Originally published as JCO Early Release 10.1200/JCO.2009.21.8180 on May 18 2009

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Soft Tissue Sarcoma Trials: One Size No Longer Fits All

Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands

Soft tissue sarcomas are a heterogeneous group of diseases that share a mesenchymal origin. Despite this heterogeneity, these tumors have always been pooled together in clinical studies and treated as if they were all the same. This issue of Journal of Clinical Oncology features five articles that each, in their own way, indicate that soft tissue sarcoma trial design should considerably be changed in future studies.

Recent molecular biology research has identified several subtype-specific oncogenes and their protein products that could serve as treatment targets. Such cancer cell–specific treatment will obviously depend on the molecular characteristic that, in the case of soft tissue sarcomas, may not be shared by all of the subtypes and would thus require subtype-specific trials and treatments.

GI stromal tumors (GISTs) may serve as the model for this. Until the year 2000, GIST used to be treated similarly to all other soft tissue sarcoma subtypes, with minimal effects from chemotherapy. Overexpression of the oncogene product receptor c-KIT (CD117), often harboring activating mutations, turned out to be a frequent—albeit not uniform—characteristic of GIST. The activity of the KIT tyrosine kinase (TK) inhibitor imatinib was clearly shown from the year 2000 onward.^1–3 Subsequent detailed analysis has revealed that exon-9 mutations in KIT are less sensitive to imatinib than others.^4–6 And the majority of KIT-negative GISTs are still sensitive to imatinib because they express mutated platelet-derived growth factor, one of the other targets of the agent.^4–6 The data indicate not only that the disease may be drug-sensitive as a result of specific molecular changes, but also that the required drug dose may be dependent on specific changes within these molecular changes.^4,6 This in itself is a historic finding.

In this issue of JCO, Demetri et al⁷ add an additional layer to dose selection. In their randomized phase II study that was the basis of marketing approval for imatinib in GIST, they sampled the first 73 of the total 147 patients to assess imatinib pharmacokinetics (PK). By analyzing the PK data,⁷ they found that despite a high interpatient variability, clinical outcomes seemed to correlate with imatinib trough plasma levels at steady-state. Patients with a minimum plasma concentration of imatinib less than 1,100 ng/mL showed a shorter time to progression of 11.3 months, compared with more than 30 months for patients with higher minimum plasma concentration. In patients harboring KIT exon 11 mutations in the tumor (n = 39), which are now known to be the most sensitive to imatinib, the clinical benefit rate (complete response + partial response + stable disease) was 67% for patients with trough levels less than 1,100 ng/mL, compared with 100% for all others (P = .001). It is important to realize that the clinical benefit was assessed by RECIST (Response Evaluation Criteria in Solid Tumors Group).⁸ We now know that RECIST does not appropriately discriminate between complete response, partial response, and stable disease in GIST but is appropriate for assessing progressive disease.⁹ Therefore, by using the clinical benefit rate (as opposed to progression) and time to progression end points, the reported observations likely have major relevance, although the sample size for the analysis is fairly small, which limits the power of the observation. We can thus not yet recommend using the data for routine monitoring purposes. As stated by the authors, phase III studies should additionally test whether monitoring imatinib plasma levels might optimize clinical outcomes for GIST patients.

The study allowed dose escalation from 400 mg to 600 mg in the case of progressive disease. By PK quartiles, the frequency of dose escalation was nine of 18 (50%) in Q1, 15 of 36 (41.7%) in Q2-Q3, and four of 19 (21%) in Q4 (P = .165, ² test). So the higher the exposure, the lower the number of processed dose escalations. Although this could lend additional support to the suggested dependence of antitumor effect on drug exposure levels, it is not known if dose escalation was performed in a consistent way.

The measured day 29 area under the curve (AUC) in this study seems to be consistently lower than the day 1 AUC, in line with previous observations.¹⁰ This could point to an increase of drug clearance over time and raises the possibility of AUC-guided intrapatient dose escalation over time. Again, much larger data sets will be needed to explore this option.

The most important conclusion from this study for trial design is that for targeted agents such as imatinib, dose selection may be based on specific mutations in the given target as well as on individual plasma exposure. For phase III studies with such agents, it may thus be important to include simple PK assessments by measuring trough levels, as well as to include detailed analysis of the molecular abnormality in the tumor tissue of the patients in the study.

As indicated above, soft tissue sarcomas perhaps should not be pooled together in clinical studies. In an effort to assess this problem, Chugh et al¹¹ performed a phase II study in 190 soft tissue sarcoma patients treated with imatinib, published in this issue of JCO, using a Bayesian hierarchical statistical model. This is an interesting model that borrows information across disease subtypes and allows for evaluation of each subtype individually. The model used both cohort expansion and early stopping rules, defined in advance, that allowed the outcomes in one subtype to influence the decision making in other subtypes. This was done under the assumption that the various subtypes are interrelated. When the study was started, it was not yet known that, in particular, the latter assumption for the molecular targets (KIT and platelet-derived growth factor) involved and the sarcoma subtypes approached were incorrect. It is therefore not fully surprising that the outcome of this negative study was completely similar to the previously reported, much smaller EORTC (European Organisation for Research and Treatment of Cancer) study.¹ The design yet remains a potential powerful clinical trial tool, provided functionality of the molecular target for tumor growth in the studied disease is an absolute given, information that is frequently still lacking in early drug development.

The study of Chugh et al¹¹ used a drug targeted against specific molecular aberrations in cancer cells, and confirms that not all soft tissue sarcomas should be pooled together in studies with such agents. This may be less obvious for cytotoxic drugs that are commonly thought to be less cancer cell–specific. Yet the literature is filling up with evidence that even for cytotoxic drugs, different soft tissue sarcoma subtypes have different treatment sensitivity.^12–19

In line with previous suggestions, including studies of cytotoxic agents,²⁰ Chugh et al pursued absence of progression, assessed by clinical benefit response, as the most important sign of potential clinical activity. Because many of the new molecularly targeted agents do not induce tumor regression, but mainly result in growth inhibition, it is necessary to change the primary end point in screening studies in the search for active treatments as well as for soft tissue sarcomas. In view of all of these, it has been proposed to consider using alternative end points such as progression-free rates (PFRs) at preset times,²⁰ or progression arrest at first evaluation.²¹ Both of these require documentation of tumor progression before study entry. This was lacking in the study of Chugh, as well as in the studies on sorafenib²² and sunitinib²³ (to be discussed) and has to be considered a weakness in each of these trials. Obviously, collecting this prestudy information could be challenging. That it is not impossible was proven in the EORTC study presented on pazopanib.²⁴

That study, together with the studies on sorafenib²² and sunitinib,²³ assessed whether inhibition of angiogenesis could potentially be meaningful in soft tissue sarcoma subtypes. Although the design was different from the design of the trial reported by Chugh et al,¹¹ but similar to the study with the mammalian target of rapamycin inhibitor AP23573,²⁵ the studies on pazopanib²⁴ and sorafenib²² both acknowledged the relevance of designing trials respecting disease subtypes. The sorafenib study²² included separate cohorts of patients with leiomyosarcoma, malignant peripheral-nerve sheath tumor, synovial sarcoma, vascular sarcomas, high-grade undifferentiated pleomorphic sarcoma, and an "other" sarcoma cohort to insure adequate inclusion of a variety of sarcoma subtypes. The pazopanib study²⁴ included four different strata: adipocytic sarcomas, leiomyosarcomas, synovial sarcomas, and an "other" soft tissue sarcoma cohort. These "other sarcoma" cohorts in essence still ignore potential differences in subtypes of soft tissue sarcomas. But, where included, some subtypes are so rare that even in a cooperative group setting it will hardly be possible to find sufficient numbers of patients to assess drug activity in each of these subsets with appropriate certainty. The ideal world in this respect will likely never exist. In both studies for each of the cohorts, a Simon optimal two-stage design was used. As a consequence, the sunitinib and sorafenib became large phase II trials including 142 and 145 patients, respectively. The study on sunitinib²⁴ followed the more conventional trial design that assumed all soft tissue sarcomas are similar.

The studies on sorafenib and sunitinib both also conventionally use response rate as the primary end point, which, in view of the above discussion, could well lead to misinterpretation of outcome. In fact, the small study on sunitinib²³ by protocol criteria has to be considered negative (< 5% objective response); yet the authors conclude "There was not, however, sufficient statistical power to draw a definite conclusion regarding its efficacy for a specific tumor type," followed with, "Suggestions of activity were observed in alveolar soft parts sarcoma, chordoma, and liposarcoma with stable disease for at least 24 weeks, though the significance of this may be confounded by the indolent natural history of these diseases." They seem to doubt their own conclusion, which is understandable if we look at the outcome of the other two studies^22,24 that both were considered positive, whereas from a TK profile perspective, the three agents under study bear major resemblances. In that respect, it is interesting to put the two large studies^22,24 into perspective. The response rate in both studies was less than 5%, so by using the same criteria as used for sunitinib²³ both studies would also have been considered negative. The PFRs in the studies strongly suggest this would have been the wrong conclusion. If we take the reference of 40% PFR at 3 months to identify a drug with potential activity,²⁰ the sorafenib study can be considered positive in angiosarcoma (3-month PFR, 64%) and high-grade undifferentiated pleomorphic sarcoma (42%). Both the sorafenib and pazopanib studies can be considered positive in leiomyosarcoma (54% and 44%, respectively), synovial sarcoma (42% and 49%, respectively) and "other" histologies. This would indicate quite broad activity and would refute the conclusion on sunitinib, with the unlikely restriction, of course, that sunitinib indeed would be a totally different agent.

Although the suggested activity profiles for sorafenib and pazopanib largely overlap if we take the 3-month PFR end point, there is a striking dissimilarity for synovial sarcomas in the 6-month PFR. Sorafenib did not yield a 6-month PFR, but for pazopanib it was 30% and well above the 20% threshold. Maybe this does point to a possible true difference between agents that have such subtle minor differences in TK inhibitory profiles. Conversely, we cannot exclude that the observation differences are simply because of study population characteristics. However, given the growth-inhibitory effect of modern agents, and the costs of these drugs in clinical practice, it may be appropriate to set our screening hurdle higher by using the 6-month PFR end point in phase II studies. This would also be in line with the results of a drug as good as imatinib in the treatment of metastatic GIST.⁹

As indicated, there are major resemblances particularly between the sorafenib and pazopanib studies. An important feature in the latter trial was that the PFRs were the primary end point, and as a consequence, proven progression at trial entry was a requirement. In this respect, this makes the outcome a little more robust than the sorafenib study that had response as primary end point.

Given the relevance of subtyping and the fact that some subtypes are apparently not sensitive (malignant peripheral nerve sheath tumor for sorafenib, liposarcoma for pazopanib), it is of crucial importance to have certainty on the diagnosis. This requires the central review of pathology that was included for the pazopanib study, but not for the sorafenib study.

Jointly, the studies on sorafenib and pazopanib suggest that inhibition of angiogenesis could be an interesting approach in the treatment of soft tissue sarcomas. A recent randomized phase II study on the angiogenesis inhibitor ABT-510²⁶ supports this notion. This is an extremely important conclusion, given the paucity of our treatment results with cytotoxic agents for soft tissue sarcomas. It would therefore be important to pursue antiangiogenics with phase III studies; indeed, a global phase III study on pazopanib in soft tissue sarcomas, with appropriate stratification for subtyping and on the basis of the phase II study results excluding liposarcomas, was recently launched.

So what should soft tissue sarcoma trials look like in the future?

• For screening phase II trials, it is important to stratify for histologic subtypes. Whether a Bayesian model can be used depends on the absolute guarantee of the functionality of the molecular abnormality targeted, which unfortunately most often is still lacking. Given the relative rarity of soft tissue sarcomas, the above means that it is likely these studies will have to be performed in a cooperative group setting or an even larger network.
  
• Given the tumor-inhibitory action of drugs in development, for screening phase II trials we should select an end point other than tumor regression. Freedom of progression seems more appropriate, and there are several ways to assess this. This means that evidence of tumor progression will have to be provided at study entry, a concept challenging for investigators, but not infeasible.
  
• In phase II and/or phase III trials, we should collect samples for pharmacokinetics to define if minimal drug concentrations have to be pursued.
  
• In all studies, we should collect tissue samples for molecular profiling to help identify the benefiting populations.
  

The time of the simple, 25-patient phase II study including all soft tissue sarcoma subtypes has likely passed. We do not treat all carcinomas in the same way; we should acknowledge that we cannot treat all sarcomas in the same way.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Jaap Verweij, Novartis (C) Stock Ownership: None Honoraria: Jaap Verweij, Novartis, GlaxoSmithKline, Pfizer Research Funding: None Expert Testimony: None Other Remuneration: None

REFERENCES

1. Verweij J, van Oosterom A, Blay JY, et al: Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target: Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 39:2006–2011, 2003.[CrossRef][Medline]

2. Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480, 2002.[Abstract/Free Full Text]

3. Verweij J, Casali P, Zalcberg J, et al: For the EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group and the Australian Gastro-intestinal trials group: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib—A randomised trial. Lancet 364:1127–1134, 2004.[CrossRef][Medline]

4. Debiec-Rychter M, Sciot R, Hogendoorn P, et al: On behalf of the EORTC Soft Tissue and Bone Sarcoma Group, The Italian Sarcoma Group and the Australasia GastroIntestinal Tumor Group: KIT mutations should drive dose selection for imatinib in patients with advanced gastrointestinal stromal tumors—Results of mutation analysis in 377 patients entered into a randomized study. Eur J Cancer 42:1093–1103, 2006.[CrossRef][Medline]

5. Heinrich MC, Owzar K, Corless CL, et al: Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 26:5360–5367, 2008.[Abstract/Free Full Text]

6. Van Glabbeke M, Owzar K, Rankin C, et al: Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: A meta-analysis based on 1640 patients. J Clin Oncol 25:546s; 2007 (suppl) abstr 10004.

7. Demetri GD, Wang Y, Wehrle E, et al: Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 27:3141–3147, 2009.[Abstract/Free Full Text]

8. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216, 2000.[Abstract/Free Full Text]

9. LeCesne A, Van Glabbeke M, Verweij J, et al: Is a stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate (IM) included in the intergroup EORTC/ISG/AGITG trial? J Clin Oncol 24:522s; 2006 (suppl) abstr 9510.[CrossRef]

10. Judson I, Ma P, Peng B, et al: Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour, a retrospective population pharmacokinetic study over time: EORTC Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 55:379–386, 2005.[CrossRef][Medline]

11. Chugh R, Wathen JK, Maki RG, et al: Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a Bayesian hierarchical statistical model. J Clin Oncol 27:3148–3153, 2009.[Abstract/Free Full Text]

12. 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 17:150–157, 1999.[Abstract/Free Full Text]

13. Sleijfer S, Ouali M, Van Glabbeke M, et al: Prognostic and predictive factors for outcome to first-line ifosfamide-containing therapy (IFM) in patients (pts) with advanced soft tissue sarcomas (STS) treated in EORTC-STBSG studies. J Clin Oncol 26:555s; 2008 (suppl) abstr 10509.

14. Grosso F, Jones RL, Demetri GD, et al: Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: A retrospective study. Lancet Oncol 8:595–602, 2007.[CrossRef][Medline]

15. Fata F, O'Reilly E, Ilson D, et al: Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer 86:2034–2037, 1999.[CrossRef][Medline]

16. Schlemmer M, Reichardt P, Verweij J, et al: Paclitaxel in patients with advanced angiosarcomas of soft tissue: A retrospective study of the EORTC soft tissue and bone sarcoma group. Eur J Cancer 44:2433–2436, 2008.[CrossRef][Medline]

17. Saroha S, Litwin S, Von Mehren M: Retrospective review of treatment for angiosarcomas at Fox Chase Cancer Center over the past 15 years. J Clin Oncol 25:553s; 2007 (suppl) abstr 10034.

18. Nagano T, Tai Y, Higashida Y, et al: Docetaxel monotherapy for angiosarcoma in an elderly patient. Arch Dermatol 143:1602–1603, 2007.[Free Full Text]

19. 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. J Clin Oncol 25:2755–2763, 2007.[Abstract/Free Full Text]

20. Van Glabbeke M, Verweij J, Judson I, et al: Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer 38:543–549, 2002.[CrossRef][Medline]

21. Verweij J, van Glabbeke M: Translating targets into treatment: Changes in trial methodology and treatment approaches for soft tissue sarcomas. ASCO Educational Book, 522–530, 2003.

22. Maki RG, D'Adamo DR, Keohan ML, et al: Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol 27:3133–3140, 2009.[Abstract/Free Full Text]

23. George S, Merriam P, Maki RG, et al: Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol 27:3154–3160, 2009.[Abstract/Free Full Text]

24. 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 27:3126–3132, 2009.[Abstract/Free Full Text]

25. Chawla S, Tolcher AW, Staddon AP: Survival results with AP23573, a novel mTOR inhibitor, in patients with advanced soft tissue and bone sarcomas: Update of phase II trial. J Clin Oncol 25:563s; 2007 (suppl) abstr 10076.

26. Baker LH, Rowinsky EK, Mendelson D, et al: Randomized phase II study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced soft tissue sarcoma. J Clin Oncol 26:5583–5588, 2008.[Abstract/Free Full Text]

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