100,000 per year in Europe. Surgery is the mainstay of therapy in the localized setting. Radiotherapy and chemotherapy are administered in the adjuvant setting when indicated. Despite correct initial local management, about one-third of the patients will eventually develop metastasis and succumb to the disease. Anthracycline-based regimens have been the backbone in STS systemic therapy in the past 30 years, being the drugs used in the adjuvant setting when indicated, and in the first line of advanced disease. Although there is no formal demonstration of the superiority of combination chemotherapy over single-agent doxorubicin in terms of overall survival (OS) in advanced disease, the combination is superior in terms of response and progression-free survival (PFS), being a valuable option when tumor shrinkage is needed to palliate symptoms or in patients with potentially resectable disease. Beside anthracyclines and ifosfamide, there are other approved drugs (trabectedin, pazopanib, and eribulin) in STS and other drugs (dacarbazine, gemcitabine, and taxanes) with activity in this disease. In previous years, due to the greater number of available systemic therapies, the outcome of patients with advanced STS has been improved, achieving a median OS of up to 18 months. The greater background on the molecular pathogenic basis of the different histologic subtypes of STS, and the development of other promising molecules, could improve these results in the future, moving from the all-fits-one approach for a more personalized therapeutic algorithm.
| Current Systemic Options|| |
Trabectedin is an alkaloid originally derived from the marine tunicate Ecteinascidiaturbinata with several described mechanisms of action: interferes with DNA transcription, produces breaks in DNA double helix (activating the homologous recombination DNA repair mechanisms), and also has anti-inflammatory and antiangiogenic activities through tumor-associated macrophages.,, Many different schedules were used during its clinical development, being 1.5 mg/m2 in 24 h continuous infusion every 21 days in the recommended dose for STS. The principal studies are summarized in [Table 1]. Trabectedin is an active drug in second-line therapy for STS regarding the definition of the European Organisation for Research and Treatment of Cancer (EORTC), consistently showing 6-month progression-free rate (PFR) > 20% (24%–37%) in all clinical trials [Table 1].
For example, a phase II trial on 54 pretreated sarcoma patients showed 3- and 6-month PFR of 39% and 24%, respectively. In a phase II EORTC study which enrolled 104 previously treated patients, PFS at 3 and 6 months was remarkable (52% and 29%, respectively). Then, a randomized study comparing two schedules of trabectedin on pretreated patients with L-sarcomas (leiomyosarcoma and liposarcoma) was published. One hundred and thirty-four patients received 1.5 mg/m2 in 24 h every 3 weeks and 136 patients received 0.58 mg/m2/week 3 out of 4 weeks. Median PFS was significantly better for the 1.5 mg/m2 every 3-week arm: 3.3 vs. 2.3 months (P = 0.041).
These data resulted in the approval of trabectedin by the European Medicines Agency (EMA) in September 2007 for adult patients with pretreated advanced STS. Recently, the data from a phase III trial comparing trabectedin vs. dacarbazine in advanced L-sarcoma, in which the trabectedin arm showed significantly better PFS (4.2 vs. 1.5 months) with similar OS (12.4 vs. 12.9 months), led to the approval of trabectedin by the Food and Drug Administration (FDA).
Although response rate by the Response Evaluation Criteria in Solid Tumor (RECIST) is low (4%–8%),,, about one-third of patients achieve disease stabilizations and prolonged disease control. In this sense, it is not uncommon to have experiences of long-responder patients for more than 1 year. The drug has a manageable toxicity profile, with neutropenia, and elevation of transaminases being the most reported G3-4 toxicities. These toxicities, however, are not accumulative and can be reduced with an adequate premedication. Regarding the duration of therapy with trabectedin, a phase II trial from the French sarcoma group (T-DIS study) showed a benefit in terms of PFS (PFS at 6 months 51.9% vs. 23.1%, P = 0.02) for those patients receiving continuous therapy with trabectedin compared with those stopping the therapy and reassuming trabectedin at progression. Based on these results, therapy with trabectedin should be maintained up to progression or intolerance.
As said before, trabectedin could interfere with transcription factors. Many sarcomas are characterized by genetic translocations resulting in fusion proteins, which could work as transcription factors. The activity of trabectedin in translocation-related sarcomas (TRS) was shown in retrospective series with myxoid liposarcoma. A randomized phase II trial on patients with pretreated TRS showed a clear benefit from trabectedin compared with best supportive care (PFS 5.6 vs. 0.9 months, hazard ratio [HR]: 0.07). A randomized phase III study of trabectedin vs. doxorubicin-based chemotherapy as the first-line therapy in patients with TRS showed no significant differences in PFS between the two groups, but this study was underpowered due to a high proportion of patients being censored.
Taking all these results together, trabectedin represents an effective and safe second-line option for all sarcoma subtypes, especially interesting in L-sarcoma.
Pazopanib is an oral multi-tyrosine kinase inhibitor (TKI), which targets vascular endothelial growth factor receptor (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptor (PDGFR-α and PDGFR-β), c-Kit, fibroblastic growth factor receptor (FGFR-1, FGFR-2, and FGFR-3), and colony stimulating factor-1 receptor (CSF-1R). The first evidence of activity of pazopanib in sarcoma derives from a phase I trial in solid tumors, in which three patients with sarcoma obtained disease stabilizations lasting more than 6 months. The recommended dose for phase II trial was defined in 800 mg daily. In a subsequent phase II trial (EORTC 62043), 142 patients with advanced pretreated STS were included in four cohorts: adipocytic sarcomas, leiomyosarcoma, synovial sarcoma, and other subtypes. The cohort of adipocytic tumors was closed because activity data did not reach the prespecified threshold. PFS rate at 12 weeks was 44% in leiomyosarcoma, 49% in synovial sarcoma, and 39% in other histologic subtypes. Nine patients (5 of them with synovial sarcoma) experienced a RECIST partial response. These results led to the phase III pivotal PALETTE study, including 372 advanced pretreated sarcoma patients, randomized to pazopanib (800 mg daily) or placebo. The study was positive for its principal objective (PFS), with a median PFS of 4.6 months (95% confidence interval [CI]: 3.7–4.8) in the pazopanib group vs. 1.6 months (95% CI: 0.9–1.8) in the placebo group (HR: 0.31, 95% CI: 0.24–0.40, P < 0.0001). No statistically significant differences in terms of OS were detected: 12.5 months (95% CI: 10.6–14.8) in the pazopanib group vs. 10.7 months (95% CI: 8.7–12.8) in the placebo group (HR: 0.86, 95% CI: 0.67–1.11, P = 0.2514). Fourteen (6%) patients obtained a RECIST partial response, and toxicity profile was predictable, being asthenia (14%), hypertension (7%), transaminases elevation (gammaglutamyl transpeptidase 13%, aspartate transaminase 10%, and alanine transaminase 8%), and anorexia (6%), the most frequent grade 3–4 adverse events. Left ventricular ejection fraction decreased in 6.7% of patients (being symptomatic only in 1%), and 5% of patients experienced deep venous thrombosis. These results enabled the FDA and EMA approval in 2012 of pazopanib for advanced pretreated STS with the exception of liposarcoma. Recently, pazopanib has been tested in adipocytic sarcomas in clinical trials, showing preliminary activity in well-differentiated/dedifferentiated (WD/DD) liposarcoma.
Eribulin mesylate is an antimitotic agent, which acts by inhibiting microtubules' growth. A phase II trial assessed the safety and efficacy of eribulin in pretreated advanced STS. One-hundred and twenty-eight patients received eribulin 1.4 mg/m2 over 2–5 min at days 1 and 8 for every 3 weeks. They were included in four strata: adipocytic sarcoma (37 patients), leiomyosarcoma (40 patients), synovial sarcoma (19 patients), and other sarcomas (32 patients). The study was positive for its primary end point (PFS at 12 weeks) in the group of adipocytic sarcoma with 15 (46.9%) patients were progression free at 12 weeks, and leiomyosarcoma (12-week PFR: 31.6%). The most common grade 3–4 adverse events were neutropenia (52%), anemia (7%), fatigue (7%), and febrile neutropenia (6%). Based on these results, a phase III trial included 452 patients with advanced pretreated adipocytic sarcoma and leiomyosarcoma, which were randomized at 1:1 ratio to receive eribulin (1.4 mg/m2, intravenous [IV] on days 1 and 8) or dacarbazine (850–1200 mg/m2, IV on day 1) for every 21 days. The study was positive for its primary end point (OS). Median OS for eribulin and dacarbazine was 13.5 and 11.5 months, respectively (HR = 0.768, 95% CI: 0.618–0.954; P = 0.017). These differences were significant (15.6 vs. 8.4 months) for liposarcoma, yet not in the leiomyosarcoma cohort. These results led to the FDA approval of eribulin in advanced pretreated liposarcoma in January 2016.
Gemcitabine is a nucleoside analog, widely used in the treatment of sarcomas, and its activity has been assessed in several clinical trials [Table 2]. Gemcitabine in monotherapy has been tested in both nonselected STS and metastatic leiomyosarcoma. Several schedules have been used, with 1.000 mg/m2 over 30 min on days 1, 8, and 15 for every 28 days being the most used schedule. Fixed-dose rates (FDRs) of infusion of gemcitabine at 10 mg/m2/min are used in clinical trials on sarcoma, based on its higher efficacy compared to short infusions in carcinomas., Gemcitabine monotherapy 1.000 mg/m2 at FDR in leiomyosarcoma resulted in 3-month PFR of 57% and 68% in nonuterine and uterine leiomyosarcoma, respectively.
Combinations of gemcitabine have also been tested. The activity of the combination of gemcitabine 900 mg/m2 on days 1 and 8 plus docetaxel 100 mg/m2 on day 8 has been assessed in pretreated advanced uterine and soft-tissue leiomyosarcoma in several small phase II trials. This regimen was considered active  for leiomyosarcoma arising at all locations although women with uterine leiomyosarcoma seemed to benefit more: the 3-month PFR for patients with uterine leiomyosarcoma was 70%–75%, in contrast to 52% in nonuterine leiomyosarcoma. Data regarding the superiority of the combination with docetaxel vs. gemcitabine alone are conflicting. One phase II randomized trial, conducted in all STS subtypes, showed significantly more objective responses (16% vs. 8%), prolonged PFS (6.2 vs. 3 months) and OS (17.9 vs. 11.5 months), favoring the combination. However, in another phase II trial, enrolling only advanced leiomyosarcoma patients, differences were not found in terms of efficacy, and patients in the combination arm experienced more toxicity.
Gemcitabine-docetaxel is widely used in the USA as upfront line (not pretreated with anthracycline) in many STS, based on the results of a clinical trial in first line, which showed median PFS of 4.4 months in metastatic uterine leiomyosarcoma. Recently, the GeDDiS study did not show superiority of the first-line gemcitabine-docetaxel over doxorubicin alone, neither in terms of PFS nor in OS in a randomized phase III trial.
Another active combination (and synergistic in preclinical experiments) is gemcitabine plus dacarbazine. Two phase II studies developed by the Spanish Sarcoma Group for Research on Sarcoma tested the combination of FDR gemcitabine 1800 mg/m2 and dacarbazine 500 mg/m2 for every 2 weeks., The first study showed the activity of this regimen, showing a 3-month PFR of 48% and a median PFS of 3.9 months. After this study, a randomized phase II trial showed the superiority of the combination over dacarbazine alone (1.200 mg/m2 every 21 days), in terms of 3-month PFR (56% vs. 37%), median PFS (4.2 vs. 2 months), and median OS (16.8 vs. 8.2 months).
Despite the fact that confirmatory phase III trials are lacking, gemcitabine combinations represent an interesting therapeutic option in patients with pretreated STS, especially in leiomyosarcomas, and perhaps in other subtypes as well, such as undifferentiated pleomorphic sarcoma.
| Other Cytotoxic Agents|| |
Temozolomide and dacarbazine
Both temozolomide and dacarbazine are alkylating agents, with temozolomide being a prodrug of dacarbazine. Both agents have shown modest activity in monotherapy in pretreated STS., Temozolomide in a prolonged schedule (75–100 mg/m2 per day during 6 consecutive weeks) was tested in 48 patients with pretreated STS. Three-month PFR was 39.5% and RECIST response rate was 15.5%, and interestingly, responding patients maintained response for a long time (median of 12.5 months). Another study with a 5-day schedule of temozolomide in pretreated STS found modest activity of this drug. However, those patients with leiomyosarcoma had a median PFS and OS of 3.9 and 30.8 months, respectively. These drugs could be especially interesting in leiomyosarcoma. Solitary fibrous tumor (SFT) also seems to benefit from dacarbazine- and temozolomide-based regimens.,
Paclitaxel has shown activity in vascular sarcomas. The French sarcoma group enrolled 30 patients with advanced angiosarcoma in a phase II trial with weekly paclitaxel 80 mg/m2 days 1, 8, and 15, for every 28 days. Four-month PFR was 45%. A subsequent trial from the same group failed to show superiority with the addition of bevacizumab to weekly paclitaxel. This drug is also active in Kaposi sarcoma.
Other targeted therapies in special histologic subtypes
Some infrequent subtypes of STS have shown characteristically specific sensitivity for TKIs: perivascular epithelioid cell tumors with mTOR inhibitors,, inflammatory myofibroblastic tumor with crizotinib, dermatofibrosarcoma protuberans and imatinib.,, Antiangiogenics such as sunitinib and cediranib have shown activity in alveolar soft-part sarcoma,, extraskeletal myxoid chondrosarcoma, and SFT.,
| Upcoming Drugs|| |
Olaratumab is a human monoclonal antibody that binds the external domain of PDGFR-α, blocking the interaction of the receptor with its ligands (PDGF-AA, PDGF-BB, and PDGFR-CC). PDGFR-α is an interesting target in sarcoma, as overexpression has been demonstrated in several sarcoma subtypes., Olaratumab showed its safety in a phase I trial, without dose-limiting toxicities described., A phase Ib/II trial in combination with doxorubicin was developed in patients with unresectable/advanced STS. Patients received the combination of 75 mg/m2 on day 1 for every 21 days with olaratumab/placebo 15 mg/kg on days 1 and 8 for every 21 days. The trial met its primary end point, showing a longer PFS for the olaratumab arm compared to the placebo arm (6.6 vs. 4.1 months, HR: 0.672). Strikingly, the patients on the combination arm achieved an impressive median OS of 25 vs. 14.7 months in the doxorubicin arm (HR: 0.44, P = 0.0005). Given these results, in September 2016, the EMA has provided a conditional marketing authorization for olaratumab in advanced/metastatic STS. A phase III trial comparing doxorubicin 75 mg/m2vs. doxorubicin 75 mg/m2 plus olaratumab 15 mg/m2 has recently completed recruitment. If these impressive results on OS are confirmed, doxorubicin in monotherapy would no longer be the standard upfront systemic treatment in advanced STS, representing the greatest paradigmatic change in the last three decades in the clinical practice of STS. Olaratumab is also being tested in combination with gemcitabine plus docetaxel in a phase Ib/II ongoing trial.
Alterations of the cell cycle regulators are a common feature of many neoplasms, including sarcoma. Palbociclib is an oral inhibitor of CDK4/6, already approved in the treatment of hormone receptor-positive metastatic breast cancer in combination with endocrine therapy., The drug has already showed activity in sarcoma. A phase II trial exploring the safety and efficacy of palbociclib in a cohort of 30 patients with pretreated WD/DD liposarcoma (harboring CDK4 amplification and functional Rb) showed a 3-month PFR of 66%, with a median PFS of 18 weeks. Neutropenia was the most frequent toxicity in these patients, being G3 in 43% of the cohort, but only one patient presented febrile neutropenia. Additional preclinical exploration of CDK4/6 inhibition with palbociclib in sarcoma cell lines as well as in xenograft models showed a good correlation between CDK4 overexpression and efficacy of palbociclib in various sarcoma subtypes. Interestingly, overexpression instead of amplification of CDK4 and no overexpression of p16 were good predictive biomarkers for efficacy.
Selinexor is a selective inhibitor of nuclear export (SINE) and acts by binding covalently to human XPO1, a member of the karyopherin b superfamily of nuclear transport proteins. XPO1 facilitates the nuclear export of RNA and proteins such as p53, retinoblastoma, and adenomatous polyposis coli, cell cycle regulators such as p21, and plays a role in mitotic progression and chromosome segregation. Recent preclinical data have shown that selinexor is able to induce apoptosis in liposarcoma and other sarcoma subtypes both in vitro and in vivo. Its safety and the first data on efficacy have been shown in a phase Ib trial in patients with refractory sarcoma, in which 7/15 (47%) of patients with liposarcoma experienced disease stabilization lasting > 4 months. An ongoing phase II/III trial will test its efficacy in advanced liposarcoma (NCT02606461).
Targeting immune system
Immunomodulation is a very topical research field in oncology, and although in sarcoma it is still in an early phase of clinical development, there is evidence to support its potential interest: some of the latest registered drugs in sarcoma, mifamurtide, trabectedin, and pazopanib, have prominent roles in immunomodulation. There is also preclinical evidence suggesting an immune-related effect (mediated by T-cell activation) of doxorubicin efficacy in sarcoma.,, One of the most well-studied targets in immune-oncology is programed death receptor 1 (PD-1), which has been minimally investigated in sarcoma patients. For other tumor types, expression of PD-1/PD-L1 not only portended a worse prognosis,, but also was predictive of response to therapy., Expression of PD-L1 in sarcoma has been demonstrated in several studies, with wide variations among series (12%–58%), suggesting doubts about the reliability of PD-L1 immunostaining., PD-L1 expression has been shown in both translocation and non-TRS: leiomyosarcoma 70%, synovial sarcoma 75%, undifferentiated pleomorphic sarcoma 82%, malignant peripheral nerve sheath tumor 50%, and Ewing sarcoma 67%. Currently, several anti-PD1 compounds are under trial in sarcoma. The preliminary results of a phase II trial with pembrolizumab on unselected sarcomas have shown responses in patients with undifferentiated pleomorphic sarcoma and liposarcoma. Other immunotherapies such as New York esophageal squamous cell carcinoma 1 (NY-ISO) inhibition have been developed in sarcoma. This antigen is expressed in several malignancies and is highly immunogenic., Recent studies have tested the expression of NY-ESO-1 in mesenchymal tumors, showing positivity in 88%–100% of myxoid liposarcoma, 49% of synovial sarcomas, 35% of myxofibrosarcomas, and 28% of conventional chondrosarcomas. Immunotherapy using autologous T-cells retrovirally transduced with an NY-ESO-1-reactive T-cell receptor (TCR) has shown promising results in patients harboring NY-ESO-1-positive synovial sarcoma. In a pilot study with 18 pretreated advanced synovial sarcoma patients, therapy with NY-ESO-1 TCR-transduced T-cells induced objective RECIST responses in 11 patients (61%). One patient even reached a complete radiologic response. Partial responses lasted for 3–18 months, and the estimated overall 3- and 5-year survival rates were 38% and 14%, respectively. In this study, the authors found a correlation between the total number of T-cells and the number of antigen-reactive T-cells administered to patients and the response to therapy, but predictive factors still need to be identified.
| Conclusion|| |
There are several active second-line options for patients with advanced STS, and as there are lacking comparative trials addressing the best sequence, the selection should be based on histologic subtype, patient characteristics, and toxicity profile among other factors. Studies focusing on predictive biomarkers are needed in advanced STS. There are several promising drugs in the development of sarcoma, and the increasing knowledge in the molecular background will be helpful to identify new potential therapeutic targets.
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Conflict of interest
There are no conflicts of interest.
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[Table 1], [Table 2]