Lung Cancer (2005) 50, 87—90

COMMENTARY

Phase II trials in mesothelioma: An increasingchallenge

Anna K. Nowak ∗

Department of Medicine and Pharmacology, University of Western Australia and Department of MedicalOncology, Sir Charles Gairdner Hospital, 4th Floor, G block, Sir Charles Gairdner Hospital, HospitalAvenue, Nedlands, WA 6009, Australia

Received 19 May 2005; accepted 26 May 2005

In this issue of Lung Cancer, two groups reportresults of phase II clinical trials in malignantmesothelioma, highlighting some of the problemsfaced by clinical trialists in 2005. Our aims indeveloping new cancer treatments are to prolongsurvival and improve symptoms or quality of life assafely and cost-effectively as possible. However,phase II studies cannot tell us if we are achievingthese aims. Phase II studies are used to establishanti-tumour efficacy before phase III testing, usingsurrogate endpoints for patient benefit, mostcommonly objective response; herein lies theproblem.

Berghmans et al. report a large phase II trialof cisplatin and epirubicin in mesothelioma whichbegan accrual in 1998, before the demonstrationof a survival benefit from cisplatin and pemetrexedin 2003 [1]. They report an objective response rateof 19% (95% CI 9—29%). This result is unlikely to

been established as a standard of care. Despite theauthors’ assertion that doxorubicin and cisplatinis considered a standard chemotherapy in thisdisease [2], this is unlikely to be supported bymost clinician—researchers in 2005 [3,4]. Peme-trexed has FDA approval for use in mesotheliomain the United States [5] and is in wide clinicaluse for this indication where it is available andfunded.

Although it may at first seem reasonable tocompare objective response rates between clini-cal trials, closer reading suggests that this may notbe the case, particularly in mesothelioma. Malig-nant mesothelioma is notoriously difficult to assessfor response, with tumour growing as a ‘‘rind’’around the hemithorax and along interlobar fis-sures. It does not conform to the roughly spher-ical growth pattern of many other malignanciesand truly bi-dimensionally measurable lesions may

engender enthusiasm for further testing when cis-platin and pemetrexed, with an objective responserate of 41% and a modest survival benefit, have

∗ Tel.: +61 8 9346 3841; fax: +61 8 9346 3390.E-mail address: anowak@cyllene.uwa.edu.au.

not be present or may not be the most repre-sentative and appropriate sites. Berghmans et al.appear to have used a modification of the WHO cri-teria to assess objective response, however, it isunclear what constitutes ‘well-outlined’ or ‘poorlyoutlined’ lesions. Are ‘well-outlined’ lesions bi-

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88 A.K. Nowak

dimensionally measurable and ‘poorly outlined’lesions uni-dimensionally measurable? Are ‘poorlyoutlined’ lesions those areas in the lower tho-rax, so difficult to measure reproducibly, or areaswhere tumour is difficult to separate from collapsedlung?

Several authors have suggested that the use ofthe WHO criteria and bi-dimensional lesions forassessment of response in this disease is problem-atic [6—9]. However, the more recent use of uni-dimensional measurement with the RECIST criteriadoes not completely solve this problem [10] anda modification has been proposed to address theparticular growth pattern of malignant mesothe-lioma [6]. Many recent trials have used predom-inantly uni-dimensional measurements of tumour‘rind’ thickness to assess response [1,11—16]. If weare to choose an arbitrary response rate ‘of inter-est’ and make the results of phase II trials appli-cable internationally, we must choose a standardmethod of measuring and reporting response. It isclear that the results of uni- and bi-dimensionalmeasurements are not always concordant [9,17].Automated assessment of tumour response on CTscan [18] or the use of PET scanning [19] may help

order to prioritize agents for phase III testing on thebasis of objective tumour responses. As we enteran era of novel biological therapies, it is becom-ing clear that radiological response using traditionalcriteria may not be the only indicator of efficacy,particularly in terms of inducing survival and qual-ity of life benefits.

Also in this issue, Mathy et al. report a phase IItrial of imatinib in malignant mesothelioma. Ima-tinib is the success story of targeted therapies,with significant activity in chronic myeloid leukemia[21] and gastro-intestinal stromal tumour (GIST)[22]. However, these two diseases have mutationsof the tyrosine kinase targets of imatinib whichare of prime importance in the pathogenesis ofthe malignancy. BCR-ABL is a constitutively acti-vated tyrosine kinase, present in almost all casesof CML. GIST commonly have gain of function muta-tions of the KIT proto-oncogene, with constitutiveactivation of KIT and resulting proliferation. Hence,with up to one-third of patients with mesotheliomaexpressing c-KIT and the possible role of platelet-derived growth factor (PDGF) in this disease, therewas some rationale to perform this study. Unfortu-nately, expression of KIT on immunohistochemistrydotdKsttbTTfepma

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to solve these problems for a future generation ofclinical trials. However, until we have better meth-ods of assessing response, it is important to reportclearly and reproducibly how measurements weredone, as well as what criteria were applied to inter-pret them.

Secondly, comparing the duration of overallsurvival between phase II trials is a trap bestavoided. Berghmans et al. suggest that a mediansurvival of 13.3 months compares favourably withthe landmark cisplatin and pemetrexed study byVogelzang et al. [1] and go on to tabulate themedian and 1-year survival of studies using cis-platin and doxorubicin. It is sufficient to commentthat the Berghmans et al. trial comprised 40%of patients with stage I/II disease, with a HR forsurvival of 1.74 when compared with patientswith stage III/IV disease in the same study—–theVogelzang et al. trial comprised 23% of patientswith stage I/II disease. There is no role for com-parison of overall survival between such phase IIstudies. In fact, the median survival of the Mathyet al. trial also reported in this issue is just over13 months and in the absence of any objectiveresponses, their conclusions are very different,namely that further study of imatinib as a singleagent therapy in mesothelioma is not justified[20].

This brings us to another set of problems in inter-preting phase II trials in mesothelioma. Phase IImethodology in medical oncology was developed in

oes not necessarily equate with an important rolef KIT in tumour growth. Whilst there is evidencehat KIT is expressed in this disease, is there evi-ence of activation? Furthermore, is activation ofIT important in supporting cell proliferation andurvival in mesothelioma? Since the inception ofhis trial, further information is emerging that ima-inib inhibits tumours with specific KIT mutationsetter than wild-type KIT or other mutations [23].he role of PDGF may confront similar problems.o improve patient selection for such trials in theuture, perhaps patients should be screened forxpression, activation or mutation of the appro-riate biological target. Strong pre-clinical scienceust inform the design of clinical trials with these

gents.Unlike many novel therapeutic agents, ima-

inib is capable of inducing impressive objectiveesponses to treatment, with more than 50% ofatients with GIST reported as partial respon-ers [22]. However, the epidermal growthactor inhibitors (gefitinib and erlotinib), VEGFnhibitors (bevacizumab), matrix metallopro-einase inhibitors and other new agents alsoeserve testing in mesothelioma. In other diseases,ovel agents can benefit patients in the absencef high single agent objective response rates [24].ow can we define activity in a phase II setting

or these agents? Early progression to randomisedhase III trials can identify improvements in survivalr time to progression, but is prolonged, expensive

Phase II trials in mesothelioma: An increasing challenge 89

and may be unethical without prior evidence ofactivity. Traditional response criteria were notdesigned to identify prolonged stable disease or so-called ‘minor responses’. Agents such as gefitiniband cetuximab have demonstrated that at leastsome small degree of objective response in phaseII testing seems to predict utility and survival ben-efits at a later stage of development. Randomisedphase II studies may provide greater evidence ofbenefit where stable disease or minor responsesare important, as may an ability to more effec-tively quantify the changes in ‘‘activity’’ reflectedin serial PET scanning following treatment [19].Alternatively, novel phase II designs using timeto progression as an endpoint could be explored[25].

Regardless of the trial design, endpoints mustbe chosen with thought and tumour measure-ment response criteria carefully described inthe protocol design and the final report. Choiceof novel agents to move to phase II trials mustbe based on robust pre-clinical information andsupplemented with adequate biological samplingof study patients. Only this way can we use whatwe have learnt about tumour biology, minimise

[8] Hillerdal G. Staging and evaluating responses in malig-nant pleural mesothelioma. Lung Cancer 2004;43:75—6.

[9] van Klaveren RJ, Aerts JG, de Bruin H, Giaccone G, Mane-gold C, van Meerbeeck JP. Inadequacy of the RECIST criteriafor response evaluation in patients with malignant pleuralmesothelioma. Lung Cancer 2004;43:63—9.

[10] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, KaplanRS, Rubinstein L, et al. New guidelines to evaluate theresponse to treatment in solid tumors. European Organiza-tion for Research and Treatment of Cancer, National CancerInstitute of the United States, National Cancer Institute ofCanada. J Natl Cancer Inst 2000;92:205—16.

[11] Byrne MJ, Davidson JA, Musk AW, Dewar J, van Hazel G, BuckM, et al. Cisplatin and gemcitabine treatment for malignantmesothelioma: a phase II study. J Clin Oncol 1999;17:25—30.

[12] Nowak AK, Byrne MJ, Williamson R, Ryan G, Segal A, Field-ing D, et al. A multicentre phase II study of cisplatinand gemcitabine for malignant mesothelioma. Br J Cancer2002;87:491—6.

[13] Fennell DA, Steele JP, Shamash J, Sheaff MT, Evans MT,Goonewardene TI, et al. Phase II trial of vinorelbineand oxaliplatin as first-line therapy in malignant pleuralmesothelioma. Lung Cancer 2005;47:277—81.

[14] Fizazi K, Doubre H, Le Chevalier T, Riviere A, Viala J, DanielC, et al. Combination of raltitrexed and oxaliplatin is anactive regimen in malignant mesothelioma: results of aphase II study. J Clin Oncol 2003;21:349—54.

[15] Otterson GA, Herndon 2nd JE, Watson D, Green MR,

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the chance of missing clinical activity and avoidprogressing too early to negative phase III trials. Inmesothelioma clinical trials, we would do well tolearn from the mistakes made in non-small cell lungcancer.

References

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[2] Berghmans T, Lafitte JJ, Paesmans M, Stach B, BerchierMC, Wackenier P, et al. A phase II study evaluating thecisplatin and epirubicin combination in patients with unre-spectable malignant pleural mesothelioma. Lung Cancer2005;50:75—82.

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[6] Byrne MJ, Nowak AK. Modified RECIST criteria for assess-ment of response in malignant pleural mesothelioma. AnnOncol 2004;15:257—60.

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17] Monetti F, Casanova S, Grasso A, Cafferata MA, Ardizzoni A,Neumaier CE. Inadequacy of the new response evaluationcriteria in solid tumors (RECIST) in patients with malignantpleural mesothelioma: report of four cases. Lung Cancer2004;43:71—4.

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20] Mathy A, Baas P, Dalesio O, van Zandwijk N. Limited efficacyof imatinib mesylate in malignant mesothelioma: A phase IItrial. Lung Cancer 2005;50:83—6.

21] Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, ReeseSF, Ford JM, et al. Activity of a specific inhibitor of theBCR-ABL tyrosine kinase in the blast crisis of chronicmyeloid leukemia and acute lymphoblastic leukemiawith the Philadelphia chromosome. New Engl J Med2001;344:1038—42.

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[24] Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H,Santoro A, et al. Cetuximab monotherapy and cetuximabplus irinotecan in irinotecan-refractory metastatic colorec-tal cancer. New Engl J Med 2004;351:337—45.

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