Study coordinator: Alexander van Akkooi (Rotterdam, NL)

1. EORTC 1208MINITUB: Prospective Registry on Sentinel Node (SN) Positive Melanoma patients with minimal SN Tumor Burden who undergo Completion Lymph Node Dissections (CLND) or Nodal Observation Study coordinator: Alexander van Akkooi (Rotterdam, NL)

2. Overview • Background and introduction • RCT’s on ELND • MSLT-1; final results NEMJ 2014 • SN Tumor Burden Retrospective EORTC data • Study objectives • Trial design • History and current status • Feasibility assessment

3. Elective Lymph Node Dissection (ELND) 4 RCT’s • WHO study, 267 vs. 286, Veronesi et al. (NEJM 1977) • No Survival Benefit • Sim et al. (Cancer 1978) • Immediate (n=54), delayed (=3 months) (n=56), no (n=63) • No Survival Benefit

4. Elective Lymph Node Dissection (ELND) • WHO study, 122 vs. 118, Cascinelli et al. (Lancet 1998) • No Survival Benefit (62% vs. 51%, P = 0.09) • Possible benefit for Node Pos pts • ELND pos vs. OBS pos (P = 0.04) • Intergroup Trial, 379 vs. 361, Balch et al. (Ann Surg Oncol 2000) • No Survival Benefit(77% vs. 73%, P = 0.12) • Non-Ulcerated (84% vs. 77%, P = 0.03) • T2 (86% vs. 80%, P = 0.03) • Extremity (84% vs. 78%, P = 0.05) • Sentinel Node Hypothesis

5. Sentinel Node (SN) Hypothesis • ELND could not detect survival benefit due to • Small benefit 5 – 10% • Potential ‘dilution’ by thin (T1) and thick (T4) melanomas • Seldom metastases / often haematogenous • Potential ‘dilution’ by N- neg pts • Cannot benefit from ELND Thus: • Identification of clinically occult metastases • All SNs progress to clinical node metastases • Intermediate thickness (T2 - T3)

6. FinalResults MSLT-1

7. MSLT-1 Morton et al. NEJM 2014 Calculated Sample Size = 900, Increased to 1200 after interim results

8. Primary End-Point: MSS Morton et al. NEJM 2014

9. DFS Secondary End-Point SN vs. OBS Local / In-transit 7.0% vs. 6.4% Nodal 4.9% vs. 14.6% Distant 13.9% vs. 11.2% Morton et al. NEJM 2014

10. Subgroup Analysis Subgroup Analysis SN pos vs. OBS node pos HR 0.56 P=0.006 Morton et al. NEJM 2014

11. New type of Subgroup Analysis • Accelerated-failure-time latent-subgroup analysis showed a clear survival benefit: • Estimated effect: • DFS 1.17 (P < 0.001) Survival increase 3.2 x • DMFS 0.73 (P = 0.04) Survival increase 2.1 x • MSS 0.68 (P = 0.05) Survival increase 2.0 x Morton et al. NEJM 2014

12. Altstein et al. Statistics in Medicine 2011

13. New type of Subgroup Analysis • Accelerated-failure-time latent-subgroup analysis showed a clear survival benefit • Non-validatedstatistical hypothesis • Developed on MSLT-1 interim data • Cannotbeused as validation!! Morton et al. NEJM 2014, Altstein et al. Statistics in Medicine 2011

14. Nodal Positivity Rate Still 2.4% difference after 10-years in Nodal Positivity between SLNB and OBS Difference is less than after 5-years Quite a significant difference based on total % of nodal positivity Morton et al. NEJM 2014

15. Prognostic False Positivity? 87 / 500 node positive in OBS-arm = 17.4% 17.4% out of 770 patients = 134 patients 134 – 31 False negatives = 103 should be SN+ 122 SN pos – 103 = 19 patients too many node pos pts in SN-arm 19 / 122 = 15.6% False Positive based on J.M. Thomas, Nat ClinPractOncol 2008

16. Hypothetical Causes of Prognostic False Positivity • Develop distant visceral metastases and die before developing clinically relevant nodal disease • Incorrect diagnosis of metastasis in case of benign capsule nevi • Minimal SN Tumor Burden • Might never progress, merely antigen presentation

17. Prognostic Heterogeneity • 5-year Survival of SN+ 56 – 75% • Depending on: • Median Breslow thickness of population • % Ulcerated Melanomas • How extensive Pathological Sampling SN van Akkooi et al. Nat Rev ClinOncol 2010

18. Difference in Biology not all SN positive patients are the same

19. Minimal SN tumor burden Rotterdam criteria 0.1-1.0 mm < 0.1 mm > 1.0 mm

20. Microanatomic Location • Microanatomic location of the metastasis within the lymph node • Subcapsular • Combined • Parenchymal • Multifocal • Extensive Dewar et al. J Clin Oncol 2004

21. SN Tumor Burden - Survival 5-year survival1 ≤ 0.1 mm 92% 0.1 – 1.0 mm 74% > 1.0 mm 59% Subcapsulair 81% Non-subcapsulair 66% Inter-Observer Reproducibility2 ICC (1 = max) • Size 0.88 • Infiltration from capsule 0.83 • Surface area in mm2 0.73 • % SN Involved 0.68 • Micro-anatomic Location 0.50 • Extracapsular Extension 0.39 • van der Ploeg et al. J ClinOncol 2011 • Murali et al. Cancer 2009

22. Study rationale • ~20% NSN+ but 100% receives CLND! • Issues: • Morbidity  • Chronic Lymph Edema • Nerve Damage • Wound infection • No clear therapeutic benefit of CLND • Which SN positive patients might safely be spared CLND? • Patient with minimal SN tumor burden: at the moment both options (CLND or not) are performed in Europe (no accepted standard of care) • Studies: • Balimoria et al. 2008 • 50% of SN+ pts in USA CLND, 50% no CLND • Regardless of SN Tumor Burden • Pasquali et al. 2012 • Heterogenous treatment of SN+ pts in Europe, USA & Australia • Already low frequency of CLND in minimal SN Tumor Burdenpts

23. Study Objective To analyze if patients with T2-T3 primary tumor andminimal SN tumor burden managed by only serial nodal observation, have a 5-year DMFI comparable to the ones who had CLND based on historical data (5-year MSS rate: 87%) Note: patients with T1 and T4 with a minimal Tumor Burden will be registered in the study for descriptive analyses only (distinct prognosis and clinical characteristics)

24. Minimal SN Tumor Burden – EORTC 1208 • Any SUB-micrometastasis with a maximum diameter < 0.1 mm, regardless of the site (Rotterdam criteria) • or • Metastases solely confined to the subcapsular (Dewar criteria)space and largest metastasis with a maximum diameter ≤ 0.4 mm (Rotterdam criteria)

25. Main eligibility criteria • Age > 18 years • Histological evidence of T2-T3 primary cutaneous melanoma • Note: patients with T1 and T4 with a minimal Tumor Burden will be registered in the study for descriptive analyses only • Patients with minimal SN tumor burden • Note: If there is more than 1 metastatic SN, the patient will be still eligible provided that all involved SN have minimal tumor burden, regardless of the amount of positive SNs and the interested basin • Absence of clinically apparent metastatic disease at the time of or before undergoing a SN procedure

26. Main eligibility criteria • No previous history of melanoma • No history of any other malignancy from which the patient has been disease-free for less than 5 years, except for non-melanoma skin cancer (Basal Cell Carcinomas or Squamous Cell Carcinomas) and in situ cervical cancer • No previous SN procedure for locally recurrent melanoma or uncertain malignant disease, such as atypical Spitz tumor/naevi

27. Primary endpoint • Distant Metastasis Free Interval (DMFI): time from SN positive biopsy until distant metastasis Secondary endpoints • Regional Control Rate: rate of lymph node dissection in the same basin where the SN was previously removed • Relapse Free Interval (RFI): time from SN positive biopsy until first relapse – regional or distant metastasis – or death due to melanoma • Melanoma Specific Survival (MSS): time from SN positive biopsy until death due to melanoma • Overall survival (OS): time from SN positive biopsy until death due to any cause • Morbidity (wound infection %, lymphedema % and neurologic damage %)

28. StudyDesign Prospective observational study: • H0: 5-year DMFI rate = 80% • H1: 5-year DMFI rate = 87% • If out of 243patientswith a minimum follow-up of 5 years, no more than 38 (15.7%) patients develop a DMetwithin 5-years (so that at least 205 (84.3%) patients are DM-free at 5 years), then one may reject the null hypothesis at alpha=0.05, and beta=0.10 (90% statistical power). • Total number of patients to be registered is 260 (243+17 drop outs) • Additionally, 26pts with T2-T3 + minimal TB who will undergo CLND will be registered and evaluated (comparison dataset: ~ 10% of sample size) • Additionally, ~50 T1 & T4 patients with minimal TB will be registered/evaluated (descriptive analysis: ~ 20% of sample size) • Accrual: 5 years; Follow-up: 10 years

29. Study Flow Chart

30. Assessments * Recommended C Only for Centers performing regular lymph node ultrasound examinations I If indicated by symptoms

31. Study history: MINITUB 2008 ExCo decision • No RCT, but Registry study • EORTC would NOT become sponsor • EORTC would let MG conduct the study • Supported the idea, but it did not fit EORTC HQ philosophy as official EORTC study September 2013: • 9 participating Centers of which 4 recruiting • 35 patients included (FPI 31-7-2009): • T1 = 2 (6.7%) • T2 = 8 (26.7%) • T3 = 13 (43.3%) • T4 = 3 (10%) • Unknown = 4 (13.3%)

32. Sponsorship Issues Sites requested a central sponsor / legal contracts MG cannot take this role / become sponsor No single investigator / site will take this role for all sites Individual sites sometimes difficult to be sponsor at own site 2012 Exco Revision Exco endorsement (EORTC 1208) EORTC will act as study sponsor; insurance Fee per patient included into registry Current Status

33. Feasibility Conservative Estimate = 75 pts / years

34. MSLT-2 EORTC 1208

35. Feasibility is clear; yes we can! Need for sufficient centers, as events are somewhat rare Please consider participation into EORTC 1208 Thank You! Please Consider us

36. Join us at: EORTC Melanoma GroupFall 2014 Meeting – Rotterdam October 16 - 18

37. Contacts: Thank you