New treatments for skin cancer coming soon. Pascal Wolter Department of General Medical Oncology University Hospitals Leuven

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1 New treatments for skin cancer coming soon Pascal Wolter Department of General Medical Oncology University Hospitals Leuven

2 Melanoma: Braf and MEK-inhibitors for BRAF mutant melanoma MEK-inhibitors for NRAS mutant melanoma Imatinib/Nilotinib for KIT-mutant melanoma other molecules in the pipeline Basal cell carcinoma: Vismodegib and others Cutaneous squamous cell carcinoma: EGFR-inhibitors

Historical overview of treatment of melanoma: 1812: René Laennec: melanoma as disease entity 1976: FDA approval of DTIC for advanced, metastatic melanoma 1988: first version of AJCC staging for

FDA/EMEA 1787: John Hunter describes melanoma 1970: Alexander Breslow: relationship between tumor thickness and prognosis 1995: Interferon-α approved by FDA for adjuvant treatment of stage IIB/III

3 Historical overview of treatment of melanoma: 1812: René Laennec: melanoma as disease entity 1976: FDA approval of DTIC for advanced, metastatic melanoma 1988: first version of AJCC staging for melanoma 1998: FDA approval for Interleukin-2 for treatment of advanced metastatic melanoma 2005: melanoma as a genetically heterogenous disease (Bastian) 2013: Dabrafenib and Trametinib approved by FDA/EMEA 1787: John Hunter describes melanoma 1970: Alexander Breslow: relationship between tumor thickness and prognosis 1995: Interferon-α approved by FDA for adjuvant treatment of stage IIB/III melanoma 2002: high frequency of Braf mutation in melanoma (Davies) : Vemurafenib and Ipilimumab approved by FDA/EMEA Anti-PD1 and several other targeted agents in pipeline Clinicaltrials.gov: 394 recruiting studies for patients with melanoma ( ) Lee C et al Clin Dermatol 31(2): (2013)

Different ways to attack melanoma: Attack directly the tumorcell: Classical chemotherapy (DTIC, Temozolomide, combinationchemotherapy) Angiogenesisinhibitors (sunitinib, bevacizumab, XL-184, E7080,)

4 Different ways to attack melanoma: Attack directly the tumorcell: Classical chemotherapy (DTIC, Temozolomide, combinationchemotherapy) Angiogenesisinhibitors (sunitinib, bevacizumab, XL-184, E7080,) KIT-inhibitors (imatinib, nilotinib) BRAF-inhibitors (sorafenib, vemurafenib, dabrafenib) MEK-inhibitors (trametinib, MEK162) Biochemotherapy or combination of immunotherapy and targeted agents Stimulate immunesystem to overcome immunoresistance Interleukin-2 Interferon-α Anti-CTL-4 antibodies (ipilimumab, tremelimumab) Anti-PD-1 / PDL-1 antibodies Vaccination therapy (peptide based, dendritic cells, adoptive Immunotherapy CDK4/6 inhibitors Allovectin-7

5 Not all melanomas are the same. Davies H et al Nature 2002;417: Maldonado et al JNCI 2003;95: Curtin et al NEJM 2005;353:

Frequency (%) of mutations in kinase signaling pathways in melanoma subtypes cutaneous acral mucosal uveal Not specified BRAF 40-60 15-20 3-5 <1 NRAS 15-25 10-15 5-15 <1 c-kit (mut) c-kit (ampl) GNαQ

6 Frequency (%) of mutations in kinase signaling pathways in melanoma subtypes cutaneous acral mucosal uveal Not specified BRAF <1 NRAS <1 c-kit (mut) c-kit (ampl) GNαQ <2 (CSD 2-17) 0-7 (CSD 6) <1 (CSD 5) < <1 <1 < ERBB PTEN PIK3CA 1-2 AKT1/3 1-2 Curtin JA J Clin Oncol 2006, 24(26): Davies MA et al Oncogene 2010, 29,

7 Not all melanomas are the same BRAF is only the beginning. Other oncogenes and tumour supressors thought to be involved in melanomagenesis: RAC1, PPP6C, SNX31, TACC1, ARID2, STK19 (Hodi et al, Krauthammer et al) MDM4 (Gembarska et al) PREX2 (Berger et al) GRIM3 (Prickett et al) And others such as : MITF, CDK4, CCND1, ERBB4, AKT1, AKT2, AKT3, NEDD9, MYK, ETV1, PTEN Flaherty K et al Nature Rev Cancer 2012, 12(5):349-61; Hodis E et al Cell 2012;150: ; Krauthammer M et al Nature Genetics 2012, 44(9): ; Gembarska A et al Nature Medicine 2012, 18(8): ; Berger MF et al Nature 2012, 485: ; Prickett TD et al Nat Genetics 2012, 43(11):

8 Not all melanomas are the same BRAF is only the beginning. Other oncogenes and tumour supressors thought to be involved in melanomagenesis: RAC1, PPP6C, SNX31, TACC1, ARID2, STK19 (Hodi et al, Krauthammer et al) MDM4 (Gembarska et al) PREX2 (Berger et al) GRIM3 (Prickett et al) And others such as : MITF, CDK4, CCND1, ERBB4, AKT1, AKT2, AKT3, NEDD9, MYK, ETV1, PTEN Hodis E et al Cell 2012;150:

9 Molecular and immunologic signaling in melanoma. Sullivan R J et al. Clin Cancer Res 2013;19:

10 Vemurafenib: the beginning Flaherty K J N Engl J Med Aug 26;363(9):

11 Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation (BRIM-3) OS at 6 m: Vem: 84% DTIC 64% Chapman P et al N Engl J Med Volume 364(26): (2011) Median PFS 5.3 m in the vemurafenib group and 1.6 m in DTIC group ORR with vemurafenib 48% with median time to response 1.45 m vs 5% with DTIC with median time to response of 2.7 m.

Safety (BRIM-2): 4 patients discontinued treatment because of adverse events 45% of the

Development of cutaneous squamous-cell carcinoma or keratoacanthoma was reported in 34

12 Safety (BRIM-2): 4 patients discontinued treatment because of adverse events 45% of the 132 patients had their dose reduced; dose interruptions were required in 85 patients (64%). Development of cutaneous squamous-cell carcinoma or keratoacanthoma was reported in 34 patients (26%), typically consisting of only one lesion (in 20 patients) or two lesions (in 6 patients). The median time to development of the first cutaneous squamous-cell carcinoma or keratoacanthoma lesion was 8 weeks. Sosman JA et al N Engl J Med 2012 Feb23;366(8):

14 Other BRAF-inhibitors Dabrafenib (Tafinlar ):

20 Possible mechanisms of resistance to BRAF inhibition: Luke JJ et al Clin Cancer Res 2011 Nov 14. MEK dependent resistance mechanisms: NRASQ61, COT, MEK-1 mutation, BRAF V600 truncation or amplification MEK-independent : PDGFR beta, IGF1R, RTK overexpression, i.e. cmet

21 Metastatic melanoma MEK-inhibitors: Trametinib, MEK-162, others RTK Ras MEKi B-Raf A-Raf MEK c-raf ERK 21 Cell Proliferation

22 22 Robert C et al ASCO 2012 abstr Flaherty KT et al N Engl J Med 2012 Jun 4. [Epub]

23 ORR Trametinib: 22% ORR chemo: 8% 23 Robert C et al ASCO 2012 abstr Flaherty KT et al N Engl J Med 2012 Jun 4. [Epub]

24 24 Robert C et al ASCO 2012 abstr Flaherty KT et al N Engl J Med 2012 Jun 4. [Epub]

25 25 Robert C et al ASCO 2012 abstr Flaherty KT et al N Engl J Med 2012 Jun 4. [Epub]

26 26 Robert C et al ASCO 2012 abstr Flaherty KT et al N Engl J Med 2012 Jun 4. [Epub]

NRAS mutant melanoma MEK-inhibitors: MEK162, GDC-0973 MEK162 = a selective inhibitor of the kinases MEK1 and MEK2, pre-clinical activity in BRAF and NRAS mutant (mt) melanoma model Open label, phase

27 NRAS mutant melanoma MEK-inhibitors: MEK162, GDC-0973 MEK162 = a selective inhibitor of the kinases MEK1 and MEK2, pre-clinical activity in BRAF and NRAS mutant (mt) melanoma model Open label, phase II study in pts with BRAFV600 and NRAS mt advanced cutaneous melanoma. MEK162 was administered orally at a starting dose of 45 mg twice daily, 66 pts: 42 BRAF mt and 24 NRAS mt, among 29 BRAF mt and 13 NRAS mt pts evaluable for efficacy, 2 confirmed and 6 unconfirmed partial responses (PRs) and 13 pts with stable disease (SD) were recorded in the BRAF arm and 3 confirmed PRs, 3 unconfirmed PR and 13 pts with SD recorded in the NRAS arm. Common treatment related adverse events (AEs), all grades (Gs) and all pts, were rash (40.9%), diarrhea (33.3%), acneiform dermatitis (27.3%), creatine phosphokinase (CK) elevation (25.8%), fatigue (18.2%) and peripheral edema (21.2%). Central serous retinopathy-like retinal events (G 1/2 only) were reported in 8 (12.1%) pts (6 G1, 2 G2). All retinal events were reversible. G3/4 AEs in >1pt were diarrhea (4.5%) and CK elevation (15.2%). MEK162 showed clinical activity in pts with BRAF and NRAS mt advanced melanoma. This is the 1st targeted therapy to show activity in pts with NRAS mt 27 melanoma. Ascierto PA et al ASCO 2012 abstr Ascierto PA et al Lancet Oncol 14(3):

28 Combination of BRAF- and MEK-inhibitors: Weber J et al ASCO 2012 abstr. 8510

29 Combination of BRAF- and MEK-inhibitors: Weber J et al ASCO 2012 abstr. 8510

30 Combination of BRAF- and MEK-inhibitors: Weber J et al ASCO 2012 abstr. 8510

31 Combination of BRAF- and MEK-inhibitors: Weber J et al ASCO 2012 abstr. 8510

32 Combination of BRAF- and MEK-inhibitors: Weber J et al ASCO 2012 abstr. 8510

33 Combination of BRAF- and MEK-inhibitors: Weber J et al ASCO 2012 abstr. 8510

34 Combination of BRAF- and MEK-inhibitors: Weber J et al ASCO 2012 abstr. 8510

35 Combination of BRAF- and MEK-inhibitors:

36 Combination of different inhibitors: TPS8603: CA : A phase I/II trial of vemurafenib and ipilimumab in patients with BRAF V600 mutation-positive metastatic melanoma (Ribas T et al) Escalating dose design to assess safety/tolerability and to determine the maximum tolerated dose (MTD) of each agent, VEM initially given alone for 28d at 960 mg BID followed by VEM in combination with Ipi iv at 3 mg/kg (induction q3w x 4 followed by maintenance (q12w), next cohort Ipi 10 mg/kg Abstract 8569: Outcomes of patients with malignant melanoma treated with immunotherapy prior to or after vemurafenib (Ackerman A et al). 43 pts, response to vemurafenib following immunotherapy appears similar to that seen in previously untreated pts. Median PFS and OS for pts receiving ipi after discontinuation of vem are poor (10/32 PD under vem pts received single-agent ipi; all 10 pts had disease progression (PD) at 6 months with a median PFS of 0.7 mo and OS of 2.2 mo), possibly due to rapid PD at the time of vem discontinuation. Prolonged OS is primarily seen with resumption of BRAF inhibition. Our data suggests that in appropriately selected pts, IT should be considered prior to BRAFi. Ribas A et al NEJM 368(14):1365-6, 2013

37 How to combination the different inhibitors?

Case 1: 04-2007: wide resection of a superficial spreading

86 mm, no ulceration, 1 mitosis/10 HPF 11-2012: multiple

lungmetastasis, BRAF V600E positive, inclusion in COMBI-V

38 Case 1: : wide resection of a superficial spreading melanoma, right upper arm, Breslow 0.86 mm, no ulceration, 1 mitosis/10 HPF : multiple subcutaneous nodules, also lymphnode-, bone and lungmetastasis, BRAF V600E positive, inclusion in COMBI-V study, start Dabrafenib (150 mg 2X/d and Trametinib 2 mg/d) : PR after 2 cycles : CR after 12 months

What about c-kit and melanoma.? In comparison with classical cutaneous melanomas melanomas arising from mucosal surfaces and from the palms, soles, and nailbeds have been shown to harbor KIT mutations.

39 What about c-kit and melanoma.? In comparison with classical cutaneous melanomas melanomas arising from mucosal surfaces and from the palms, soles, and nailbeds have been shown to harbor KIT mutations. Previous clinical trials testing the efficacy of single-agent imatinib for the treatment of melanoma were disappointing: Two phase II trials did not reveal any objective responses in 41 patients (Ugurel et al, Wyman et al). The authors concluded that imatinib had no therapeutic effect in melanoma and should no longer be investigated. In a third phase II study with 21 melanoma patients there was only one patient with a partial response lasting 12,8 months, interestingly a patient with metastatic acral lentiginous melanoma. Frequency (%) of mutations in kinase signaling pathways in melanoma subtypes c-kit (mut) c-kit (ampl ) cutaneous acral mucosal uveal <2 (CSD 2-17) 0-7 (CSD 6) < <1 Curtin JA J Clin Oncol 2006, 24(26): ; Antonescu CR et al. Int J Cancer 2007;121: ; Heinrich MC et al. J Clin Oncol 2008;26(suppl. 20, abstr.9016); Ugurel S et al. Br J Cancer 2005;92: ; Wyman K et al. Cancer 2006;106: ; Kim KB et al. Br. J Cancer 2008;99:

40 Hodi FS J Clin Oncol 2008, 26(12):

41 # 9001: A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT. Three prior phase II studies of Imatinib mesylate (IM) in 62 pts with advanced melanoma reported only 1 response in a pt with acral melanoma. A proportion of melanomas arising from acral, mucosal, and chronic sun damaged (CSD) sites are characterized by KIT mutations (mut) or amplifications (amp) phase II study of Imatinib restricted to pts with melanoma harboring such alterations in KIT (screening by FISH or mutational analysis in KIT) 81 pt tumors screened: 17 (21%) had a KIT mut or amp: 5/22 (23%) acral, 12/45 (27%) mucosal, 0/13 (0%) CSD, 0/1 (0%) unknown primary. 12 (15%) had a mut only; 4 (5%) had an amplification only; 1 (2%) had both. 15 have been treated, with 12 evaluable for response. 2 pts achieved a CR 2 pts with PR 6 pts SD 2 pts PD While IM has limited activity in a non-selected melanoma pt population, a substantial proportion of melanomas harboring KIT mut or amp appear to respond. Carvajal RD J Clin Oncol 27:15s, 2009 (suppl; abstr 9000)

42 CR: 2/25 (8%) PR: 2/25 (8%) Trans PR: 2/25 (8%) SD (> 12 wks): 5/25 (20%) Median TTP: 12 wks Median OS: 46 wks Carvajal RD JAMA 305(22): , 2011 All 6 responses in tumors with exon 11 L576P or exon 13 K642E mutations

Case 2: 21-02-2011: Curettage van een geülcereerd pigmentletsel ter hoogte van de plantaire zijde van de linker hallux. APO: maligne melanoom, Clark IV, Breslow 3mm, niet in toto verwijderd.

43 Case 2: : Curettage van een geülcereerd pigmentletsel ter hoogte van de plantaire zijde van de linker hallux. APO: maligne melanoom, Clark IV, Breslow 3mm, niet in toto verwijderd : Resectie maligne melanoom op de linker hallux, met 1 cm marge tot op de peesschede, toonde nog residuele tumor van 6 mm dik, met positief diep sectievlak : Amputatie linker hallux op niveau van MTP gewricht : diagnose longmetastasen Vroeger DTIC mono Nu: eerst KIT mutatie analyse!

44 Case 2: : KIT mutatie analyse: puntmutatie p.leu576pro in exon 11 inclusie in TEAM rial, start Nilotinib, 2x400 mg/d : PR na 2 cycli

45 Algorithm for the treatment of patients with metastatic melanoma: Pflugfelder A, J Dtsch Dermatol Ges Aug;11 Suppl 6:1-116

There is a ray of hope, but several question remain to be answered! How to reconcile immunotherapy and targeted agents? Is sequential treatment better than combination therapy?

46 There is a ray of hope, but several question remain to be answered! How to reconcile immunotherapy and targeted agents? Is sequential treatment better than combination therapy? What are the clinical and molecular predictors of response? What are the mechanisms of primary or secondary resistance? How can response be maintained? Should these drugs be used in monotherapy or in combination with cytotoxic chemotherapy and/or immunotherapy?

47 Recently stopped, ongoing and planned studies in metastatic melanoma: CoBrim: Phase III, double blind, placebo-controlled study of Vemurafenib + placebo versus Vemurafenib in combination with GDC-0973 in previously untreated BRAFv600-Mutation positive patients with inresectable locally advanced or metastatic melaoma MK : A Multicenter, Randomized, Controlled, Three-Arm, Phase III Study to Evaluate the Safety and Efficacy of Two Dosing Schedules of MK-3475 Compared to Ipilimumab in Patients with Advanced Melanoma NEMO: The NEMO trial (NRAS melanoma and MEK inhibitor): A randomized Phase III, open label, multicenter, two-arm study comparing the efficacy of MEK162 versus dacarbazine in patients with advanced unresectable or metastatic NRAS mutation-positive melanoma EMR : A multicentre, open label, randomized Phase II trial of the MEK inhibitor pimasertib or dacarbazine in previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma CA : A Phase 3, Randomized, Double-Blind Study of Nivolumab Monotherapy or Nivolumab Combined with Ipilimumab Versus Ipilimumab Monotherapy in Subjects with Previously Untreated Unresectable or Metastatic Melanoma. Planned - MEK162x2110: A Phase Ib/II, multicenter, open-label, dose escalation study of LGX818 in combination with MEK162 in adult patients with BRAF V600 - dependent advanced solid tumors (LEE011) CA : A Randomized Double-Blind Phase III Study of Ipilimumab Administered at 3 mg/kg vs at 10 mg/kg in Subjects with Previously Treated or Untreated Unresectable or Metastatic Melanoma MEK116513: A Phase III, randomized, open-label study comparing the combination of the BRAF inhibitor, GSK and the MEK inhibitor, GSK to the BRAF inhibitor vemurafenib in subjects with advanced (Stage IIIc) or metastatic (Stage IV) BRAF V600E/K mutation-positive melanoma TEAM: Nilotinib in acral, mucosal or CSD skin melanoma with KIT mutation/amplification CA : A Randomized, Open-Label Phase III Trial of BMS versus Investigator s Choice in Advanced (Unresectable or Metastatic) Melanoma Patients Progressing Post Anti-CTLA-4 Therapy. cancertrials.be or pascal.wolter@uzleuven.be, tel: 016/341012

BCC: Vismodegib (GDC-0449) and LDE-225 GDC-0449 (Roche): Phase II study of GDC-0449, a hedgehog pathway inhibitor in patients with locally advanced (labcc) or metastatic basal cell carcinoma (mbcc)

48 BCC: Vismodegib (GDC-0449) and LDE-225 GDC-0449 (Roche): Phase II study of GDC-0449, a hedgehog pathway inhibitor in patients with locally advanced (labcc) or metastatic basal cell carcinoma (mbcc) presented at EADO: 104 pts, ORR in labcc 43 ( 60) %, mbcc 30 (-40%) STEVIE: Safety study to give patients access to GDC-0449 (UZLeuven) LDE-225 (Novartis): Phase 2 study with LDE-225 in patients with Nevoid Basal Cell Carcinoma Syndrome (NBCCS BCC) started in UZ Leuven and ULB Erasme Phase 2 study with LDE-225 (completed,st. Augustinus, Wilrijk, and UCL, St. Luc). Sekulic A et al abstract CO14 EADO Nantes Schematic representation of the hedgehog (Hh) signaling pathway. (A) In the absence of Hh ligand, PATCHED protein (PTCH) is present in the primary cilium and prevents smoothened (SMO) from accessing it. The zinc finger transcription GLI3 gets partially degraded by the proteosome into an N-terminal repressor fragment (GLI3-REP) via a mechanism that involves the primary cilium. GLI3-REP moves to the nucleus where it silences transcription of Hh target genes. (B) In the presence of Hh ligand, Hh binding to PTCH1 leads to its internalization and degradation, allowing SMO to move into the cilium leading to the stabilization and activation of GLIs. Activated GLIs (GLI2/3-ACT) migrate to the nucleus to stimulated Hh target gene transcription. These include GLI1 and PTCH1 in positive and negative feedback loops, respectively.

49 Case 3: : locally advanced basal cell carcinoma with infiltration of the external auditory canal, patient refused radical surgical excision : start vismodegib 150 mg/d : PR after 2 months : CR after 5 months

SCC of the skin: EGFR - inhibitors Cetuximab: Phase II study of Cetuximab, an Epidermal growth factor receptor (EGFR) inhibitor in patients with unresectable SCC in 1 st line: 36 pts, 8 PR, 2 CR (ORR

samples of 10 patients Panitumumab: Phase II study ongoing UCL, St. Luc, JF Beaurain Uribe P et al Pathol Res Pract 2011 Jun 15;207(6):337-42.

50 SCC of the skin: EGFR - inhibitors Cetuximab: Phase II study of Cetuximab, an Epidermal growth factor receptor (EGFR) inhibitor in patients with unresectable SCC in 1 st line: 36 pts, 8 PR, 2 CR (ORR = 28%), DCR at 6 weeks 69%) Gefitinib: Phase 2 study with neoadjuvant Gefitinib in 23 patients with SCCS before surgery and/or RT CR: 18%, PR: 27% No EGFR-activating mutations identified in tumor samples of 10 patients Panitumumab: Phase II study ongoing UCL, St. Luc, JF Beaurain Uribe P et al Pathol Res Pract 2011 Jun 15;207(6): Epub 2011 Maubec E et al J Clin Oncol 29: , 2011 Lewis CM et al Clin Cancer Res 2012 epub Fig. 1. Representative examples of EGFR protein expression in cutaneous squamous cell carcinoma. (A) Normal skin adjacent to tumor 1. (B) Cutaneous squamous cell carcinoma (tumor 1) with high EGFR expression levels in membrane but also in cytoplasm

51 Disclosures of Potential Conflict of Interest: Employment or leadership positions Consultant or Advisory Role Stock ownership Honoraria Research funding Other remunenration no unpaid no no Pfizer GSK Bayer Novartis No travel grants

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