1. Cases on 1st line use of Ipilimumab in BRAF+ patients, sequencing of therapies Erika Richtig

2. 11/2008 Ulcerated melanoma left arm, tumor thickness 8 mm, Clark level V, vascular invasion BRAF V600E 12/2008 Sentinel node biopsy left axilla - 1 Sentinel lymph node with 1mm mikrometastasis; pN-1(mi)(sn) 01/2009 Lymph node dissection left axilla: 14 lymph nodes – tumor free 11/2012 Lymph node metastases in the lung - Surgery 02/2013 Pulmonary lymph node dissection (tumor free) female, 1957

4. 11/2008 Ulcerated melanoma left arm, tumor thickness 8 mm, Clark level V, vascular invasion BRAF V600E 12/2008 Sentinel node biopsy left axilla - 1 Sentinel lymph node with 1mm mikrometastasis; pN-1(mi)(sn) 01/2009 Lymph node dissection left axilla: 14 lymph nodes – tumor free 11/2012 Lymph node metastases in the lung - Surgery 02/2013 Pulmonary lymph node dissection (tumor free) 01/2014 Lung metastases and metastases in the pulmonary lymph nodes female, 1957

6. 11/2008 Ulcerated melanoma left arm, tumor thickness 8 mm, Clark level V, vascular invasion BRAF V600E 12/2008 Sentinel node biopsy left axilla - 1 Sentinel lymph node with 1mm mikrometastasis; pN-1(mi)(sn) 01/2009 Lymph node dissection left axilla: 14 lymph nodes – tumor free 11/2012 Lymph node metastases in the lung - Surgery 02/2013 Pulmonary lymph node dissection (tumor free) 01/2014 Lung metastases and metastases in the pulmonary lymph nodes 02-04/2014 Four treatments of ipilimumab 05/2014 Response PD in Recist PR in irRC 07/2014 Response SD in Recist and irRC female, 1957

7. 09/2004 Melanoma tumor thickness 1.6 mm, left lower leg BRAF V600E 09/2004 Sentinel node biopsy left inguinal region – 1 sentinel node tumor free 11/2004-04/2006 adjuvant treatment with interferon-alfa 3 Mill units 3x/week 10/2011 Lymph node metastases left inguinal and iliacal region – Surgery (6 out of 18 positive) 07/2012 Lung metastases 09/2012 Pulmonary lymph node metastases and new metastases left iliacal region male, 1959

9. 09/2004 Melanoma tumor thickness 1.6 mm, left lower leg BRAF V600E 09/2004 Sentinel node biopsy left inguinal region – 1 sentinel node tumor free 11/2004-04/2006 adjuvant treatment with interferon-alfa 3 Mill units 3x/week 10/2011 Lymph node metastases left inguinal and iliacal region – Surgery (6 out of 18 positive) 07/2012 Lung metastases 09/2012 Pulmonary lymph node metastases and new metastases left iliacal region 10/2012 - 01/2013: Four treatments of ipilimumab 04/2013 Response PR in Recist and irRC 09/2013 Response SD of known metastases in both, but newly grown lymph node metastasis left cervical region – Surgery 11/2013 Response PR 04/2014 Solitary small lesion in the brain, not clearly metastasis 06/2014 Response PD (brain metastases) 07/2014 Radiotherapy of the whole brain male, 1959

11. 07/2009 Biopsy of a solitary lung metastasis, no primary tumor 07/2009 Surgery BRAF V600E male, 1939

12. 07/2009 Biopsy of a solitary lung metastasis, no primary tumor 07/2009 Surgery BRAF V600E 10/2009 multiple lung metastases, liver metastases, metastasis of the left adrenal gland 11/2009-03/2010 Six cycles of dacarbazine 03/2010 Response SD 08/2010 Response CR 01/2011 Excision of subcutaneous metastasis right abdomen 02/2011 Bone metastases right hip and right upper arm – Surgery right hip, radiotherapy right upper arm, lymph node metastases right iliacal region male, 1939

14. 07/2009 Biopsy of a solitary lung metastasis, no primary tumor 07/2009 Surgery BRAF V600E 10/2009 multiple lung metastases, liver metastases, metastasis of the left adrenal gland 11/2009-03/2010 Six cycles of dacarbazine 03/2010 Response SD 08/2010 Response CR 01/2011 Excision of subcutaneous metastasis right abdomen 02/2011 Bone metastases right hip and right upper arm – Surgery right hip, radiotherapy right upper arm, lymph node metastases right iliacal region 04/2011-01/2012 Treatment with vemurafenib 05-07/2011 Response SD 09/2011 Response CR (except bone metastasis right upper arm: SD) 01/2012 Response PD (new lymph node metastases retroperitoneal and iliacal region) 02-04/2012 Four treatments of ipilimumab 07/2012 Response PR in Recist and irRC Since 11/2012 Response CR, ongoing male, 1939

15. 12/2003 Melanoma, left upper arm, tumor thickness 1.75mm, sentinel node biopsy left axilla with metastasis 02/2004 Lymph node dissection (tumor free) 03/2004-03/2005 adjuvant treatment with interferon alfa 2a 3Mill IU 3x/week sc 08/2006 Lymph node metastases left axilla – Surgery 07/2007 solitary liver metastasis – Surgery female, 1950

17. 12/2003 Melanoma, left upper arm, tumor thickness 1.75mm, sentinel node biopsy left axilla with metastasis 02/2004 Lymph node dissection (tumor free) 03/2004-03/2005 adjuvant treatment with interferon alfa 2a 3Mill IU 3x/week sc 08/2006 Lymph node metastases left axilla – Surgery 07/2007 solitary liver metastasis – Surgery 08-11/2007 Chemotherapy (3 cycles) 11/2007 Response PD (new metastasis in the pancreas) 12/2007 Surgery 01-02/2008 Chemotherapy (2 cycles) 03/2008 and 04/2008 Response PD (subcutaneous metastases – Surgery, solitary brain metastasis) female, 1950

19. 12/2003 Melanoma, left upper arm, tumor thickness 1.75mm, sentinel node biopsy left axilla with metastasis 02/2004 Lymph node dissection (tumor free) 03/2004-03/2005 adjuvant treatment with interferon alfa 2a 3Mill IU 3x/week sc 08/2006 Lymph node metastases left axilla – Surgery 07/2007 solitary liver metastasis – Surgery 08-11/2007 Chemotherapy (3 cycles) 11/2007 Response PD (new metastasis in the pancreas) 12/2007 Surgery 01-02/2008 Chemotherapy (2 cycles) 03/2008 and 04/2008 Response PD (subcutaneous metastases – Surgery, solitary brain metastasis) 04-10/2008 Chemotherapy (8 cycles) 11/2008 Response CR in the brain 02/2011 new liver metastasis – Chemoembolisation 07/2011 new liver metastases 07-09/2011 Four cycles of ipilimumab 12/2011 Response PR (liver) 03/2012 Response CR (liver), PD (lung, pulmonary lymph nodes) female, 1950

21. 12/2003 Melanoma, left upper arm, tumor thickness 1.75mm, sentinel node biopsy left axilla with metastasis 02/2004 Lymph node dissection (tumor free) 03/2004-03/2005 adjuvant treatment with interferon alfa 2a 3Mill IU 3x/week sc 08/2006 Lymph node metastases left axilla – Surgery 07/2007 solitary liver metastasis – Surgery 08-11/2007 Chemotherapy (3 cycles) 11/2007 Response PD (new metastasis in the pancreas) 12/2007 Surgery 01-02/2008 Chemotherapy (2 cycles) 03/2008 and 04/2008 Response PD (subcutaneous metastases – Surgery, solitary brain metastasis) 04-10/2008 Chemotherapy (8 cycles) 11/2008 Response CR in the brain 02/2011 new liver metastasis – Chemoembolisation 07/2011 new liver metastases 07-09/2011 Four cycles of ipilimumab 12/2011 Response PR (liver) 03/2012 Response CR (liver), PD (lung, pulmonary lymph nodes) 03/2012 Start treatment with vemurafenib 05/2012 Response SD (lung) 07-08/2012 Iritis both eyes – dose reduction to 50% 09/2012-09/2013 Response PR 12/2013 Response CR female, 1950

22. Ipilimumab or BRAF Inhibitor Retrospektive Study (34 patients) 6 Patienten IPI → BRAF Inhibitor (100% disease control rate) 28 Patienten BRAF Inhibitor → IPI (12 rapidly PD and death) comment: „Data suggest that disease progression is often rapid after resistance to vermurafenib and that this may not be the optimal time to start immunotherapy“. Ascierto PA, Simeone E, Giannarelli D, et al. Sequencing of BRAF inhibitors and ipilimumab in patients with metastatic melanoma: a possible algorithm for clinical use. J Transl Med 2012; 10: 107

23. Immunotherapy is an appropriate initial option for many patients with BRAFV600E mutant metastatic melanoma Michael B. Atkins, M.D. ; Deputy Director Georgetown-Lombardi Comprehensive Cancer Center Ipilimumab oder BRAF Inhibitor

24. Immunotherapy is an appropriate initial option for many patients with BRAFV600E mutant metastatic melanoma Michael B. Atkins, M.D. ; Deputy Director Georgetown-Lombardi Comprehensive Cancer Center Ipilimumab oder BRAF Inhibitor

25. Which drug, and when, for patients with BRAF-mutant melanoma? Sekwon Jang, Michael B Atkins Lancet Oncol 2013; 14: e60–69 Ipilimumab oder BRAF Inhibitor

27. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Ascierto PA, et al. Cancer Invest. 2014 May;32(4):144-9.

28. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Ascierto PA, et al. Cancer Invest. 2014 May;32(4):144-9.

29. Around every cancer - there is a patient German Cancer Congress, Berlin, 2014

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