1. Selezione dei pazienti affetti da melanoma Vanna Chiarion Sileni Melanoma and Skin Cancer Unit IOV-IRCCS, Padova

2. Prognostic factors in metastatic melanoma 1362 pts enrolled in 8 studies ECOG in the last 25 years Median OS 6.4 months (CI 6.1-6.9) Multiple metastases RR= 1.3 ECOG PS >1 RR = 1.49 GI metastases RR =1.49 Liver metastases = 1.44 Pleural metastases RR =1.35 LDH  RR = 1.89 FAL  RR = 1.76 Previous immunotherapy RR = 0.84 Female gender RR = 0.87 Response to the treatment RR = 0.4 J Manola JCO 18; 3782-3793,2000

3. LDH is the most important prognostic factor C. Balch. JCO 27:6199,2009

4. Metastatic Melanoma : Single Agent Options Overall responses with monotherapy Khayat, Educational Book, ASCO 2000

8. Patient selection Factors to recommend high-dose IL-2 or immunotherapies Good PS (ECOG 0-1) Normal LDH Cutaneous or subcutaneous metastases only or less than three organs involved No brain metastases

10. BO 84 y protocol Ca184 EAP Courtesy V Chiarion Sileni

11. BO anni 84 Ipi 3 mg/kg q 21d x 4

13. EORTC Protocol 16032 (Coso 059) Jun 2005 Sep 2005 Nov 2005

14. EORTC Protocol 16032 (C0s0 059) courtesy V. Chiarion Sileni Aug 2005 Nov 2005 Jan 2006

16. Different incidence of Braf mutation with age and sun exposure

17. JCO 2011 IOV-IRCCS

18. Cancer 2011

19. MOLECULAR TARGETS MELANOMA PATHWAY

21. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0123456789101112 Time (months) Overall survival (March 31, 2011 cutoff) 1314 No. of patients at risk Dacarbazine Vemurafenib 338 337 302 336 268 334 232 317 186 285 145 218 111 178 83 125 43 82 26 54 12 22 5 11 0404 0202 0000 Vemurafenib (N=337) Est 6 mo survival 83% Median follow-up 6.2 mo Dacarbazine* (N=338) Est 6 mo survival 63% Median follow-up 4.5 mo Overall survival (%) Hazard ratio 0.44 (95% CI; 0.33 - 0.59) Post-progression use of ipilimumab: 17% dacarbazine patients vs 6% vemurafenib patients Dacarbazine median OS 7.9 mo *Dacarbazine patients who received vemurafenib after the IA (by DSMB recommendation; N=50) were censored at the date of crossover

22. Confirmed objective response rates (RECIST 1.1) across vemurafenib clinical trial programme PLX 06-02 Phase I BRIM 2 BRIM-3 ORR (final analysis at OS IA, 30 Dec 2010) Vemurafenib (95% CI) 56.0% (38–74) 53.0% (44–62) 48.4% (42–55) Dacarbazine (95% CI) –– 5.5% (3–9)

24. Clinical case 1 F 21-y old Nov 2005 NM on the left arm : pT4bN2aM0 HDI 1 month iv and 6 months LDI sc Feb ‘06 Oct ‘06 Feb ‘09 subcutaneous multiple recurrences: Sur Jan ’10 subcutaneous multiple lesions: S + RT Mar ’10 recurrence in axillary lymph-node and iliac: DTIC+DDP x 4 NC (CT and PET scan) Jul ’10 FMT only induction: plt G4 toxicity and pelvic PD Nov ’10 ipilimumab 3 mg/kg x 4 well tolerated: PD April’11 surgical resection of pelvic mass (symptomatic) and left ovary Aug’ 11 started vemurafenib 960 mg x 2 on protocol M025515 ongoing Tolerance: photosensitization,weight loss, dry skin, curly hair

25. Aug 2011 Oct 2011 V. Chiarion Sileni courtesy Dec 2011 Mar 2012

26. May 2012 V. Chiarion Sileni courtesy

27. Clinical case 1 resection and DC vaccination ? radical resection alone or continuing vemu ? ECT and to continue vemu ?

28. Clinical case 2 M 30-y old, May 2004 SSM in the back High IM and axillary mets pT2a N1aM0 adjuvant HDI for 1 y regular FU till Jan ‘11 Lung bilateral recurrence and mediastinal node: evaluation for S excluded Apr ’11 he started DTIC for 8 cycles: SD followed by PD lung and bone Oct 2011 Vemurafenib + zoledronic acid: ongoing in Sep ’12 Toxicity: photosensitization and plantar hyperkeratosis ( G2)

29. Oct 2011 Dec 2011 Jul 2012 Apr 2012 V.Chiarion Sileni courtesy

30. Clinical case 2 Options: Continue treatment without any change ? Stop Vemu and restart it at PD ? Ipilimumab asap or at PD ?

31. Clinical case 3 F 29-y old: NM on the shoulder Mar 2010 pT4bN0 Jan ’11 lung multiple mets: DDP+DTIC x 6 Cycles: SD- PD Sep ’11 evaluation for protocol M025515 screen failure due to elevated LFT Jan 2011 retested, started vemuradenib

32. Jan 2012 Mar 2012 May 2012 V. Chiarion Sileni courtesy

33. Aug 2012 Jun 2012 Sep 2012 V. Chiarion Sileni courtesy

34. Clinical case 3 In pts who develop CNS mets during vemu should the treatment be stopped ?

35. Rochet N, NEJM 2011 Feb 2011Aug 2011

36. B. Neyns Mel Res 2012

43. Conclusions (1) After 30 years of extensive researches two new different drugs showed an increase of OS in metastatic melanoma The effect of ipilimumab is not directly related to the tumor response, need time and a good PS, seems independent from disease extension and location Ipilimumab exerts some activity also in metastatic mucosal and ocular melanoma and in brain metastases when asymptomatic

44. Conclusions (2) BRAFi exert their effect rapidly and in a large proportion of patients arboring BRAF mutation BRAFi showed efficacy in brain metastases Combination of BRAFi with MEKi seems to prolong response duration Efficacy in the adjuvant setting, activity and safety in combination with other target therapies, with other immuno-modulating agents and with anti- angiogenetic agents are undervaluation