Breakthrough and Landscape of Acral and Mucosal Melanomas. Jun Guo. M.D., Ph.D Peking University Cancer Hospital & Institute

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1 Breakthrough and Landscape of Acral and Mucosal Melanomas Jun Guo. M.D., Ph.D Peking University Cancer Hospital & Institute

2 Current status of advanced melanoma

3 Current status of advanced MM Targeted therapy and Immunotherapy have prolonged the survival time 1 y OS rate from 30%~to 73%, 2 y OS rate from 15% to 50% 50% 40% 40%

4 Trends of Incidence and mortality in Asia Only incidence is increasing but mortality remains stable in Australia and USA Both Incidence and mortality are increasing fast in Asia Insufficient management of melanoma? More aggressive pathological subtypes? Age standardised rate Australia Age standardised incidence and mortality rates by year in Australia Year Source: Australian Institute of Health and Welfare Australian Institute of Health and Welfare M. inc. USA Adapted from Rigel et al. J Am Acad Dermatol. 34:839 (1996) Jamal et al. CA Cancer J Clin. 54:8 (2004) China Year Male:Incidence Female:Incidence Male:Mortality Female:Mortality Book: Chinese Cancer Registry Annual Report from

5 Location Caucasian Asian <5% Acral+mucosal 70% Acral+mucosal

6 Appearance

7 Targeted Therapy

8 Background MAPK pathways well investigated CKIT/RAS/BRAF/MEK New Targets warranted? mtor pathways Rb-CDK4 pathways GNAQ/11

9 BRAF Mutation BRAF Mut prevalence in China :25% Caucasians :40~60% IF=5.53 Dong J, et al. Cancer Res. 2003;63:

10 Comparisons of different BRAFi Similar efficacy of different BRAFi : ORR~50%,PFS 5~6m almost 9 times of DTIC (Chemo), 4 times of PFS prolonged

11 BRAFi+MEKi: better efficacy PFS +~3.5m ORR 15-20%

12 BRAFi in acral melanoma- not so good Key points:poor efficacy in acral melanomas compared with non acral skin melanomas Adapted from Bai X, et al Beijing International melanoma Congress

13 2016 ASCO---who can not benefit from BRAFi COMBI Dtrial: BRAFi+MEKi vs BRAFi genomic analysis who can benefit from BRAFi?

14 Study Design N = 947 screened N = 423 Dabrafenib + trametinib 150 mg BID + 2 mg QD n = 211 Dabrafenib + placebo 150 mg BID + placebo QD n = 212 BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; QD, once daily; ULN, upper limit of normal.

15 Short survival with CDK pathway abbreviations Half of the survival time with CDKN2A muts or deficiency (OS,P=0.027; PFS, P<0.001)

16 CNV of CDK4/CCND1/p16 INK4a in Acral Melanomas Key point: high prevalence of CDKN2A loss CyclinD1 gain 和 CDK4 gain in Acral MM Adapted from Guo J, et al ASCO annual meeting poster discussion

17 Transitional research in CDK4 pathways Key Words: CDK4/6 inhibitor (PD or LEE011) in melanoma harboring CNV in the CDK4 pathway maybe a useful strategy for Chinese acral melanomas. Clinical trial( target CDK ) is ongoing in China Adapted from Guo J, et al ASCO annual meeting poster discussion

18 Why? the poor efficacy of BRAFi in Acral MM Reason possible:high prevalence of CNVs in acral MM! Solutions:BRAFi+CDKi maybe more important than BRAFi+MEKi in those BRAF V600 Acral MM. Adapted from Bai X, et al Beijing International melanoma Congress

19 CKIT gene Prevalence of C KIT abbreviations is 17%; Acral and mucosal : 34% and 32% IF=7.74

20 Efficacy of CKITi in advanced MM A phase II, open label, Multicenter clinicial trials First and large scale reported More effective in 11 and 13 exon mut simultaneously (~35%) Guo J, Si L, Kong Y, et al. J Clin Oncol.2011, 29 (21):2904-9

21 Cited by NCCN guidelines

22 2016 ASCO---better CKITi? A phase II trial of Novel CKITi (Dasatinib) in CKIT mut MM

23 Results Dasatinib is no better than imatinib and the response rate was 20%

24 New Targets----mTOR pathways MAPK pathway PI3K-AKT-mTOR pathway mtor mutation rate was 2.6% in multiple tumors (341/13815) 1. Adapted from Sosman, Curr. Oncol. Rep.11,405 (2009) 2.

25 Genetic Mutations of mtor in Chinese Melanoma mtor mutations are prevalent in AM and MM Subtype mtor mutation No. Positive % Acral Mucosal CSD Non-CSD UP Total Clin Cancer Res; 2016 Feb 15;22(4):

26 Summary of Genetic Mutations in mtor Of the 43 cases with mtor mutations, 37 different mutations were detected 5 recurrent mtor mutations were found: V1275A (3 cases), P1128L (2 cases), C1303R (2 cases), G1914A (2 cases) and bp[del TGCCGCCACCAC] (2 cases). Clin Cancer Res; 2016 Feb 15;22(4):

27 Functional Analysis of mtor Mutations Cell proliferation assays were performed in selected mtor mutants. P2213S and H1968Y was inhibited by AKTi (AZD5363) or PI3Ki (LY294002), while still sustained in the presence of PI3K inhibitor BKM120 or BLY719. Clin Cancer Res; 2016 Feb 15;22(4):

28 mtor mutation and clinicopathologic factors with OS Univariate analysis showed mtor a poor prognostic factor (P=0.031) Multivariate analysis showed mtor also a poor prognosic factor (P=0.08) P = Clin Cancer Res; 2016 Feb 15;22(4):

29 mtori Registered Clinical trial The phase II trial of mtori for advanced melanomas with mtor mutation Open label, one arm trial, opened on Aug 2014, 48 pts planned

30 GNAQ/11 Pathway GNAQ/11 mut will activate MAPK pathway GNAQ/11 mut is more common in uveal and mucosal melanomas Clin Cancer Res, 2013; 19:

31 GNAQ/11 pathway in China (284 samples) Prevalence of GNAQ/11 is 9.5% The common hotspot is Q209P/L Poor prognosis of GNAQ/11 mut Sheng X...Guo J. Eur J Cancer Sep;65:

32 Transitional significance of GNAQ/11 pathway MEKi would be effective to GNAQ/11 mut. Phase I clinicial trial is in planning. Sheng X...Guo J. Eur J Cancer Sep;65:

33 Summary Targeted Therapy BRAF V600 is an important oncogene BRAFi+MEKi: Better efficacy in non acral MM BRAFi+CDKi: maybe effecitive in CNVS acral MM CKIT is also an important oncogene Variable mut hotspot Powerful CKITi warranted New targets:mtor CDK GNAQ in acral and mucosal melanmas

34 Immunotherapy

35 PD-1i is a miracle?!

36 Durable Response (Pemb,2016ASCO updated) 3 yosrate: 40%(naïve: 45%) 97% 的 CR pts remained response even stopped usage.

37 Durable Response (Nivo) Median duration of response was 22.9+m 46% pts show responses in 8 th week. 16 th week was more common Many pts remained response even discontinued nivo Presented By Howard Kaufman at 2014 ASCO Annual Meeting

38 Immunotherapy also works in China?

39 Meta-analysis from 6 trials--mucosal

40 Mucosal melanoma -Efficacy only half of cutaneous melanoma!!

41 Acral melanoma-no solid evidence Phase I trial is going on and part of pts showed the response. Acral melanoma,male,64 yrs PR, PFS:6m+ Before After

42 Typical CT images Acral melanoma, F,59 岁 yrs PR, PFS:3m+ Before After disappear disappear disappear

43 Future of immunotherapy

44 Other combinations PD-1i +anti-vessels or TVEC or BRAFi+MEKi ORR > 50%

45 Better immune targets? Better targets? TIM 3 LAG 3 Et al.

46 How will PD1-I Change the Landscape Tumor Control Rate now > 50% Kinetics of Response much better 1 3 months vs 3 6 months Durability of disease control remarkable Immune related Toxicity profile better PD1 Ipilimumab Combinations Promising Other? COMBOs PD1 IPI Chemo OS

47 Thanks!