Breakthrough and Landscape of Acral and Mucosal Melanomas Jun Guo. M.D., Ph.D Peking University Cancer Hospital & Institute
Current status of advanced melanoma
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%
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 70 60 50 40 30 20 10 Australia Age standardised incidence and mortality rates by year in Australia 0 1960 1970 1980 1990 Year 2000 2010 2020 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) 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1998 1999 China 2000 2001 2002 2003 2004 2005 2006 Year 2007 2008 2009 2010 Male:Incidence Female:Incidence Male:Mortality Female:Mortality Book: Chinese Cancer Registry Annual Report from 1998-2010
Location Caucasian Asian <5% Acral+mucosal 70% Acral+mucosal
Appearance
Targeted Therapy
Background MAPK pathways well investigated CKIT/RAS/BRAF/MEK New Targets warranted? mtor pathways Rb-CDK4 pathways GNAQ/11
BRAF Mutation BRAF Mut prevalence in China :25% Caucasians :40~60% IF=5.53 Dong J, et al. Cancer Res. 2003;63:3883-3885.
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
BRAFi+MEKi: better efficacy PFS +~3.5m ORR 15-20%
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. 2014 Beijing International melanoma Congress
2016 ASCO---who can not benefit from BRAFi COMBI Dtrial: BRAFi+MEKi vs BRAFi genomic analysis who can benefit from BRAFi?
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.
Short survival with CDK pathway abbreviations Half of the survival time with CDKN2A muts or deficiency (OS,P=0.027; PFS, P<0.001)
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. 2016 ASCO annual meeting poster discussion
Transitional research in CDK4 pathways Key Words: CDK4/6 inhibitor (PD-0332991 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. 2016 ASCO annual meeting poster discussion
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. 2014 Beijing International melanoma Congress
CKIT gene Prevalence of C KIT abbreviations is 17%; Acral and mucosal : 34% and 32% IF=7.74
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
Cited by NCCN guidelines
2016 ASCO---better CKITi? A phase II trial of Novel CKITi (Dasatinib) in CKIT mut MM
Results Dasatinib is no better than imatinib and the response rate was 20%
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. http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/mtorpathway
Genetic Mutations of mtor in Chinese Melanoma mtor mutations are prevalent in AM and MM Subtype mtor mutation No. Positive % Acral 207 22 10.6 Mucosal 104 15 14.4 CSD 28 2 7.1 Non-CSD 57 3 5.2 UP 18 1 5.6 Total 414 43 10.3 Clin Cancer Res; 2016 Feb 15;22(4):1018-27.
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 5490-5501bp[del TGCCGCCACCAC] (2 cases). Clin Cancer Res; 2016 Feb 15;22(4):1018-27.
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):1018-27.
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 = 0.034 Clin Cancer Res; 2016 Feb 15;22(4):1018-27.
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 https://clinicaltrials.gov/ct2/show/nct01960829?term=everolimus+melanoma&rank=1
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; 19:5320-5328
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. 2016 Sep;65:156-63.
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. 2016 Sep;65:156-63.
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
Immunotherapy
PD-1i is a miracle?!
Durable Response (Pemb,2016ASCO updated) 3 yosrate: 40%(naïve: 45%) 97% 的 CR pts remained response even stopped usage.
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
Immunotherapy also works in China?
Meta-analysis from 6 trials--mucosal
Mucosal melanoma -Efficacy only half of cutaneous melanoma!!
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
Typical CT images Acral melanoma, F,59 岁 yrs PR, PFS:3m+ Before After disappear disappear disappear
Future of immunotherapy
Other combinations PD-1i +anti-vessels or TVEC or BRAFi+MEKi ORR > 50%
Better immune targets? Better targets? TIM 3 LAG 3 Et al.
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
Thanks!