NCRI Melanoma Clinical Studies Group

Annual Report 2012/2013

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NCRI Melanoma CSG Annual Report 2012/13

1. Executive Summary This last year has been a transition period for the Melanoma CSG in several ways. Under a new chairman, the group has become more compact and each member now has a clearly defined role to play, with a primary focus on expanding the academic trials portfolio. In terms of absolute numbers, recruitment to melanoma research studies was anticipated to fall significantly following closure of recruitment to the national adjuvant AVAST-M trial (CI: Corrie) in March 2012. In contrast, a plethora of commercial sponsored trials in advanced disease have entered the portfolio, with potential to recruit small numbers of patients only. CSG members (Drs James Larkin, Paul Nathan & Pippa Corrie) have been active in influencing industry trial design, securing UK involvement in a highly competitive international landscape and ensuring strategic placement with sites across the country, with green shoot sites being selected to work with industry for the first time in some cases. While actual numbers of patients entering these trials are relatively low, our ability to successfully contribute to and oversee efficient recruitment to time and target of an extensive, complex and rapidly changing portfolio including registration trials is anticipated to reap benefits: gaining Pharma confidence should encourage placing more studies in the UK at an earlier phase of development and offer opportunities for investigator-initiated trials in the future. The portfolio has diversified this year to include studies in rare melanomas, radiotherapy and two surgical studies are in development. A valuable CSG strategy day was held in November 2012, stimulating ideas for non-melanoma research, which will be taken forward in 2013.

2. Top three achievements in the year The three main achievements for the Group this year are:

NICE approval of vemurafenib and ipilimumab (NICE TAs 268 and 269, December 2012) CSG members were closely involved in the registration (NIHR adopted) trials leading to licensing of both these ground-breaking agents now offering patients with advanced melanoma survival gain for the first time. During the first half of the year, CSG members (Drs Paul Lorigan, Paul Nathan & Pippa Corrie) were closely involved with the NICE deliberations, playing a significant role in reversing initial negative FADs and ultimately securing establishment of both drugs as standard of care in England and Wales.

Results of three national trials AVAST-M (interim results LBA, oral presentation), DOCMEK (final results, poster presentation) and SUAVE (final results, poster discussion) accepted for presentation at ASCO 2013.

Securing placement of the BMS sponsored first line trial of nivolumab vs ipilimumab vs nivolumab+ipilimumab in the UK (NCRN 551) Following early experience with PD-1 and PDL-1 antibodies, the ground breaking BMS sponsored international trial of the PD-1 McAb, nivolumab, as first line therapy for metastatic melanoma appeared unlikely to be offered to the UK, in part, since

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ipilimumab is not a first line standard of care. In addition, the sponsor expressed views that slow R&D processes meant that the UK was not competitive for international studies. Several CSG members (Drs Larkin, Nathan, Corrie) were influential to change decisions within BMS and secure 6 UK sites to recruit to this trial.

3. Structure of the Group The group has retained 2 subgroups this year, the Non-Melanoma Skin Cancer Subgroup, chaired by Dr Catherine Harwood and the Rare Melanomas Subgroup, chaired by Dr Paul Nathan. Membership of the subgroups can be found in Appendix 1. In addition, other members of the CSG have specific lead roles:

Professor Ruth Plummer Translational research

Dr Katherine Acland SPED member

Dr Sarah Danson MAPS management

Dr Jenny Nobes Radiotherapy research

Mr Marc Moncrieff Surgical research

Drs Pippa Corrie & Paul Nathan CSG Portfolio Delivery Task Group

4. Achievements and challenges of the subgroups Non-melanoma Skin Cancers Subgroup Under new chairmanship, the subgroup has fostered relationships with colleagues at the University of Nottingham, intended to facilitate development of new clinical trials particularly focusing on squamous cell carcinoma (SCC) in the first instance. After extensive preparatory work, the SPOT study (RfPB funded) is due to open next year. Merkel cell cancer initiatives have progressed well - the UK MCC-1 phase 2 trial of 2nd line pazopanib has opened, a trial of 1st line therapy was submitted to EME in March 2013, national guidelines are still in evolution. Dr John Lear continues to explore opportunities for basal cell carcinoma (BCC) trials. Rare Melanomas Subgroup The CSG now has an established programme of academic clinical trials in advanced uveal and ckit mutant acral/mucosal melanomas. The SUAVE trial closed to recruitment this year, with results due to be presented at ASCO 2013. Dr Ernie Marshall, SUAVE CI, has led an international rare cancers initiative which has resulted in a first trial approved by CTAAC in March 2013 (see below). The NICAM single arm phase 2 feasibility trial of nilotinib in ckit mutant metastatic acral/mucosal melanomas (CI: Dr James Larkin) is nearing completion, with a follow-on trial (PIANO) approved by CTAAC, which will test a potentially more active novel Plexxicon agent in this rare patient group.

5. Task groups/Working parties The Melanoma CSG volunteered to be part of the CSG Portfolio Delivery Task Group pilot initiated this year and we had our first teleconference in January 2013. The teleconference discussions raised a number of issues, which, going forward, should ensure that the Task Group is of value in defining future strategy of the Melanoma CSG. Of note, the NCRN focus had been on academic studies only. However, the Melanoma CSG was very clear that there needs to be cohesion between the academic and commercial elements of the portfolio if the CSG is to deliver its strategic role. In addition, for the discussions to be informative, detailed trial statistics including breakdown of set up times, recruitment

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target and actual recruitment by site, needs to be provided. CTUs have confirmed they can provide this level of detail, while commercial trial activity is forwarded to the NCRN CC, albeit in a less timely fashion. Incorporation of these proposals to future discussions should improve the quality of the next TC planned for later in 2013. The CSG does not have any other formal working parties currently. However, the group is working specifically to develop surgical and radiotherapy research studies. A second surgeon, Mr Oliver Cassell, has been appointed to the CSG to assist taking forward 2 key surgical studies in development. For radiotherapy, a clinical oncologist, Dr Jenny Nobes, was appointed and has been working to bring several key international radiotherapy studies originating from the Australian and New Zealand Melanoma Trials Group (ANZMTG) to the UK. Her role will be interrupted temporarily due to maternity leave, due April 2013.

6. Patient recruitment summary for last 5 years Recruitment to melanoma trials is highly influenced by availability of adjuvant trials. Recruitment was expected to drop significantly in 2012/13 following closure of the AVAST-M trial. Two new commercial sponsored portfolio adjuvant trials in BRAF mutant melanoma have taken longer to open than anticipated, but both are now in the process of opening to recruitment in a number of UK sites. Recruitment to these 2 trials is likely to be significantly lower than for AVAST-M given the 50% prevalence of BRAF mutation, up to 12 UK sites per trial due to open, and the level of complexity of these trials will influence patient participation. In the last year, recruitment to interventional trials therefore reflects recruitment to advanced melanoma trials only. These have involved limited (generally under 10) UK sites and tend to open and close quite quickly due to rapid, competitive international recruitment. Involving either new BRAF targeted agents or novel immunotherapies, these trials are an order of magnitude more complex than historical melanoma trials, requiring co-ordination of multiple support services (eg. dermatology, ophthalmology, cardiology) as well as tumour sample collection before and during the study, when feasible. These additional requirements influence patient eligibility as well as their acceptance to participate, especially when vemurafenib and ipilimumab are now available as standard of care. Despite these challenges, the melanoma community is highly motivated to embrace trials offering state of the art treatment in genetically defined patient subgroups: BRAF wild type, BRAF mutant, NRAS mutant and CKIT mutant.

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Table 1 Summary of patient recruitment over 5 years by RCT/Non-RCT

Year All subjects Cancer patients only % of cancer patients relative to incidence

Non-RCT RCT Non-RCT RCT Non-RCT RCT

2007/2008 287 119 266 105 3.2 1.3

2008/2009 257 623 257 279 3.1 3.4

2009/2010 393 1183 393 392 4.7 4.7

2010/2011 786 632 786 500 9.5 6.0

2011/2012 705 505 691 505 8.3 6.1

Table 2 Summary of patient recruitment by Interventional/Non-interventional

Year All participants Cancer patients only % of cancer patients relative to incidence

Non-interventional

Interventional Non-interventional

Interventional Non-interventional

Interventional

2012/2013 534 140 534 140 4.3 1.1

7. Links to other CSGs and international groups Our main links are currently with the EORTC Melanoma Group, IRCI and the ANZMTG. EORTC Currently, the EORTC does not have any melanoma trials open to recruitment in the UK. An adjuvant trial in stage II ulcerated melanoma is being set up and will involved a number of UK sites. However, the highly selected patient population means that recruitment numbers will be low. The opportunity for a new, large scale adjuvant trial is not yet clear. This may depend on the results of the AVAST-M trial, the EORTC 18071 trial of ipilimumb and a GSK sponsored trial of the MAGE A3 vaccine. While AVAST-M is reporting interim results at ASCO this year, the other 2 trials are not due to report until 2014. As CI for the AVAST-M trial, the CSG Chair is maintaining links with the EORTC Melanoma Group with a view to exploring opportunities for future adjuvant trials primarily in BRAF WT melanoma. IRCI As previously discussed, a tripartite phase II trial in advanced uveal melanoma led by the NIH (USA) has recently been approved by CTAAC and will involve 3 UK sites. It is hoped that this may foster future collaborative opportunities on a larger scale in the future. AZNMTG (Australia and New Zealand Melanoma Trials Group) Largely through 2 group members (Mr Marc Moncrieff & Dr Jenny Nobes), we are exploring opportunities to collaborate with AZNTMG and/or bring new AZNTMG trials to the UK, particularly focussing on surgery and radiotherapy.

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8. Funding applications in last year Table 3 Successful funding applications for the year

Title Acronym CI Funding body

A randomised phase two-arm phase II study of Trametinib alone and in combination with GSK214795 in patients with advanced uveal melanoma *IRCI Study

Dr Ernie Marshall CTAAC

There were no outline submissions made. Two surgical studies were submitted for funding this year:

The MICL study, originally submitted to CTAAC but not accepted there because the end point was not thought to be relevant, was resubmitted to RfPB. Unfortunately funding was not secured, despite the question being highly pertinent to patients’ surgical experience. Other funding opportunities are being considered.

The MelMart surgical margins study was submitted as an outline proposal to the HTA in January 2013, outcome pending.

A Merkel Cell study was submitted to EME in March 2013.

9. Industry sponsored trials portfolio This year, 7 industry sponsored clinical trials were open for recruitment. The majority focussed on advanced cutaneous melanoma. Two industry sponsored adjuvant trials were initially expected to run sequentially, but ultimately will be run concomitantly. The CSG chair took the initiative to work with industry leads and UK CIs to manage placement of these 2 trials strategically across the UK and to include green shoot sites. The net effect appears to have been successful in securing a larger than anticipated number of sites spread across the country due to recruit to these trials. The benefit in terms of patient accrual will be monitored in the next year. International competition to access promising new agents such as the PD-1 antibody, nivolumab, is fierce. A ground breaking BMS sponsored trial of nivolumab vs ipilimumab vs the combination regimen looked like it would not be placed in the UK, particularly since ipilimumab is not a first line treatment option in the UK. However, thanks to considerable effort from 3 CSG members (Drs Corrie, Larkin & Nathan), BMS took the decision to include 6 UK sites. This enormously exciting trial is due to open Q2 2013.

10. Collaborative partnership studies with industry Results of the DOCMEK trial (AZ initiative) were presented at the US Society of Melanoma Research annual meeting in November 2012 and updated as a poster at ASCO 2013. The PACMEL trial (GSK partnership) opened this year, completed its dose escalation phase and the randomised stage is now opening in multiple sites across the UK. Several new study proposals in both cutaneous and uveal melanoma are planned to be submitted for consideration at the May 2013 NCRI/AZ alliance meeting.

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11. Progress towards achieving 3 year strategy The 3 year strategy identified in the 2010/11 annual report was based on the January 2011 strategy review. Key elements of the strategy (in italics) and progress made is described as follows: • Continuing to provide clinical trial opportunities with relevant translational research for melanoma

patients. This is prioritised in all trial design • The opportunity for translational research is being considered with any new studies in development.

The Melanoma CSG is participating in the CSG Portfolio Delivery Task Group pilot. • Developing a strategy to attract new and young investigators, which includes inviting newly

appointed consultants with melanoma as a major part of their job plan to attend the CSG meeting. New appointments have been made this year to bring in new, young investigators in the fields of surgery (Mr Oliver Cassell), radiotherapy (Dr Jenny Nobes) and medical oncology (Dr Clive Mulatero).

• Publication and presentation strategy. The CSG has had 3 national studies accepted for presentation at ASCO 2013. The group has discussed the need to ‘brand’ CSG trials in presentations and will also take forward an authorship policy in the coming year.

• Clinical trials strategy day. Currently, NCRI trials are publicised via the national melanoma conference organised annually by MelanomaFocus, formally known as the UK Melanoma Study Group. It is not clear whether a separate strategy day is warranted, but may be justified as and when the portfolio broadens beyond melanoma systemic therapies. This position will be kept under regular review.

• Applying pressure to Industry to include more centres in phase 3 studies. This is exemplified by the successful intervention and influence exerted by the CSG chair regarding site selection for the 2 adjuvant BRAF mutant melanoma trials and the ongoing work of UK CIs in placing international commercial trials.

12. Impact of clinical trials on routine UK clinical practice NICE approval of vemurafenib and ipilimumab will make a significant impact on clinical practice. In 2012, NICE initially issued negative FADs for both vemurafenib and ipilimumab, despite both agents being shown to improve survival of metastatic melanoma patients, due to lack of convincing evidence of their cost-effectiveness. Having been involved in the pre and post registration international multicentre trials of these agents, CSG members representing the Royal College of Physicians and industry were influential in a remarkable reversal of the decision, so that in December 2012, positive NICE guidance was published for both drugs. This was a tremendous achievement, since the outcome of these deliberations is likely to set a precedent for evaluation of subsequent targeted agents and immunotherapies being developed in this disease.

13. Consumer involvement The group started the year with 3 PPI representatives. During the course of the year, one member stood down due to ill health (melanoma recurrence) and, sadly, passed away. We retain 2 excellent PPI members who are actively engaged with our 2 subgroups and other studies in development.

14. Open meetings / annual trials days The Melanoma CSG has not undertaken a formal national open trials day. As last year, the CSG contributed to the national melanoma conference, Melanoma Focus, held at the Royal College of Physicians of London, October 2012. The NCRI CSG Secretariat provided a trials summary booklet which was included in the delegate pack, name badges for delegates and speakers and assisted with

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registration on the day. The speakers were directed to refer to NIHR portfolio studies, where appropriate. The CSG undertook an internal strategy day in November 2012, which was an extremely useful opportunity to review (in particular) opportunities for academic, investigator-led research. This was especially valuable from the point of view of stimulating non-melanoma skin cancer research and several new ideas stemming from that day are now being developed as formal new research study proposals.

15. Priorities and challenges for the forthcoming year The Group’s priorities for the year are to:

Secure funding for academic multicentre trials in areas other than melanoma systemic therapy: our goal is for at least 1 surgical study and 1 non-melanoma skin cancer study to be funded.

Seek opportunities to develop an adjuvant trial in BRAF WT patients at high risk of recurrence

Oversee the NIHR melanoma trials portfolio at a time when the threshold for industry sponsored trials is being substantially lowered, to ensure national research targets are met.

16. Concluding remarks In this year of change, the Melanoma CSG has had success, with the results of 3 national systemic therapy trials accepted for presentation at ASCO 2013 and the first 2 new treatments impacting on melanoma patient survival entering routine clinical practice, both of which were trialled in the UK. With new membership, the group has diversified and is developing new research studies in rare melanomas, non-melanoma skin cancer and surgery. To maintain our academic reputation and recruitment, the coming year needs be one of converting concepts to securing funding.

17. Appendices 1. Membership of main CSG and subgroups 2. Portfolio Maps 3. Publications in previous calendar year 4. Major international presentations in previous year

Dr Pippa Corrie (Melanoma CSG Chair)

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Appendix 1

CSG and Subgroup membership

CSG Membership

Member Location

Dr Katharine Acland Buckinghamshire

Mr Oliver Cassell Oxford

Dr Pippa Corrie Cambridge

Dr Sarah Danson Sheffield

Dr Catherine Harwood London

Dr Lynne Jamieson Salford

Dr James Larkin Sutton

Dr John Lear Manchester

Dr Jerry Marsden Birmingham

Dr Ernie Marshall Wirral

Mr Marc Moncrieff Norwich

Dr Clive Mulatero Leeds

Dr Paul Nathan Middlesex

Dr Jenny Nobes Norwich

Professor Ruth Plummer Newcastle

Mr Simon Rodwell Bury St. Edmunds

Mr John Rouse Derbyshire

Professor John Wagstaff Swansea

Professor Keith Wheatley Birmingham

Subgroup Membership

Non-Melanoma Skin Cancer Subgroup Rare Melanomas Subgroup

Dr Catherine Harwood (Chair) Dr Paul Nathan (Chair)

Dr Neil Steven Professor Julia Newton-Bishop

Dr Pat Lawton Professor Ian Cree

Dr Jenny Nobes Professor Martin Cook

Professor Keith Wheatley Dr Paul Lorigan

Dr John Lear Dr James Larkin

Dr Charlotte Proby Dr Ernie Marshall

Dr Steve Nicholson Professor Peter Hoskin

Dr Jerry Marsden Dr Ewan Brown

Mr Marc Moncrieff

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Appendix 3 Publications arising from the Group’s portfolio ITEM Marshall, E., 2012, “A phase II study of Imatinib in the treatment of patients with metastatic uveal melanoma,” ASCO Annual Meeting. SUAVE Marshall, E., Coupland, S., Corrie, P., Damato, B., Danson, S., Dobson, L., Evans, J., Goodman, A., Kalirai, H., Jones, S., Kumar, S., Larkin, J. G. M., Lorigan, P., Nicholson, S., Ottensmeier, C., Silcocks, P., Steven, N., Tudur-Smith, C., Nathan, P. D. 2012, “A randomized phase II study of sunitinib versus dacarbazine in the treatment of patients with metastatic uveal melanoma,” J Clin Oncol 30, ASCO Annual Meeting. BRIM 3 Chapman, P. B., Hauschild, A., Robert, C., Larkin, J. M. G., Haanen, J., Ribas, A., Hogg, D., Hamid, O., Ascierto, P. A., Testori, A., Lorigan, P., Dummer, R., Sosman, J. A., Garbe, C., Maio, M., Nolop, K. B., Nelson, B. J., Joe, A. K., Flaherty, K. T. and McArthur, G. A. (2012), “Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma,” J Clin Oncol 30, ASCO Annual Meeting. METRIC Flaherty K.T., Robert, C., Hersey, P., Nathan, P., Garbe, C., Milhem, M., Demidov, L. V., Hassel, J. C., Rutkowski, P., Mohr, P., Dummer, R., Trefzer, U., Larkin, J. M,, Utikal, J., Dreno, B., Nyakas, M., Middleton, M. R., Becker, J. C., Casey, M., Sherman, L. J., Wu, F. S., Ouellet, D., Martin, A. M., Patel and K., Schadendorf, D. (2012), “Improved survival with MEK inhibition in BRAF-mutated melanoma,” N Engl J Med, 367(2) pp. 107-14. Epub 2012 Jun 4. Robert, C., Flaherty, K. T., Hersey, P., Nathan, P. D. Garbe, C., Milhem, M. M., Demidov, L. V., Hassel, J. C., Rutkowski, P., Mohr, P., Dummer, R., Trefzer, U., Larkin, J. M., Utikal, J., Casey, M., Sherman, L., Crist, W. A., Wu, F. S., Patel, K., Schadendorf, D. (2012) , “Phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM),” J Clin Oncol 30, ASCO Annual Meeting. DOCMEK DOC-MEK: a double blind randomised phase 2 trial of docetaxel with or without selumetinib (AZD6244; ARRY-142886) in wt BRAF advanced melanoma. M. R. Middleton, L. Collins1 A. Gupta, A. Thomason1 R. Lisle, M. Churchman, S. Love, J. Larkin, R. Plummer, P. Nathan,S. Danson, C. Ottensmeier, P. Lorigan, M. Harries. Society for Melanoma Research 2012 Congress

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Appendix 4 Presentations arising from the Group’s portfolio DOC-MEK: a double blind randomised phase 2 trial of docetaxel with or without selumetinib (AZD6244; ARRY-142886) in wt BRAF advanced melanoma. M. R. Middleton. Society for Melanoma Research 2012 Congress