REVIEW URRENT C OPINION
Current clinical trials for advanced osteosarcoma and soft tissue sarcoma Stefan Sleijfer a and Hans Gelderblom b
Purpose of review Sarcomas form a rare group of tumors greatly differing between each other in biology, behavior, and sensitivity to treatments. Their rarity and heterogeneity render it very challenging to conduct clinical trials, a phenomenon taking place in virtually all tumor types wherein detailed characterization reveals that most histopathologically categorized tumor groups consist of many small subentities. As sarcoma clinicianscientists have already long faced the challenges accompanying trials in rare tumors, lessons learned from sarcoma studies apply also to other tumor types. This review addresses current clinical trials in osteosarcomas and soft tissue sarcomas (STSs). Recent findings A wide range of antitumor agents is being explored in osteosarcomas and STS. Although studies increasingly take into account the heterogeneity of sarcomas by stratifying studies for subtypes or by performing studies in specific subtypes only, still many studies are conducted in patients unselected for sarcoma subtype thereby being at risk to miss potential antitumor activity limited to specific subgroups. Summary Consensus on what preclinical work is needed before starting sarcoma trials in humans, how to select patients, trial design, and the choice of endpoints is warranted. To address the challenges accompanying studies in sarcoma, global collaboration should become more intensified. Keywords bone sarcomas, new treatments, soft tissue sarcomas
INTRODUCTION The group of sarcomas is a very rare and heterogeneous group of tumors. Based on the different sites of origin and insights on how sarcomas should be treated, the most commonly used categorization of sarcomas for treatment decision making divides sarcomas into osteosarcomas, small round cell sarcomas (mainly Ewing sarcomas), soft tissue sarcomas (STSs), and gastrointestinal stromal tumors (GISTs). However, this classification oversimplifies reality. For example, more than 50 different subtypes are distinguished in the STS group by histopathological examination alone, whereas using molecular characterization, the number of distinct subentities further increases. The recognition that the group of sarcomas comprises many small subsets with important differences in genetic background, clinical behavior, and sensitivity to systemic antitumor compounds has confronted physician-scientists with many challenges. This holds true for treatment decision making but also for designing clinical trials for www.co-oncology.com
subgroups that constantly become smaller in numbers of available patients. As such, sarcomas form a prototype for all tumor types and lessons learned from clinical trials in sarcomas are applicable to non-sarcoma tumor types as well wherein likewise, most histopathologically defined tumor types actually comprise many small molecular subsets. This review focuses on current clinical trials in osteosarcomas and advanced STS. It does not intend to provide a complete oversight of all the clinical studies ongoing, but aims to describe which classes
a
Department of Medical Oncology, Erasmus MC – Cancer Institute, Erasmus University Medical Center, Rotterdam and bDepartment of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands Correspondence to Stefan Sleijfer, MD, PhD, Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel: +31 10 7034447; fax: +31 10 7043001; e-mail: [email protected] Curr Opin Oncol 2014, 26:434–439 DOI:10.1097/CCO.0000000000000093 Volume 26 Number 4 July 2014
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Clinical trials in sarcomas Sleijfer and Gelderblom
KEY POINTS This manuscript provides an overview on current clinical trials in osteosarcomas and advanced STS. Important aspects in study design such as stratification for subtypes or choice of endpoint are frequently not sufficiently taken into account. Global consensus on how to select patients, trial design, and the choice of endpoints is warranted.
of drugs are currently explored, the directions in which sarcoma clinical trials develop, and potential pitfalls in designing sarcoma studies.
OSTEOSARCOMAS Osteosarcoma mainly occurs in people between 0 and 24 years with an estimated yearly incidence of approximately five new cases per million. Systemic agents play an important role in treatment of patients presenting with localized disease, in addition to surgery, as well as in the metastatic setting.
Current treatment The introduction of multiagent (neo)adjuvant chemotherapy for osteosarcoma in the 1960s has increased long-time survival from 10–15% to 55–70% [1]. Commonly used drugs are doxorubicin, methotrexate, cisplatin, ifosfamide, and to a lesser extent etoposide. A recent meta-analysis shows that a three-drug regimen including the most active drug doxorubicin is the most efficacious regimen [2]. In Europe, but not in the United States, the drug muramyl-tripeptide (MTP), which is likely to act through immune activation, was registered in combination with chemotherapy for the primary treatment of osteosarcoma [3,4]. However, how to put the outcomes of the study underlying registration [3,4] into perspective is still heavily debated [5]. Consequently, in the most recent European Society for Medical Oncology guidelines on bone tumors, no consensus could be reached on its routine use [6]. For recurrent systemic disease, there is no standard treatment other than re-challenging patients to the drugs mentioned above.
Developments in clinical studies and drug classes being studied in osteosarcoma Given the presumed immunogenicity of osteosarcoma, pegylated interferon (PEG-IFN) was studied in patients with a good pathological response to preoperative chemotherapy in the primary treatment of
nonmetastatic high-grade osteosarcoma in the transatlantic phase III EURAMOS study (NCT00134030) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). From the 1034 eligible patients, 715 were randomized (69%) and only 76% of the patients allocated to PEG-IFN actually started treatment, mainly because of patient refusal. The eventfree survival (primary endpoint) was not statistically improved in the PEG-IFN arm, though this may have been influenced by the high treatment refusal rate [7]. Another agent, which additionally to effects on the bone may also yield immune activation, is zoledronate. Following preclinical evidence of the activity of this third-generation bisphosphonate against osteosarcoma [8] and the first clinical feasibility study [9], a randomized phase III study investigates the addition of zoledronate to multiagent chemotherapy (NCT00470223) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). In the relapsed metastatic disease, several agents failed to improve outcome including mammalian target of rapamycin (mTOR) inhibitors [10]. The vascular-endothelial growth factor receptor (VEGFR) inhibitor sorafenib showed promising results in a phase II study: median progression-free survival (PFS) and overall survival (OS) were 4 and 7 months, respectively, comparing favorably with historical controls [11]. A randomized study with this or another VEGFR inhibitor needs to confirm these findings to change practice. A placebo-controlled randomized phase II study assesses the Src inhibitor saracatinib after resection of pulmonary metastases (NCT00752206) (Clinical Trials Gov. http://clinical trials.gov/ assessed on 20 January 2014). In addition to these ‘targeted’ approaches, immunotherapy remains an attractive target in osteosarcoma given the intriguing outcomes with the immune modulator MTP [3,4]. Novel studies with this and other immune-modulating agents, such as checkpoint inhibitors, are therefore warranted.
SOFT TISSUE SARCOMAS STS mainly affects people between 60 and 70 years but with a wide spread in age. Estimated annual incidence is approximately five new cases per 100 000. The role of systemic agents in the treatment of patients in the adjuvant setting is heavily debated and will not be discussed here. Systemic agents form the mainstay of treatment for those with metastatic disease.
Current standard Numerous antitumor compounds have activity in the diverse STS subgroups, but only a few have been
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studied in randomized, controlled phase III trials. Doxorubicin monotherapy has long been considered standard first-line treatment for advanced STS patients, regardless of subtype [12]. Though ifosfamide monotherapy has equivalent efficacy [13], doxorubicin is preferred given its more favorable toxicity profile. A phase III study showed that the combination of doxorubicin and ifosfamide, both administered at full single-agent doses, improved response rate (13 vs. 26%) and median PFS (4.5 vs. 7.4 months) over doxorubicin. The OS, however, the primary study endpoint, was equivalent [14]. As expected, toxicity was much greater in the combination arm. Many still consider, therefore, doxorubicin monotherapy as standard first line, though for fit patients in high need for a response, for example, because of a large mass causing pain, the combination can be considered [15]. In patients failing to doxorubicin-based or ifosfamide-based chemotherapy, the tyrosine kinase inhibitor (TKI) pazopanib targeting amongst others VEGFR has been registered. Following a phase II study in four tumor strata showing that pazopanib had insufficient activity against adipocytic sarcomas warranting further investigation [16], a phase III study showed the superiority of pazopanib over placebo in terms of PFS in nonadipocytic STS [17 ]. &&
Developments in clinical studies and drug classes being studied in STS Most studies in advanced STS performed until a few years ago grouped all STS subtypes together. This was mainly prompted by the rare incidence of STS rendering it difficult to stratify for the diverse subtypes or to perform studies in a specific tumor type. However, the great heterogeneity in sensitivity to systemic agents between STS subtypes and the enormous impact that may have on outcome of clinical studies is increasingly recognized. For example, pazopanib did show sufficient activity prompting further study in a phase III study in synovial sarcomas, leiomyosarcomas and the group of other STS, but not in adipocytic tumors [16]. If pazopanib had been explored in a phase II study in which all STS tumor types were included without stratification and predominantly patients with advanced adipocytic sarcomas would have been included, then the antitumor activity of pazopanib would probably not have been detected. Consequently, STS studies must either be randomized with controlled equal distribution of subtypes across the different treatment arms or in case of nonrandomized studies, must be performed in selective tumor subtypes or stratified for STS subentity. 436
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Nevertheless, there is still a substantial number of studies in which all STS subgroups can be included without stratification. This mostly concerns studies in which agents with known activity are combined with each other or that new agents are added to a standard agent. An example of the latter is a phase III study of doxorubicin versus the combination of doxorubicin with TH-302, a prodrug that under hypoxic circumstances converts into the alkylator bromo-isophosphoramide mustard (NCT01440088) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). Another study in which all STS subtypes, liposarcomas excepted, can be included is a randomized phase II study of gemcitabine with pazopanib versus gemcitabine combined with docetaxel in pretreated patients (NCT01593748) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). Previously, the combination of gemcitabine and docetaxel showed superior outcomes over gemcitabine alone in a group of patients with a broad range of histologies [18] and is widely used. Although gemcitabine was not considered active in a group of unselected STS [19], gemcitabine induces antitumor activity against leiomyosarcomas [20]. As a result, the interpretation of the outcome of the randomized study comparing gemcitabine/docetaxel versus gemcitabine/pazopanib is hindered if leiomyosarcoma patients are not equally distributed between both treatment arms. Another study ongoing in patients who failed to prior chemotherapy but unselected for STS subtype is a randomized study comparing gemcitabine/docetaxel versus the same regime combined with MORAb-004, an antibody against endosialin, which is expressed on tumor-associated pericytes (NCT01574716) (Clinical Trials Gov. http://clinical trials.gov/ assessed on 20 January 2014). Several single-arm phase II studies have been initiated in advanced STS patients examining novel agents such as cabozantinib (NCT01755195) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014), a dual inhibitor of MET and VEGFR, and ENMD-2076, an aurora A kinase inhibitor (NCT01719744) (Clinical Trials Gov. http://clini caltrials.gov/ assessed on 20 January 2014). The rationale behind these studies is that the VEGFVEGFR pathway, MET, and aurora A kinase can be deregulated in sarcomas [21,22]. However, as it is unlikely that these agents will show equivalent activity against all STS subtypes, such studies are at risk to miss potential benefit in a particular STS subtype if not stratified for subtype. In order to attenuate this, several single-arm phase II studies on novel compounds have a design in which the activity is separately and simultaneously assessed in diverse STS subtypes cohorts. Examples include axitinib, a VEGFR-TKI (NCT01140737) Volume 26 Number 4 July 2014
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(Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014) and MLN8237, an aurora A kinase inhibitor (NCT01653028) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). Also the microtubilin-targeting agent eribulin has been assessed in such a design. In a nonrandomized phase II study, eribulin had sufficient antitumor activity in pretreated patients with adipocytic tumors and leiomyosarcomas warranting further investigation in a phase III study [23]. The phase III study comparing eribulin to dacarbazine in these particular STS subtypes has recently completed accrual (NCT01327885) (Clinical Trials Gov. http://clinical trials.gov/ assessed on 20 January 2014). Additionally to design, also the choice of the primary endpoint is crucial. In many phase II studies, response rate is endpoint. However, antitumor agents can prolong PFS or OS without inducing tumor shrinkage. For such agents, the PFS is a valid endpoint, in particular, when assessed in a randomized setting [24]. In that sense, the randomized, double-blind, placebo-controlled, phase II study on regorafenib in advanced STS patients failing to anthracyclines, which is performed in four different strata (liposarcoma, leiomyosarcoma, synovial sarcoma and group of other eligible sarcomas), with PFS as primary endpoint, is a very well designed study (NCT01900743) (Clinical Trials Gov. http:// clinicaltrials.gov/ assessed on 20 January 2014). There is an increasing number of trials in which only one or two STS subentities are studied. This applies particularly to leiomyosarcomas, as this subtype is relatively frequent. Leiomyosarcomas exhibit sensitivity to a wide range of antitumor agents. Besides doxorubicin and ifosfamide, other regimens include gemcitabine, the combination of gemcitabine/docetaxel, dacarbazine, pazopanib, and trabectedin. Apart from a study comparing gemcitabine versus the combination gemcitabine/docetaxel showing equivalent activity [20], none of these regimens have been compared head-to-head in leiomyosarcomas. The outcome of a randomized study of trabectedin versus dacarbazine in advanced leiomyosarcomas is therefore of major interest (NCT01343277) (Clinical Trials Gov. http://clinical trials.gov/ assessed on 20 January 2014). Another study assesses the combination of gemcitabine/ pazopanib in pretreated patients with metastatic leiomyosarcoma (NCT01442662) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). However, how such a combination compares to one of the agents administered as monotherapy cannot be established from a nonrandomized trial like this one [25]. A trial from which certainly a conclusion can be drawn is a phase III study in uterine leiomyosarcoma
in which the added value of bevacizumab to the widely used gemcitabine/docetaxel combination is examined (NCT01012297) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). Bevacizumab enhances the outcomes of several chemotherapeutic regimens in other diseases such as colorectal cancer. There is however evidence that the added value of bevacizumab depends on the chemotherapeutic agent with which it is combined. In breast cancer, the added value of bevacizumab to three weekly docetaxel seems to be less profound compared with that observed with weekly paclitaxel [26]. Furthermore, bevacizumab enhanced antitumor effects from paclitaxel, but not from gemcitabine in a preclinical model [27]. Obviously, these results cannot be translated to leiomyosarcoma patients, but it is questionable whether gemcitabine and docetaxel are the most attractive agents to be explored together with bevacizumab. Also in liposarcoma, several studies are ongoing. Importantly, also the group of liposarcomas is a heterogeneous one in which several subgroups differing in genetic background and clinical behavior can be distinguished [28]. De-differentiated liposarcomas are characterized by co-amplification of MDM2 and CDK4. Clearly, amplification of a gene does not imply that such a gene is also a tumordriving factor, but based on preclinical models and on interesting data in the pre-operative setting [29 ], ongoing clinical trials on CDK4 and MDM2 inhibition in de-differentiated liposarcoma have a strong rationale (NCT01209598, NCT01636479) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). A first phase II study in CDK4-amplified liposarcomas showed interesting results [30]. Other tumor types in which studies are ongoing include alveolar soft part sarcomas (ASPSs). ASPS is a very rare and extremely chemo-resistant STS subtype, characterized by a specific translocation [t(X,17)(p11;q25)], which eventually leads to uncontrolled transcription of TFE3-regulated genes such as c-MET and several pro-angiogenic factors. Cediranib, a VEGFR-TKI, yielded an unprecedented high response rate of 35% together with durable disease stabilization in a single-arm study [31]. To put the activity of VEGFR-TKIs better into perspective, a randomized phase II trial comparing sunitinib versus cediranib has been started (NCT01391962) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014) as well as a randomized, double-blind placebo-controlled phase II study (NCT01337401) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). Also in metastatic angiosarcomas, several studies are ongoing. In addition to diverse VEGFR-TKIs
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such as pazopanib (NCT01462630), a randomized phase II study explores the efficacy of weekly paclitaxel versus that of the combination of bevacizumab and weekly paclitaxel (NCT01303497) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014).
DISCUSSION As becomes apparent from this review, many studies are ongoing in advanced osteosarcoma and STS. Regimens currently being explored in osteosarcoma and STS are as follows: (1) Osteosarcoma (a) Primary treatment: (i) Maintenance pegylated interferon (PEG-IFN) (ii) Zoledronate (bisphosphonate) added to standard chemotherapy (b) Relapsed disease: (i) Sorafenib (VEGFR-TKI) (ii) Saracatinib (src inhibitor) (2) STS (a) First-line setting: (i) Combination of doxorubicin with TH302 (b) Second line and beyond: (i) Gemcitabine with pazopanib (ii) Gemcitabine/docetaxel with MORAb004 (antibody against endosialin) (iii) Cabozantinib (dual inhibition of MET and VEGFR) (iv) ENMD-2076and MLN8237 (aurora A kinase inhibitors) (v) Axitinib and regorafenib (VEGFRTKIs) (vi) Erubilin (in leiomyosarcoma and liposarcoma) (vii) Trabectedin (in leiomyosarcoma) (viii) Gemcitabine/pazopanib (in leiomyosarcoma) (ix) Bevacizumab with gemcitabine/docetaxel(in leiomyosarcoma) (x) PD0332991 (CDK4 inhibitor in dedifferentiated liposarcoma) (xi) SAR405838 (MDM2 inhibition in dedifferentiated liposarcoma) (xii) Cediranib and sunitinib (VEGFR-TKI in ASPS) (xiii) Pazopanib (in angiosarcoma) (xiv) Bevacizumab with weekly paclitaxel (in angiosarcoma) Unfortunately, because of poor study designs, many of these studies will not yield robust 438
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outcomes, particularly in advanced STS wherein great differences in clinical behavior and sensitivity to antitumor compounds across subtypes can largely impact study outcomes. Results from single-arm trials in which all sarcoma subtypes are grouped together or from studies on drug combinations in which one of the compounds has known antitumor activity will therefore be impossible to interpret [25]. Additionally to design, also the choice of the endpoint is crucial, particularly in single-arm phase II screening studies. The presumed mechanism of action of the drug under study should be taken into account. A drug that is cytostatic rather than cytotoxic is unlikely to induce a high response rate. In such cases, an endpoint capturing the drug’s ability to induce disease stabilization is indicated such as the progression-free rate at 3 months. Importantly, in such a case, only patients with objective progression within 3 months before study entry should be included. Otherwise, it cannot be excluded that cases with no progression at this time point do so because of an indolently growing tumor [24]. For many studies, the underlying rationale to explore a certain drug or combination is that the presumed target of treatment does occur in the tumor type of interest or that in case of combinations, both drugs exert activity as single agent. Obviously, such observations do not guarantee success. More insight into the mechanism of action or interaction between drugs is required before embarking on large and expensive clinical trials. Clearness about the mechanism of action hopefully allows to identify predictive profiles, which can be used to select the right patients for the studies. Additionally to preclinical models, insight into mechanisms of action and early hints whether or not a compound exerts effects against a particular sarcoma subtype can be obtained from small proofof-concept studies in the pre-operative period in patients with nonmetastatic disease. A nice example of this approach is a study on a MDM2 antagonist administered for a short period prior to tumor resection in which the surgical specimen was assessed for drug-specific effects [29 ]. &&
CONCLUSION The great necessity of studies in sarcomas is underlined by the poor prognosis that patients with these diseases face, in particular those with metastatic disease. Given the difficulties of performing studies in sarcomas because of their rarity and heterogeneity, consensus on how to structure and conduct clinical studies in sarcoma is needed. This applies on the work that needs to be done before the initiation Volume 26 Number 4 July 2014
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of clinical trials, the exact design, selection of patients, and the choice of endpoints. Global collaboration as offered by networks such as EURAMOS and World Sarcoma Network is imperative to achieve this. Acknowledgements Research funding: S.S. received funding from GSK, Pharmamar, Amgen, Roche; speaker’s fee: GSK. H.G. received funding from Novartis, Pfizer, GSK. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Puri A, Jaffe N, Gelderblom H. Osteosarcoma: lessons learned and future avenues. Sarcoma 2013; 2013:641687. 2. Anninga JK, Gelderblom H, Fiocco M, et al. Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur J Cancer 2011; 47:2431–2445. 3. Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 2005; 23:2004–20114. 4. 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; 26:633–638. 5. Bielack SS, Marina N, Ferrari S, et al. Osteosarcoma: the same old drugs or more? J Clin Oncol 2008; 26:3102–3103. 6. ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (Suppl 7):vii100–vii109. 7. Bielack S, Smeland S, Whelan J, et al. MAP plus maintenance pegylated interferon a-2b (MAPIfn) versus MAP alone in patients with resectable highgrade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 ‘good response’ randomization. J Clin Oncol )2013; (31suppl); abstr LBA1050. 8. Evdokiou A, Labrinidis A, Bouralexis S, et al. Induction of cell death of human osteogenic sarcoma cells by zoledronic acid resembles anoikis. Bone 2003; 33:216–228. 9. Goldsby RE, Fan TM, Villaluna D, et al. Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Eur J Cancer 2013; 49:2384–2391. 10. 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; 31:2485–2492. 11. Grignani G, Palmerini E, Dileo P, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol 2012; 23:508– 516. 12. Sleijfer S, Seynaeve C, Verweij J. Using single-agent therapy in adult patients with advanced soft tissue sarcoma can still be considered standard care. Oncologist 2005; 10:833–841.
13. Lorigan P, Verweij J, Papai Z, et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 2007; 25:3144–3150. 14. Judson I, Verweij J, Gelderblom H, et al. Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol 2012; 23 (suppl 9); LBA7. 15. Blay JY, Sleijfer S, Scho¨ffski P, et al. International expert opinion on patienttailored management of soft tissue sarcomas. Eur J Cancer 2014; 50:679– 689. 16. 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; 27:3126–3132. 17. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft&& tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379:1879–1886. This is a phase III study showing the efficacy of TKIs in STS. 18. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol 2007; 25:2755– 2763. 19. Svanca´rova´ L, Blay JY, Judson IR, et al. Gemcitabine in advanced adult softtissue sarcomas A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002; 38:556–559. 20. Pautier P, Floquet A, Penel N, et al. Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group Study (TAXOGEM study). Oncologist 2012; 17:1213–1220. 21. Lahat G, Zhang P, Zhu QS, et al. The expression of c-MET pathway components in unclassified pleomorphic sarcoma/malignant fibrous histiocytoma (UPS/MFH): a tissue microarray study. Histopathology 2011; 59:556–561. 22. Brewer Savannah KJ, Demicco EG, et al. Dual targeting of mTOR and auroraA kinase for the treatment of uterine Leiomyosarcoma. Clin Cancer Res 2012; 18:4633–4645. 23. Scho¨ffski 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; 12:1045–1052. 24. Sleijfer S, Wagner AJ. The challenge of choosing appropriate end points in single-arm phase II studies of rare diseases. J Clin Oncol 2012; 30:896– 898. 25. Van Glabbeke M, Steward W, Armand JP. Non-randomised phase II trials of drug combinations: often meaningless, sometimes misleading. Are there alternative strategies? Eur J Cancer 2002; 38:635–638. 26. Rossari JR, Metzger-Filho O, Paesmans M, et al. Bevacizumab and breast cancer: a meta-analysis of first-line phase III studies and a critical reappraisal of available evidence. J Oncol 2012; 2012:417673. 27. Shaked Y, Henke E, Roodhart JM, et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 2008; 14:263–273. 28. Jones RL, Fisher C, Al-Muderis O, et al. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer 2005; 41:2853–2860. 29. Ray-Coquard I, Blay JY, Italiano A, et al. Effect of the MDM2 antagonist && RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 2012; 13:1133–1140. This is the study showing the great potential of performing screening studies with novel drugs in the pre-operative setting in patients. 30. Dickson MA, Tap WD, Keohan ML, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 2013; 31:2024–2028. 31. Kummar S, Allen D, Monks A, et al. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol 2013; 31:2296–2302.
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Current clinical trials for advanced osteosarcoma and soft tissue sarcoma Stefan Sleijfer a and Hans Gelderblom b
Purpose of review Sarcomas form a rare group of tumors greatly differing between each other in biology, behavior, and sensitivity to treatments. Their rarity and heterogeneity render it very challenging to conduct clinical trials, a phenomenon taking place in virtually all tumor types wherein detailed characterization reveals that most histopathologically categorized tumor groups consist of many small subentities. As sarcoma clinicianscientists have already long faced the challenges accompanying trials in rare tumors, lessons learned from sarcoma studies apply also to other tumor types. This review addresses current clinical trials in osteosarcomas and soft tissue sarcomas (STSs). Recent findings A wide range of antitumor agents is being explored in osteosarcomas and STS. Although studies increasingly take into account the heterogeneity of sarcomas by stratifying studies for subtypes or by performing studies in specific subtypes only, still many studies are conducted in patients unselected for sarcoma subtype thereby being at risk to miss potential antitumor activity limited to specific subgroups. Summary Consensus on what preclinical work is needed before starting sarcoma trials in humans, how to select patients, trial design, and the choice of endpoints is warranted. To address the challenges accompanying studies in sarcoma, global collaboration should become more intensified. Keywords bone sarcomas, new treatments, soft tissue sarcomas
INTRODUCTION The group of sarcomas is a very rare and heterogeneous group of tumors. Based on the different sites of origin and insights on how sarcomas should be treated, the most commonly used categorization of sarcomas for treatment decision making divides sarcomas into osteosarcomas, small round cell sarcomas (mainly Ewing sarcomas), soft tissue sarcomas (STSs), and gastrointestinal stromal tumors (GISTs). However, this classification oversimplifies reality. For example, more than 50 different subtypes are distinguished in the STS group by histopathological examination alone, whereas using molecular characterization, the number of distinct subentities further increases. The recognition that the group of sarcomas comprises many small subsets with important differences in genetic background, clinical behavior, and sensitivity to systemic antitumor compounds has confronted physician-scientists with many challenges. This holds true for treatment decision making but also for designing clinical trials for www.co-oncology.com
subgroups that constantly become smaller in numbers of available patients. As such, sarcomas form a prototype for all tumor types and lessons learned from clinical trials in sarcomas are applicable to non-sarcoma tumor types as well wherein likewise, most histopathologically defined tumor types actually comprise many small molecular subsets. This review focuses on current clinical trials in osteosarcomas and advanced STS. It does not intend to provide a complete oversight of all the clinical studies ongoing, but aims to describe which classes
a
Department of Medical Oncology, Erasmus MC – Cancer Institute, Erasmus University Medical Center, Rotterdam and bDepartment of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands Correspondence to Stefan Sleijfer, MD, PhD, Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel: +31 10 7034447; fax: +31 10 7043001; e-mail: [email protected] Curr Opin Oncol 2014, 26:434–439 DOI:10.1097/CCO.0000000000000093 Volume 26 Number 4 July 2014
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Clinical trials in sarcomas Sleijfer and Gelderblom
KEY POINTS This manuscript provides an overview on current clinical trials in osteosarcomas and advanced STS. Important aspects in study design such as stratification for subtypes or choice of endpoint are frequently not sufficiently taken into account. Global consensus on how to select patients, trial design, and the choice of endpoints is warranted.
of drugs are currently explored, the directions in which sarcoma clinical trials develop, and potential pitfalls in designing sarcoma studies.
OSTEOSARCOMAS Osteosarcoma mainly occurs in people between 0 and 24 years with an estimated yearly incidence of approximately five new cases per million. Systemic agents play an important role in treatment of patients presenting with localized disease, in addition to surgery, as well as in the metastatic setting.
Current treatment The introduction of multiagent (neo)adjuvant chemotherapy for osteosarcoma in the 1960s has increased long-time survival from 10–15% to 55–70% [1]. Commonly used drugs are doxorubicin, methotrexate, cisplatin, ifosfamide, and to a lesser extent etoposide. A recent meta-analysis shows that a three-drug regimen including the most active drug doxorubicin is the most efficacious regimen [2]. In Europe, but not in the United States, the drug muramyl-tripeptide (MTP), which is likely to act through immune activation, was registered in combination with chemotherapy for the primary treatment of osteosarcoma [3,4]. However, how to put the outcomes of the study underlying registration [3,4] into perspective is still heavily debated [5]. Consequently, in the most recent European Society for Medical Oncology guidelines on bone tumors, no consensus could be reached on its routine use [6]. For recurrent systemic disease, there is no standard treatment other than re-challenging patients to the drugs mentioned above.
Developments in clinical studies and drug classes being studied in osteosarcoma Given the presumed immunogenicity of osteosarcoma, pegylated interferon (PEG-IFN) was studied in patients with a good pathological response to preoperative chemotherapy in the primary treatment of
nonmetastatic high-grade osteosarcoma in the transatlantic phase III EURAMOS study (NCT00134030) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). From the 1034 eligible patients, 715 were randomized (69%) and only 76% of the patients allocated to PEG-IFN actually started treatment, mainly because of patient refusal. The eventfree survival (primary endpoint) was not statistically improved in the PEG-IFN arm, though this may have been influenced by the high treatment refusal rate [7]. Another agent, which additionally to effects on the bone may also yield immune activation, is zoledronate. Following preclinical evidence of the activity of this third-generation bisphosphonate against osteosarcoma [8] and the first clinical feasibility study [9], a randomized phase III study investigates the addition of zoledronate to multiagent chemotherapy (NCT00470223) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). In the relapsed metastatic disease, several agents failed to improve outcome including mammalian target of rapamycin (mTOR) inhibitors [10]. The vascular-endothelial growth factor receptor (VEGFR) inhibitor sorafenib showed promising results in a phase II study: median progression-free survival (PFS) and overall survival (OS) were 4 and 7 months, respectively, comparing favorably with historical controls [11]. A randomized study with this or another VEGFR inhibitor needs to confirm these findings to change practice. A placebo-controlled randomized phase II study assesses the Src inhibitor saracatinib after resection of pulmonary metastases (NCT00752206) (Clinical Trials Gov. http://clinical trials.gov/ assessed on 20 January 2014). In addition to these ‘targeted’ approaches, immunotherapy remains an attractive target in osteosarcoma given the intriguing outcomes with the immune modulator MTP [3,4]. Novel studies with this and other immune-modulating agents, such as checkpoint inhibitors, are therefore warranted.
SOFT TISSUE SARCOMAS STS mainly affects people between 60 and 70 years but with a wide spread in age. Estimated annual incidence is approximately five new cases per 100 000. The role of systemic agents in the treatment of patients in the adjuvant setting is heavily debated and will not be discussed here. Systemic agents form the mainstay of treatment for those with metastatic disease.
Current standard Numerous antitumor compounds have activity in the diverse STS subgroups, but only a few have been
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studied in randomized, controlled phase III trials. Doxorubicin monotherapy has long been considered standard first-line treatment for advanced STS patients, regardless of subtype [12]. Though ifosfamide monotherapy has equivalent efficacy [13], doxorubicin is preferred given its more favorable toxicity profile. A phase III study showed that the combination of doxorubicin and ifosfamide, both administered at full single-agent doses, improved response rate (13 vs. 26%) and median PFS (4.5 vs. 7.4 months) over doxorubicin. The OS, however, the primary study endpoint, was equivalent [14]. As expected, toxicity was much greater in the combination arm. Many still consider, therefore, doxorubicin monotherapy as standard first line, though for fit patients in high need for a response, for example, because of a large mass causing pain, the combination can be considered [15]. In patients failing to doxorubicin-based or ifosfamide-based chemotherapy, the tyrosine kinase inhibitor (TKI) pazopanib targeting amongst others VEGFR has been registered. Following a phase II study in four tumor strata showing that pazopanib had insufficient activity against adipocytic sarcomas warranting further investigation [16], a phase III study showed the superiority of pazopanib over placebo in terms of PFS in nonadipocytic STS [17 ]. &&
Developments in clinical studies and drug classes being studied in STS Most studies in advanced STS performed until a few years ago grouped all STS subtypes together. This was mainly prompted by the rare incidence of STS rendering it difficult to stratify for the diverse subtypes or to perform studies in a specific tumor type. However, the great heterogeneity in sensitivity to systemic agents between STS subtypes and the enormous impact that may have on outcome of clinical studies is increasingly recognized. For example, pazopanib did show sufficient activity prompting further study in a phase III study in synovial sarcomas, leiomyosarcomas and the group of other STS, but not in adipocytic tumors [16]. If pazopanib had been explored in a phase II study in which all STS tumor types were included without stratification and predominantly patients with advanced adipocytic sarcomas would have been included, then the antitumor activity of pazopanib would probably not have been detected. Consequently, STS studies must either be randomized with controlled equal distribution of subtypes across the different treatment arms or in case of nonrandomized studies, must be performed in selective tumor subtypes or stratified for STS subentity. 436
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Nevertheless, there is still a substantial number of studies in which all STS subgroups can be included without stratification. This mostly concerns studies in which agents with known activity are combined with each other or that new agents are added to a standard agent. An example of the latter is a phase III study of doxorubicin versus the combination of doxorubicin with TH-302, a prodrug that under hypoxic circumstances converts into the alkylator bromo-isophosphoramide mustard (NCT01440088) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). Another study in which all STS subtypes, liposarcomas excepted, can be included is a randomized phase II study of gemcitabine with pazopanib versus gemcitabine combined with docetaxel in pretreated patients (NCT01593748) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). Previously, the combination of gemcitabine and docetaxel showed superior outcomes over gemcitabine alone in a group of patients with a broad range of histologies [18] and is widely used. Although gemcitabine was not considered active in a group of unselected STS [19], gemcitabine induces antitumor activity against leiomyosarcomas [20]. As a result, the interpretation of the outcome of the randomized study comparing gemcitabine/docetaxel versus gemcitabine/pazopanib is hindered if leiomyosarcoma patients are not equally distributed between both treatment arms. Another study ongoing in patients who failed to prior chemotherapy but unselected for STS subtype is a randomized study comparing gemcitabine/docetaxel versus the same regime combined with MORAb-004, an antibody against endosialin, which is expressed on tumor-associated pericytes (NCT01574716) (Clinical Trials Gov. http://clinical trials.gov/ assessed on 20 January 2014). Several single-arm phase II studies have been initiated in advanced STS patients examining novel agents such as cabozantinib (NCT01755195) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014), a dual inhibitor of MET and VEGFR, and ENMD-2076, an aurora A kinase inhibitor (NCT01719744) (Clinical Trials Gov. http://clini caltrials.gov/ assessed on 20 January 2014). The rationale behind these studies is that the VEGFVEGFR pathway, MET, and aurora A kinase can be deregulated in sarcomas [21,22]. However, as it is unlikely that these agents will show equivalent activity against all STS subtypes, such studies are at risk to miss potential benefit in a particular STS subtype if not stratified for subtype. In order to attenuate this, several single-arm phase II studies on novel compounds have a design in which the activity is separately and simultaneously assessed in diverse STS subtypes cohorts. Examples include axitinib, a VEGFR-TKI (NCT01140737) Volume 26 Number 4 July 2014
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(Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014) and MLN8237, an aurora A kinase inhibitor (NCT01653028) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). Also the microtubilin-targeting agent eribulin has been assessed in such a design. In a nonrandomized phase II study, eribulin had sufficient antitumor activity in pretreated patients with adipocytic tumors and leiomyosarcomas warranting further investigation in a phase III study [23]. The phase III study comparing eribulin to dacarbazine in these particular STS subtypes has recently completed accrual (NCT01327885) (Clinical Trials Gov. http://clinical trials.gov/ assessed on 20 January 2014). Additionally to design, also the choice of the primary endpoint is crucial. In many phase II studies, response rate is endpoint. However, antitumor agents can prolong PFS or OS without inducing tumor shrinkage. For such agents, the PFS is a valid endpoint, in particular, when assessed in a randomized setting [24]. In that sense, the randomized, double-blind, placebo-controlled, phase II study on regorafenib in advanced STS patients failing to anthracyclines, which is performed in four different strata (liposarcoma, leiomyosarcoma, synovial sarcoma and group of other eligible sarcomas), with PFS as primary endpoint, is a very well designed study (NCT01900743) (Clinical Trials Gov. http:// clinicaltrials.gov/ assessed on 20 January 2014). There is an increasing number of trials in which only one or two STS subentities are studied. This applies particularly to leiomyosarcomas, as this subtype is relatively frequent. Leiomyosarcomas exhibit sensitivity to a wide range of antitumor agents. Besides doxorubicin and ifosfamide, other regimens include gemcitabine, the combination of gemcitabine/docetaxel, dacarbazine, pazopanib, and trabectedin. Apart from a study comparing gemcitabine versus the combination gemcitabine/docetaxel showing equivalent activity [20], none of these regimens have been compared head-to-head in leiomyosarcomas. The outcome of a randomized study of trabectedin versus dacarbazine in advanced leiomyosarcomas is therefore of major interest (NCT01343277) (Clinical Trials Gov. http://clinical trials.gov/ assessed on 20 January 2014). Another study assesses the combination of gemcitabine/ pazopanib in pretreated patients with metastatic leiomyosarcoma (NCT01442662) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). However, how such a combination compares to one of the agents administered as monotherapy cannot be established from a nonrandomized trial like this one [25]. A trial from which certainly a conclusion can be drawn is a phase III study in uterine leiomyosarcoma
in which the added value of bevacizumab to the widely used gemcitabine/docetaxel combination is examined (NCT01012297) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). Bevacizumab enhances the outcomes of several chemotherapeutic regimens in other diseases such as colorectal cancer. There is however evidence that the added value of bevacizumab depends on the chemotherapeutic agent with which it is combined. In breast cancer, the added value of bevacizumab to three weekly docetaxel seems to be less profound compared with that observed with weekly paclitaxel [26]. Furthermore, bevacizumab enhanced antitumor effects from paclitaxel, but not from gemcitabine in a preclinical model [27]. Obviously, these results cannot be translated to leiomyosarcoma patients, but it is questionable whether gemcitabine and docetaxel are the most attractive agents to be explored together with bevacizumab. Also in liposarcoma, several studies are ongoing. Importantly, also the group of liposarcomas is a heterogeneous one in which several subgroups differing in genetic background and clinical behavior can be distinguished [28]. De-differentiated liposarcomas are characterized by co-amplification of MDM2 and CDK4. Clearly, amplification of a gene does not imply that such a gene is also a tumordriving factor, but based on preclinical models and on interesting data in the pre-operative setting [29 ], ongoing clinical trials on CDK4 and MDM2 inhibition in de-differentiated liposarcoma have a strong rationale (NCT01209598, NCT01636479) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). A first phase II study in CDK4-amplified liposarcomas showed interesting results [30]. Other tumor types in which studies are ongoing include alveolar soft part sarcomas (ASPSs). ASPS is a very rare and extremely chemo-resistant STS subtype, characterized by a specific translocation [t(X,17)(p11;q25)], which eventually leads to uncontrolled transcription of TFE3-regulated genes such as c-MET and several pro-angiogenic factors. Cediranib, a VEGFR-TKI, yielded an unprecedented high response rate of 35% together with durable disease stabilization in a single-arm study [31]. To put the activity of VEGFR-TKIs better into perspective, a randomized phase II trial comparing sunitinib versus cediranib has been started (NCT01391962) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014) as well as a randomized, double-blind placebo-controlled phase II study (NCT01337401) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014). Also in metastatic angiosarcomas, several studies are ongoing. In addition to diverse VEGFR-TKIs
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such as pazopanib (NCT01462630), a randomized phase II study explores the efficacy of weekly paclitaxel versus that of the combination of bevacizumab and weekly paclitaxel (NCT01303497) (Clinical Trials Gov. http://clinicaltrials.gov/ assessed on 20 January 2014).
DISCUSSION As becomes apparent from this review, many studies are ongoing in advanced osteosarcoma and STS. Regimens currently being explored in osteosarcoma and STS are as follows: (1) Osteosarcoma (a) Primary treatment: (i) Maintenance pegylated interferon (PEG-IFN) (ii) Zoledronate (bisphosphonate) added to standard chemotherapy (b) Relapsed disease: (i) Sorafenib (VEGFR-TKI) (ii) Saracatinib (src inhibitor) (2) STS (a) First-line setting: (i) Combination of doxorubicin with TH302 (b) Second line and beyond: (i) Gemcitabine with pazopanib (ii) Gemcitabine/docetaxel with MORAb004 (antibody against endosialin) (iii) Cabozantinib (dual inhibition of MET and VEGFR) (iv) ENMD-2076and MLN8237 (aurora A kinase inhibitors) (v) Axitinib and regorafenib (VEGFRTKIs) (vi) Erubilin (in leiomyosarcoma and liposarcoma) (vii) Trabectedin (in leiomyosarcoma) (viii) Gemcitabine/pazopanib (in leiomyosarcoma) (ix) Bevacizumab with gemcitabine/docetaxel(in leiomyosarcoma) (x) PD0332991 (CDK4 inhibitor in dedifferentiated liposarcoma) (xi) SAR405838 (MDM2 inhibition in dedifferentiated liposarcoma) (xii) Cediranib and sunitinib (VEGFR-TKI in ASPS) (xiii) Pazopanib (in angiosarcoma) (xiv) Bevacizumab with weekly paclitaxel (in angiosarcoma) Unfortunately, because of poor study designs, many of these studies will not yield robust 438
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outcomes, particularly in advanced STS wherein great differences in clinical behavior and sensitivity to antitumor compounds across subtypes can largely impact study outcomes. Results from single-arm trials in which all sarcoma subtypes are grouped together or from studies on drug combinations in which one of the compounds has known antitumor activity will therefore be impossible to interpret [25]. Additionally to design, also the choice of the endpoint is crucial, particularly in single-arm phase II screening studies. The presumed mechanism of action of the drug under study should be taken into account. A drug that is cytostatic rather than cytotoxic is unlikely to induce a high response rate. In such cases, an endpoint capturing the drug’s ability to induce disease stabilization is indicated such as the progression-free rate at 3 months. Importantly, in such a case, only patients with objective progression within 3 months before study entry should be included. Otherwise, it cannot be excluded that cases with no progression at this time point do so because of an indolently growing tumor [24]. For many studies, the underlying rationale to explore a certain drug or combination is that the presumed target of treatment does occur in the tumor type of interest or that in case of combinations, both drugs exert activity as single agent. Obviously, such observations do not guarantee success. More insight into the mechanism of action or interaction between drugs is required before embarking on large and expensive clinical trials. Clearness about the mechanism of action hopefully allows to identify predictive profiles, which can be used to select the right patients for the studies. Additionally to preclinical models, insight into mechanisms of action and early hints whether or not a compound exerts effects against a particular sarcoma subtype can be obtained from small proofof-concept studies in the pre-operative period in patients with nonmetastatic disease. A nice example of this approach is a study on a MDM2 antagonist administered for a short period prior to tumor resection in which the surgical specimen was assessed for drug-specific effects [29 ]. &&
CONCLUSION The great necessity of studies in sarcomas is underlined by the poor prognosis that patients with these diseases face, in particular those with metastatic disease. Given the difficulties of performing studies in sarcomas because of their rarity and heterogeneity, consensus on how to structure and conduct clinical studies in sarcoma is needed. This applies on the work that needs to be done before the initiation Volume 26 Number 4 July 2014
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of clinical trials, the exact design, selection of patients, and the choice of endpoints. Global collaboration as offered by networks such as EURAMOS and World Sarcoma Network is imperative to achieve this. Acknowledgements Research funding: S.S. received funding from GSK, Pharmamar, Amgen, Roche; speaker’s fee: GSK. H.G. received funding from Novartis, Pfizer, GSK. Conflicts of interest There are no conflicts of interest.
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