Current and future options in the treatment of Uveal Melanomamelanoma-course.com/files/143/15-SOPHIE.pdf · 2017. 5. 22. · High risk definition 5-yr MFS

Current and future options in the

treatment of Uveal Melanoma

Sophie Piperno-Neumann

Institut Curie, Paris, France

27 April 2017

Institut Curie - nom de l’émetteur - Titre de la présentation 03 juin 2013

Uveal Melanoma: the disease

and the challenges

Institut Curie SPN, 27 APR 2017

■ Rare tumor: 6 new cases per million per year - up to 50% of patients develop metastases in 2-3 years - via hematogenous spread - liver is the predominant site of relapse in > 80%patients

■ The metastatic risk is the major challenge in UM

BSC systemic immuno/chemotherapy liver surgery OS 2-6 mo 6-12 mo 10-24 mo <25% resectable pts ■ No treatment in the metastatic setting has improved survival No adjuvant treatment capable to prevent (micro)metastases

■ Risk factors for metastasis - Tumor diameter, ciliary body or extraocular spread, epithelioid cell type - Cytogenetics : Monosomy 3 - Genomics (aCGH, FISH, MLPA): Chr 3 chr 8 status are independent variables for metastasis - Gene Expression Profiling : Class 1-low risk/class 2-high risk

Prescher 1996, Onken 2004, Damato 2009, Cassoux 2013


Early detection of metastases

Institut Curie, SPN, 27 APR 2017

■ Retrospective study in 2241 patients (Desjardins, 2006): 5-yr MFS 81% and 5-yr OS 78% (mFU: 6 yrs)

■ International recommendations: 6 monthly liver US for all patients N risk Fu modalities metastatic rate Hicks (1998) 245 all US, Chest Xray, LFTs 22% Eskelin (1999) 390 all US, LFTs 16% COMS (2004) 2320 all LFTs 24%

→No impact on outcome (survival , R0 liver resection rate)

■ NICE 2015 Uveal Melanoma UK National Guidelines (http://melanomafocus.com/) 7 th TNM staging system Prognostic biopsy Multidisciplinary team prognostication and surveillance “Patients judged at high-risk of developing metastases should have 6-monthly life-long surveillance incorporating a clinical review, nurse specialist support and liver-specific imaging by a non-ionising modality. Liver function tests alone are an inadequate tool for surveillance. »

■ High risk patients surveillance

Definition of high risk? no consensus: clinical vs genomic vs GEP? Best imaging modalities? Optimal interval and duration of screening?

http://melanomafocus.com/


Early detection of metastases


Marshall et al, BJO 2013 Piperno-Neumann et al, JFO 2015

Primary endpoint

Surveillance methods

detection of asymptomatic liver mets with MRI LFTs and biannual liver MRI

R0 liver resection rate

LFTs and biannual liver MRI

Period Number of patients

2000-2010 188/279 screened

2006-2009 100 /102

High risk definition 5-yr MFS<50% using the Liverpool prognosticator tool on line

large tumors (LTD>15mm or thickness>8mm) or extrascleral extension or M3

Detection of mets before symptoms LFTs MRI

- 92%

- 98%

Genomic risk 97% M3 29% M3 28% M3+8g

Median Follow up (months) Median Metastasis-Free Survival Median OS

29 18 34

49 30 59

Metastatic pts Eligible for liver surgery

90 (48%) 38 (42%)

60 (60%) 25 (42%)

R0 Liver surgery Med OS of R0 pts /metastatic pts (months)

12 (13%) 24/ 12

8 (13%) 40 /14

Institut Curie - nom de l’émetteur - Titre de la présentation 03 juin 2013Institut Curie, SPN, 27 APR 2017

First randomized study 1988-1995 Institut Curie

348 High risk pts

Thickness>5 mm and/or diameter>10 mm

Observation versus DTIC 250 mg/m2 D1-D5 D29, 6 cycles

Endpoints: Overall survival (OS)

Metastasis-Free Survival (MFS)

■ Desjardins et al, 1998 med FU 3 yrs 5-yr OS 70% 68% obs vs 72 % DTIC

■ Piperno-Neumann, 2006 med FU 12.6 yrs

10-yr OS 57% 53% obs vs 62 % DTIC

■ March 2007 : Kaplan Meier survival curves in 137 pts with LTD>15 mm

5-yr OS 44% 33% obs vs 55% DTIC

Adjuvant DTIC versus observation for high-risk patients: long-term results

0.0

0.2

0.4

0.6

0.8

1.0

months

percent

OVERALL SURVIVAL & TREATMENT ARM

observationDTIC

0 24 48 72 96 120 144 168 192 216

p=0.05

LTD>15 mm


■ Multicentre Randomized Phase III study (EudraCT 2008-005691-27)

■ Adjuvant Fotemustine, 6 cycles, 100 mg/m2 IV 1 h versus observation

■ Primary Objective: Metastasis Free Survival rate

■ Secondary Objectives: Overall Survival, Safety (NCI-CTC v3), quality of life (QLQ- C30)

■ UM patients with high-risk of metastasis, defined by:

Clinical criteria: LTD ≥ 15 mm with extra scleral extension and/or retinal detachment or LTD ≥ 18 mm AND/ OR Genomic high risk signature (aCGH +/-LOH): Monosomy 3 or partial deletion of 3p associated with 8 gain

■ Statistics To improve the 5-Y MFS rate from 50% w/o adjuvant treatment to 70 % with Fotemustine, 302 patients have to be recruited, 99 events are needed to observe the expected benefit with a

type I error of 5% and a power of 95 %. Annual IDMC: no safety concern Interim analysis for futility after 50% of the required target events have been observed

■ Planned treatment period: 20 weeks Follow up period: 3 years (LFTs/3 mo, liver MRI or CT/6 mo, whole body CT/12 mo)

FOTEADJ Study


FOTEADJ Study

• Futility analysis: 224 first ® patients (11feb 2016) median FU: 27 months, 2-year MFS: 70.6 %, no chance to observe any significant statistical difference at the end of the study

• IDMC recommendations: - stop randomization - amend the study : « interventional surveillance » in high-risk patients (April 2016) - final analysis: Q1 2017

• FOTEADJ: First adjuvant randomized phase III trial based on genomic analysis. FNA biopsies should precise the rate of genomic high risk in small tumors.

FINAL RESULTS :

ASCO, Melanoma Oral Session, June 4 2017


On going Adjuvant studies


Treatment Status Status/Results ClinicalTrials.gov identifier

-Cisplatin, sunitinib, and tamoxifen San Diego

Ph II, 50 clinical high risk pts, May 2007-Dec 2012

unknown no results available

NCT00489944

-Dacarbazine and IFNα2b Cleveland

38 pts, M3 and/or 8q Nov 2009- Mar 2017

active, not recruiting no results available

NCT01100528

-Sunitinib vs valproic acid Thomas Jefferson Univ

R Ph II, class 2 or M3+8q 90 pts, Nov 2014- Feb 2019

recruiting NCT02068586

-Crizotinib MSKCC/Columbia

Ph II, 30 class 2 high risk pts Mar 2015-Aug 2019


-Dendritic cells +autologous tumor RNA vaccination University Hospital Erlangen

Ph III, 200 high risk pts (M3) vs observation June 2014-June 2020


-mRNA (encoding gp100 and/or tyrosinase)-transfected DC vaccination Radboud University

Ph I/II, recruiting 30 HLA-A2 positive pts M3 June 2009- Apr 2016

terminated (slow accrual)

NCT00929019


Effectiveness of Treatments for Metastatic Uveal Melanoma JAMES J. AUGSBURGER, ZÉLIA M. CORRÊA, AND ADEEL H. SHAIKH(Am J Ophthalmol 2009;148:119–127)

▶ 80 identified publications between Jan 1, 1980 and June 30, 2008

12 (15.0%) review articles without original information

2 (2.5%) review articles combined with case reports

22 (27.5%) case reports

16 (20.0%) retrospective descriptive case series reports

3 (3.75%) pilot studies of a novel intervention

2 (2.5%) prospective phase I clinical trials

8 (10.0%) prospective phase I/II clinical trials

15 (18.75%) prospective phase II clinical trials

▶ 25 (30%) prospectives studies

None of these articles reported a randomized phase III clinical trial.

Metastatic UM: published peer-review data


Loco-regional: surgery chemo- or immuno-embolization isolated hepatic perfusion intra-arterial hepatic chemotherapy

Systemic: chemotherapy targeted agents immunotherapy

Treatment options for MUM


SURGERY-Retrospective series

n R0 resection Median survival (mo)

All pts/ R0 pts

Salmon (1998) 75 20 (27%) 9 22

Rivoire (2005) 63 14 (22%) 15 25

Mariani (2009) 255 76 (29%) 14 27

► Prognostic factors: DFI>24 mo, nb lesions ≤4, no miliary

▶ No prospective comparative study - Optimal preoperative staging?

>2/3 of pts do have more extensive hepatic or extrahepatic disease

- Radiofrequency ablation indications?

- Multimodality cytoreductive strategy?


Regional treatment: Hepatic transarterial chemoembolization (TACE)

►

Embolization of the hepatic artery with polyvinyl sponge and cisplatin (2 case reports) C.Humberto Carrasco et al. JAMA 255: 3152-54 1986

drug n Response rate (%) Median survival (mo)

Mavligit 1988 CDDP 30 46% 11

Patel 2005 BCNU 24 21% (1CR+4PR) 5

Vogl 2006 MMC 12 25% (3PR+5SD) 21

Sharma 2008 CDDP/DOX/MMC 20 0% (13 SD) 9


Regional treatment: Isolated hepatic perfusion(LPAM)

► Non randomized studies Limited number of patients Treatment-related toxicities are frequent and can be severe Progression of extra hepatic sites despite control of liver metastasis

►Ph III trial comparing IHP with BAC underway (NCT01785316)

n Response Rate (%) Median survival (mo)

Alexander 2000 22 59 11

Alexander 2003 29 62 12

Van Iersel 2008 12 33 12

Van Etten 2009 8 37 11

Olofsson 2014 34 68 24

• Device designed to administer high-dose chemotherapy to the liver while reducing systemic exposure

• Percutaneous Alternative to IHP • 3 procedural steps: Isolation, chemosaturation, filtration • Marketed as Delcath Hepatic CHEMOSAT® Delivery System (device only) in EU/

Investigational drug/device combination product regulated as a drug in the U.S.

Liver Isolated Via Double Balloon Catheter In IVC

Melphalan Infused Directly Into Liver Via Catheter In Hepatic Artery

Blood Exiting The Liver Filtered By Proprietary Extra-corporeal Filters


Regional treatment: Percutaneous hepatic perfusion with melphalan (PHP-Mel)► Randomized Phase III study: Chemosaturation-PHP

versus Best Alternative Care (BAC)

▶ Primary Endpoint: hepatic Progression Free Survival(hPFS) Cross-Over of BAC patients at hepatic progression

▶ Secondary Endpoints: Response rate & Duration of Response; Overall Survival;

Safety & Tolerability

▶ Stratification: Cutaneous versus Ocular

▶ Lead Center: National Cancer Institute (NIH), JF Pingpank

▶ Melphalan dose = 3.0 mg/kg

▶ 93 patients: 89% ocular, 41% extrahepatic disease Prior tts:

systemic (chemo- or immunotherapy) 20%

regional (chemo- or radiembolisation, surgery) 9%

▶AE related to bone marrow suppression, 4 deaths attributed to PHP-Mel Hughes et al, Ann Surg Oncol 2016


FOCUS: A Randomized, Controlled, Phase 3 Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Melphalan/PHP Treatment in Patients with Hepatic-Dominant Ocular Melanoma vs BAC

.

Parameter FOCUS Study

Conducted 2016-2019

Population Metastatic Ocular Melanoma , mets ≤ 50% tumor burden in the liver

N 240

# of Sites 30 (12 in US; 18 in Western EU)

Primary Endpoint OS

Secondary endpoints PFS, ORR (determined by Investigator)

Exploratory endpoints PFS, ORR, hPFS, hORR (determined by IRC) QoL, PK (sparse and pop), exposure and SAEs

Randomization Cross-over

1:1 No

BAC options DTIC, Ipi, Pembro, TACE

Stratification 1.) Liver burden 2.) Choice of BAC tx prior to randomization

Filters New design built in-house (up to 95% efficiency)


Regional treatment: Immunoembolization

LAK cells Keilholz 1994 n=5 no response GM-CSF Sato, 2008 n=34 mOS 14 mo High-Dose Immunoembolization: GM-CSF < 1500 ug versus > 1500 ug versus CE with BCNU

N=53 median OS HDE 20.4 mo LDE 13 mo CE 9.8 mo

Yamamoto et al, Radiology, 252:290-8, 2009

Radioembolization - Yttrium-90 microspheres: (90Y) pure-beta emitter, tissue penetration of 2.5 mm , max range: 1.1 cm

- Pretreated patients series : 9 pts: 1 CR, 6 PR , 1-yr OS: 80% (Kennedy et al., 2009) 20 pts: clinical benefit in 62% , mOS: 10 mo (Gonsalves et al., 2011) 13 pts: 8PR and 2 SD, mOS: 7 mo (Klingenstein et al., 2013)

- On going trials in combination with sorafenib (NCT01893099) or ipilimumab (NCT01730157)


Systemic chemotherapyn Response rate

(%)Median PFS (months)

Median OS (months)

Single agent Dacarbazine, Fotemustine, Cisplatin

Temozolomide Bedikian 2004

>50

14

0-19%

0

?

1,8

4-9

-

BOLD-Interferonα Kivela 2003

20 6-14% 1,9 12

Dacarbazine-Treosulfan O’Neill 2006

15 0+2 SD 3 9

Treosulfan-Gemcitabine Schmittel 2005

14: T<3g/m2 19: T>3,5

0+4SD 1PR+10SD

- -

6 9

Treosulfan+/-Gemcitabine Schmittel 2006

24 Treo 24 Treo+G

0+3SD 1PR+7 SD

2 3 p=0.08

- -

Paclitaxel Homsi 2010

22 1PR+7 SD - 9,8


Intra arterial chemotherapy-FotemustinRetrospective series n Response rate (%) Median survival (mo)

Leyvraz 1997 31 40 14

Becker 2000 + IL2/IFN 23 22 12

Egerer 2001 7 28 24

Siegel 2006 16 28 22

Peters 2006 101 36 15

Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial N=171 (2005-2011), mFU: 1,6 yr Stop for futility OS analysis RR : 10,5 vs 2,4% (pS) mPFS:4,5 vs 3,5 mo (pS) mOS: 14,6 vs 13,8 mo (pNS)

S. Leyvraz, S. Piperno-Neumann, S. Suciu, et al, Annals of Oncology 25: 742–746, 2014

Biological potential targets in uveal melanoma

Increased expression

BCL2 (100%)

Cyclin D1 (60%)

HDM2 (100%)

P21 (20%)

pERK (70%)

pAKT (50%)

α5b1(50%)

αvb3 (20%)

MMP-2 (50%)

MMP-9 (50%)

FGF-2 (90%)

VEGF (25%)

E-Cadherin

cMET (86%)

IGFR-1(73%)

cKIT (64%)

Decreased expression

INK4A (30%)

PERP (50%)

GNAQ


KIT and antiangiogenic agents

Drug Patients # Response # mPFS/OS months

Remarks/Reference

Imatinib 800 (KIT-inh) 600

13 12

1 SD 1 SD

-/10.8 -/6.8

Penel, 2008 Hofmann, 2009

Sunitinib (PDGFR,VEGFR

and c-KIT inh)

20

Suni vs DTIC 74

1PR, 12 SD

0 vs 8%

4/8

2.8/6.4vs 3.9/ 8.7

Mahipal, 2012

Sacco, ASCO 2013 (stop for futility)

Sorafenib-CarboTXL

(Raf, VEGFR, PDGFR, c-KIT and Flt-3 inh)

24 9 SD 4/11 Bathia, 2012

Bevacizumab (VEGFi)

35 8 SD 3/12 Piperno-Neumann, 2016

Aflibercept (VEGF-Trap)

10 5 SD 5.7/19 Tarhini, 2011 (toxicity)


c-MET pathway ► MET signaling stimulates cell growth, invasion and metastasis in many cancer types. Upregulation of MET is a consequence of GNAQ/11 activating mutation present in 80% UM.

► UM models Role of c-Met overexpression and its ligand HGF (Hepatocyte Growth Facto ) in cell migration/metastasis

Crizotinib (ALK and c-MET TKI) - inhibits phospho-Met in vitro - reduces onset of metastasis but seems not sufficient to decrease tumor growth in xenografts (Surriga, 2013)

►Early trials Cabozantinib (MET and VEGF inh) 11 SD/23 MUM pts mPFS/OS: 5/12 mo (Daud, ASCO 13)

→Ph II vs DTIC ongoing (NCT01835145), stop for toxicity


GNAQ/11 downstream targets ► GNAQ/11 mutations leads to a cascade activation of phospholipase C, that ends up to a PKC-dependant MEK/ERK/MAPK cascade and PI3K-AKT activation - No small molecules targeting directly the activated domain like BRAF in CM, but rationale for targeting downstream pathways, including MEK and PKC.

► AEB071 (sotrastaurin, Novartis) -Potent, selective oral inhibitor of the classical (α, β), and novel (δ, ε, η, θ) isoforms of PKC, which causes selective growth inhibition through preclinical targeting of PKC/ERK1/2 and PKC/NF-kB pathways (Wu et al., 2012) - Preclinical data : efficacy in 100% mutated UM cell lines (Bastian et al.)


Recent trials with MEK/PKC inhibitors


Remarks/Reference

Trametinib (MEK1/2 inh)

16 (part of Ph I)

8 SD (2mo) 4SD (4 mo)

1.8/- Falchook, 2012

Selumetinib (MEK1/2 inh)

120 Selu vs DTIC

ORR: 14 vs 0% SD: 50 vs 23%

PFS: 4 vs1,7 OS: 11.8 vs 9.1 Carvajal, 2014

AEB071 (sotrastaurin, PKCi)

141 Ph I/II

PR 2% SD 50%

PFS: 3,8 Piperno-Neumann, ASCO 2014

AEB071+Binimetinib (MEK162)

Ph Ib/II (n=38)

May 2015:early termination (combo toxicity)

SUMIT trial Selumetinib+DTIC vs placebo +DTIC

n=129 ® Ph III

(3:1)

3,1 vs 0% PFS: 2,8 vs 1,8 Carvajal, SMR 2015

Trametinib vs Trame+GSK2141795

(AKTi)

Target n=80 ® Ph II

(1:1) US only

ORR: Trametinib: 1/18

(6%) Tram + AKTi: 1/21

(5%)

PFS: 3,925 vs 3,9

Arm B accrual halted Toxicity of the combo led to

frequent dose reductions


On going trials in MUM


Treatment Status Status/Results ClinicalTrials.gov identifier

-Selumetinib +Paclitaxel Ph II, 50 pts May 2007-Dec 2012

recruiting EUDRACT: 2014-004437-22

-LXS196 (PKCi 2nd generation) Ph I-II , 100 pts FeB 2016- Dec 2017


-Glembatumumab (Antibody-Drug Conjugate CR011)

Ph II, 34 pts Jan 2015- Feb 2017


-AEB071 + BYL719 (PI3Ki) Ph Ib, 50 pts Nov 2014-Dec 2018


-Cabozantinib vs DTIC ® Ph II, 69 pts June 2013-Nov 2017

Active, not recruiting NCT01835145

-Vorinostat (HDAC i) Ph II, 40 pts Apr 2012- Nov 2017

not recruiting NCT01587352


Immunotherapy in Metastatic Uveal Melanoma


Remarks/Reference

Ipilimumab CTLA4 mab

Retrospective

Prospective

13 39 22 82

53

2 SD 1CR+1PR

1PR 1irPR+24irSD

16 SD

-/8 -/9,6

2,9/5,2 3,6/6

2,8/6,8

Danielli, 2012 Luke, 2013

Telderman, 2013 Maio, 2013

Zimmer, 2015

Tremelimumab

+ IFN α

11

8

0

1 CR, 4 SD

2,9/12,8

-

Joshua, 2015 (stop for futility)

Tarhini, 2011

Nivolumab Pembrolizumab PD-1 inhibitors

8 8

1SD 1CR+2PR 3/-

Weber, 2013 Kottschade, 2016

Adoptive T-cell therapy

(autologous TILs)21

ongoing1 CR+ 6PR - Chandran, 2017

Institut Curie - nom de l’émetteur - Titre de la présentation 03 juin 2013Institut Curie, SPN, 27APR 2017

- Eye: immune-privileged site, could be responsive to T cell-based immunotherapy

-PDL1 expression in primary UM: 89% PDL1+, 39% high expression (p=40) (Zoroquiain, ARVO 2015)

- Ipilimumab results: <5% objective responses - Nivolumab/Pembrolizumab case reports: 3/7 OR in Kottschade report; 7/8 PD in Weber study concerning ▶ NOT an indication to rush all patients onto antiPD1therapy outside trials

- Ongoing studies - Pool existing data: clinicopath predictive of response (Tsai et al, ASCO 2015) retrospective and prospective study in France: imMUno - Phase 2 Pembrolizumab (NCT02359851) - Phase 2 Nivolumab+ Ipilimumab (NCT01585194) and GEM1402 (NCT02626962) ▶ Need translational correlates: PDL1, serial immunophenotyping of tumors, genomic analyses

UM and immunotherapy


- Lack of systemic treatment with OS advantage in UM

- Better understanding of the biology and key signaling pathways

● Identification of deregulated pathways/mutations: driver mutations by WES and RNAseq, epigenetic map of UM models and tumor samples, pathways downstream of GNAQ/GNA11 ● Understanding of UM tropism for the liver and its microenvironment ● Development of relevant metastatic models (i.e. cell lines and PDX) ● Drug sensitivity/efficacy preclinical assays

- Prospective trials based on identification of molecular targets validated in preclinical models

- International collaboration needed International Rare Cancer Initiative (2010): NCRN,CR-UK, NCI, EORTC H2020 grant (2016) EURACAN (2017) : European network for rare adult tumors

Conclusion / Key Messages

Documents

Current and future options in the treatment of Uveal Melanomamelanoma-course.com/files/143/15-SOPHIE.pdf · 2017. 5. 22. · High risk definition 5-yr MFS