Marlana Orloff, MD presents on Liver Directed Therapy at the 2017 CURE OM Patient & Caregiver Symposium.

1. MRF
CURE-OM
6th
Annual
Patient and
Caregiver
Symposium
3.11.17
LIVER DIRECTED THERAPY
FOR METASTATIC UVEAL
MELANOMA
Marlana Orloff, MD
Assistant Professor
Department of Medical Oncology
Thomas Jefferson University
Sidney Kimmel Cancer Center

2. Approximate 5 year survival 70-80%
About 50% of patients will develop metastatic disease
One year survival 13-15%*
Median survival after development of metastatic disease ranges 2-15
months*
Liver most common site of metastases
 About 50% of patients with metastatic disease may have liver only disease for
majority of their disease course
UVEAL MELANOMA
* In the literature though not necessarily reflective of more current clinical experience

3. SITE OF METASTASES
J G Lorigan et al 1991

4. Patients presenting with varied disease presentations
 Liver only : small disease burden
 Liver only : large disease burden
 Liver predominant but extra-hepatic present
 Extra-hepatic only
 Metastatic disease at time of eye diagnosis
 Recurrence during adjuvant treatment
 Recurrence >15+ years after eye diagnosis
 Treatment naïve
 Heavily pre-treated
 Some tumors grow very fast
 Some tumors grow slower
 … And everything in between
PATIENT PRESENTATIONS

5. RAPID GROWTH
MRI normal 6 months prior

6. RAPID GROWTH
12/17/2013
4/30/2014 6/2/2014

7. SLOW GROWTH
12/30/15 12/20/16

8. MERITS OF TRANS-ARTERIAL CATHETER-
DIRECTED TREATMENT OF LIVER TUMORS
Liver tumors obtain the majority of their blood supply from
the hepatic artery.
Normal liver parenchyma has a dual blood supply
 Portal vein (~75%)
 Hepatic artery (~25%)
Trans-arterial catheter-directed therapies allow localized
treatment to liver tumors while sparing normal liver
parenchyma
Delivery of medication to liver tumors at a higher
concentration could be achieved while minimizing systemic
toxicity

9. Melanoma in
the liver
Embolization
drugs
administered
through
catheter
Melanoma

10.  Bland embolization
 Immunoembolization
 GM-CSF +/- IL-2
 Radioactive microspheres
 SirSpheres
 Chemoembolization
 BCNU
 Chemoembolization with Drug-Eluding Beads
 DEBDOX
 DEBIRI
 Hepatic arterial infusion
 Fotemustine
 BCNU
 Percutaneous Hepatic Perfusion (PHP)
 Melphalan
 Isolated Hepatic Perfusion (IHP)
 Melphalan
 *Surgical Resection / Ablation
TYPES OF LIVER DIRECTED TREATMENTS

11. IMMUNOEMBOLIZATION

12. Destruction of tumor by embolization could control tumor
progression locally and provide tumor antigens to the local
immune system
Concurrent use of GM-CSF and IL-2 induces an inflammatory
response in the tumor and surrounding tissue which may
improve the anti-cancer immune response
Local stimulation of the immune system may result in the
development of a systemic immune response against tumor
cells which may suppress the growth of distant tumors
IMMUNOEMBOLIZATION
RATIONALE

13. Purpose was to investigate feasibility and safety
2000 – 2004, single institution
34 of 39 patients had MUM
<50% tumor involvement, unresectable
Lobar hepatic artery embolization every 4 weeks using escalating dose of
GM-CSF (25-2000 mcg) emulsifiedwith Ethiodol followed by Gelfoam, for
6 treatments
Imaging (CT, MRI) and clinical assessment after every other treatment to
assess response (RECIST)
Primary end-points were dose-limiting toxicity and maximum tolerated
dose
IMMUNOEMBOLIZATION
PHASE 1
JCO 2008 26:5436-5442

14. 6 procedures/patient (median, range 1-14)
32% responded (2 CR, 8 PR)
32% stable disease
OS: 14.4 months (median)
 (33.7 months for CR/PR, 12.4 months SD/PD)
Survival: 1 yr. 62%, 2 yr. 26%
PFS-liver: 4.8 months (median)
PFS-systemic: 10.4 months (median)
1 patient remains alive > 10 years
IMMUNOEMBOLIZATION
PHASE 1
JCO 2008 26:5436-5442

15. IMMUNOEMBOLIZATION
2 months laterInitial

16. IMMUNOEMBOLIZATION
2 months laterInitial

17. High dose IE (>1500mcg) vs historic data from Phase II TACE with BCNU
 Excluded those with >50% liver involvement
Longer OS (20.4 vs. 9.8 months, median)*
Longer PFS-L (9.3 vs. 6.4 months, median)
Longer PFS-S (12.4 vs. 4.8 months, median)*
Systemic progression was delayed in the high-dose IE group, suggesting
an induction of a systemic immune response against the melanoma cells
IMMUNOEMBOLIZATION
COMPARED TO HISTORIC PHASE II TACE WITH BCNU
* P < 0.5
Radiology 2009; 252:290-298

18. About 10% of patients have an amazing response to immunoembolization
 After receiving a few treatments stabilization, sometimes shrinkage, and decreased
viability
 Treatment breaks for months to years
 Embolic agent transient so repeated procedures possible
EXCEPTIONAL RESPONDERS
10/2010 1/2017

19. RADIOEMBOLIZATION

20. Yttrium-90 radioactive beads administered IHA
Multiple series of showing Y90 in MUM patients
 11 patients treated across 5 centers between 2005-2007
 77% response rate
 80% 1 year survival
 13 patients 2005-2011 as salvage therapy
 Median tumor burden 31%
 62% response rate
 Median survival 7 months
RADIOEMBOLIZATION

21. Retrospective
 71 patients, 82% salvage; 2007 - 2012
 Median PFS-L 5.9 months
 Median OS after treatment 12.3 months
 Median OS following diagnosis of liver mets 23.9 months (range, 6.2 – 69
months)
Current Prospective Trial
 Just finished accrual
 48 patients – half first line and half post IE
 11/2011 - 3/2017
 Biomarker correlates and pre-treatment biopsies
 Data pending
RADIOEMBOLIZATION
JEFFERSON EXPERIENCE
Am JCO; 2016;39:189-195

22. RADIOEMBOLIZATION
Pre: 7/21/16 Post: 2/7/17

23. CHEMOEMBOLIZATION

24. CHEMOEMBOLIZATION
Author Pt # Drug (s) OS Resp* OS Non-Resp Median OS
Mavligit ’88 30 Cisplatin 14 6 11
Cantore ’94 8 Carboplatin -- -- 15
Bedikian ’95 44 Cisplatin 14.5 5 6
Sato ’95 14 Cisplatin -- -- 6.6
Patel ’05 24 BCNU (100mg) 21.9 3.3 5.2
Huppert ’09 14 Cisplatin/Carboplatin 14.5 10 11.5
Vogl ’07 12 Mitomycin C 21 16.5 21
Dayani ’09 21 Mitomycin C, Cisplatin,
Doxorubicin
12.7 3.7 7.6 (mean)
Gupta ’10 125 Mostly Cisplatin 15.8 6.1 6.7

25. MD Anderson experience
 125 patients (Jan 1992-Dec 2005)
 122 received cisplatin
 65 also received vinblastine or vinblastine/dacarbazine
Overall Survival 6.7 months (median, n=113):
 < 25% 14 months
 25-50% 5.1
 >50-75% 5.5
 >75% 2.4
Recommend against treatment when >75% tumor replacement
CHEMOEMBOLIZATION

26. 50 patients with >50% tumor replacement at presentation (Jan 2004 –
Nov 2011)
200 mg BCNU
Median survival 7.1 months
22% 1 yr. survival
Neither pre-treatment LDH (> or < 500) nor tumor burden (50-59%, 60-
75%, > 75%) had effect on survival
CHEMOEMBOLIZATION
JEFFERSON EXPERIENCE
AJR 2015; 205:429-433

27. CHEMOEMBOLIZATION WITH BCNU
2/19/2016 1/22/201
7

28. 10 patients 2007-2008
 100-200 mg Irinotecan administered in 2-4 ml of 100-300/300-500
micron DC Beads
 All 10 patients had objective response
Single Arm Phase 2 trial
 52 patients Jan 2007-Feb 2010
 Median treatments per patient 1.6
 100mg in 10 patients, remainder 200mg
 Tumor reduction by imaging (“necrosis and reduction of contrast
enhancement”):
 > 90% (n=17)
 80-90% (n=30)
 60-80% (n=3)
 PFS-L 7.5 months, OS 13.9 months (both median)
CHEMOEMBOLIZATION
WITH DRUG ELUDING BEADS: IRINOTECAN
In Vivo. 2009 Jan0Feb;23(1):131-7
Annals G & H 2012; 3:9-14

29. 19 patients, no prior treatments
July 2011 – January 2013, retrospective review
Poor candidates for other liver-directed therapies
 (Tumors > 5 cm, > 50% tumor burden, rapid growth)
< 4 ml 100-300 micron LC Beads/150 mg adriamycin
 (14/36 treatments received full dose)
13/19 patients proceeded to BCNU chemoembolization
Based on disparate response, patients divided into “nodular” vs.
“infiltrative” pattern, based on MRI appearance
CHEMOEMBOLIZATION
DEBDOX FOLLOWED BY BCNU
JEFFERSON EXPERIENCE
JVIR 2014; 25: S45

30. CHEMOEMBOLIZATION
DEBDOX FOLLOWED BY BCNU
SURVIVAL BY TUMOR TYPE
Nodular vs Infiltrative Disease
Nodular
Infiltrative
Time (months)
SurvivalProbability(%)

31.  Nodular (n=11): 3 PR, 7 SD, 1 PD
 Infiltrative (n=8): 1 PR, 3 SD, 4 PD
Survival
Mean
(mos) 95% CI
Median
(mos) 95% CI
Nodular 22.8 15.7 - 29.8 --- ---
Infiltrative 4.7 1.6 - 7.9 2.9 1.8 -7.9
Overall 16.0 11.6 - 20.4 9.1 2.9 -12.8
Chi-square = 8.4
p value = 0.0037
CHEMOEMBOLIZATION
DEBDOX FOLLOWED BY BCNU
JEFFERSON EXPERIENCE

32. CHEMOEMBOLIZATION
DEBDOX FOLLOWED BY BCNU
JEFFERSON EXPERIENCE
Initial
15
months
later

33. PERCUTANEOUS AND
ISOLATED HEPATIC
PERFUSION

34. AKA PHP: Closed circuit perfusion of high doses of chemotherapy
 “Chemosaturation”
Melphalan is drug of choice at 3mg/kg
 Whole liver infused at each treatment
 Every 6 weeks for up to 6 treatments
DELCATH catheter system
Prior clinical trial followed by expanded access study
PERCUTANEOUS HEPATIC PERFUSION

35. Infusion catheter
Venous Return
Filter
Blood post liver and pre-filter

36. PERCUTANEOUS HEPATIC PERFUSION
"Percutaneous Hepatic Perfusion for Unresectable Metastatic
Ocular Melanoma to the Liver: A Multi-Institutional Report of
Outcomes."
 Recent presentation on 49 patients treated between 2008 and 2016 at either
Moffitt Cancer Center or University Hospital Southampton
 Total of 115 treatments
 Median treatments per patient was 2
 Hepatic response on 46 patients
 45% CR or PR
 37% with SD
 Median overall survival predicted to be 657 days in all comers
 1,207 days (3.4 years) in responders
 Common side effects anemia, thrombocytopenia, and neutropenia
Presented at Regional Cancer Therapies 12th
International Symposium February 21, 2017

37. “Hepatic Progression-free and Overall Survival After Regional
Therapy to the Liver for Metastatic Melanoma”
 Retrospective review of 30 patients treated with either PHP or other liver
directed treatment
 12 patients PHP
 6 patients radioembolization
 12 patients chemoembolization
 Median Hepatic PFS 361 versus 80 versus 54 days
 Median OS 608 versus 295 versus 265
PERCUTANEOUS HEPATIC PERFUSION
AM J Clin Onc. 2017 Jan 04

38. FOCUS Phase III trial of PHP versus Best
Alternative Care
 1:1 Randomized trial
 BAC options include chemoembolization,
ipilimumab, pembrolizumab, or dacarbazine
 Many active US sites
 Multidisciplinary team required
PERCUTANEOUS HEPATIC
PERFUSION

39. AKA IHP: Surgical procedure resulting in closed circuit to allow perfusion
of high doses of chemotherapy
In a trial of 34 patients
 OS with IHP was 24 months
Retrospective 10 year long single center experience in 91 patients from
2003-2012 (UM/CM = 32)
 Response rate for melanoma 51.7%
Phase III versus BAC ongoing in Europe
ISOLATED HEPATIC PERFUSION
Ann Surg Onc 2014; 21:466-72
Ann Surg 2014 May;259(5):953-9

40. SURGICAL RESECTION AND
ABLATION

41. Reserved for limited clinical situations
Solitary metastases or true oligometastatic disease in patients often >5
years from primary eye diagnosis
 Known different tumor velocity the longer one is from their primary eye
diagnosis
In early metastatic situations often see “peppering” at the time of the
initial surgical attempt
 Rarely get true negative surgical margin due to micrometastatic disease
Ablation is a less invasive approach to attack on solitary metastases
 Radiofrequency
 Cryoablation
 Other techniques
SURGICAL RESECTION AND ABLATION

42. Multiple liver metastases seen
during attempted resection of
solitary liver lesion
 Imaging only noted solitary lesion
SURGICAL RESECTION AND ABLATION

43. ABLATION

44. ABLATION
6/3/2015 12/8/2016

45. LIVER DIRECTED THERAPY
PROGRAM AT THOMAS
JEFFERSON

46. National referral center (+ Canada)
3/4 of our patients live outside of PA, NJ, DE
Weekly MUM multidisciplinary conference
Weekly MUM multidisciplinary clinic with two medical oncologist, three
interventional radiologists, radiation oncology, and surgery
> 600 hepatic embolization procedures per year
All discussed treatment options are offered except IHP
 Immunoembolization (60%)
 Radioactive microspheres (10%)
 Chemoembolization, (30%)
 Drug-eluting beads
 Percutaneous Hepatic Perfusion
CURRENT LIVER DIRECTED PROGRAM AT
THOMAS JEFFERSON UNIVERSITY

47. Uveal Melanoma with
Metastases
Solitary or Oligometastatic disease
greater than 5 (+/-) years after primary
uveal melanoma treatment
Consider Surgery,
RFA, Cryoablation
Liver Only or Liver Dominant
Liver
Directed
Treatment†
Systemic
Therapy
Options
Yes No
Immunoembolization*
Radioembolization*
Chemoembolization*
Drug-Eluting Beads
Percutaneous Hepatic
Perfusion (On Trial)
IHP (referral)
Ipilimumab*
Keytruda*
Opdivo*
VPA*
Other HDACi*
Clinical Trial
IMC-gp100 (HLA A2)
BET Inhibitor
Referral
+/-
*Combination
liver directed
and systemic
when
appropriate
†
Liver directed
options often based
on disease burden
after consideration
for clinical trial
•<50% and limited
extrahepatic
consider IE or RE
•If <50% largest
tumor > 5-6cm and
nodular consider
DEBDOX followed
by BCNU
•If >50% liver
involvement with
liver dominant CE
•Progression after
IE consider RE or
CE

48. Certainly there are patients in whom it does not control hepatic disease
despite best efforts
Occasional anatomy issues exclude patients from certain treatments
 Notably Radioembolization and PHP
Extra-hepatic disease is always a concern
 Combination systemic and hepatic strategies
Need better tools to predict who more likely to be an “exceptional
responder” and to what upfront therapy
Requires skilled interventional radiologists
LIVER DIRECTED THERAPY
LIMITATIONS AND CONSIDERATIONS

49. THANK YOU