Patient Education Series Systemic Treatment Options for Uveal MelanomaDo not download, distribute or copywithout the express permission of the Richard D. Carvajal, MDOcular Melanoma Foundation (OMF). Memorial Sloan-Kettering Cancer CenterThese materials are for educationaluse only. No information providedherein constitutes a medicaldiagnosis, advice, or treatment.Please consult a healthcareprofessional for a specificexamination and evaluation of yourcondition. Under no circumstancesshall OMF nor the authors listedherein be held liable for anything thatmay arise from anyone following anyadvice, treatment, etc. included,alluded to, or otherwise referenced toherein.
Richard D. Carvajal, MD Memorial Sloan-Kettering Cancer Center Rich Carvajal is a medical oncologist with a special interest in the treatment of melanoma and sarcoma. His research is focused on the development of new targeted drugs and immunologic therapy against these diseases, with the hope of attacking cancer cells while minimizing damage caused to normal cells. Education: MD, New York University School of Medicine Residencies: University of Michigan Medical Center Fellowships: Memorial Sloan-Kettering Cancer Center Board Certifications: Internal Medicine, Medical Oncology, Hematology Clinical Expertise: Melanoma; Sarcoma Appointments for New Patients: 646-497-9067 Phone: 646-888-4161 PatientEducation Series
Systemic Treatment Options for Uveal Melanoma Richard D. Carvajal, M.D. Assistant Attending Physician Melanoma/Sarcoma Service Memorial Sloan‐Kettering Cancer Center
Who is a Cancer Survivor? “An individual is considered a cancer survivor from the time of diagnosis through the balance of his or her life. Family members, friends, and caregivers are also impacted by the survivorship experience and are therefore included in this definition.” -National Coalition for Cancer Survivorship Consolidation Initial Long-Term Active Therapy Therapy/Diagnosis Survivorship Observation Twombly R. J Natl Cancer Inst. 2004. Mullan F. N Engl J Med. 1985.
Topics1. What is uveal melanoma?2. What FDA approved treatment options are available for this disease?3. What clinical trials are currently available specifically for patients with uveal melanoma?4. How do I find and participate in a clinical trial?
Ocular Melanoma• Uveal Tract – >95% of ocular melanomas• Conjunctiva – <4% of ocular melanomas• Orbit/Eyelid – <1% of ocular melanomas
Uveal Melanoma The most common primary eye cancer in adults Represents 5% of all melanomas Biologically distinct from skin melanoma Plaque brachytherapy (radiation treatment) or enucleation (surgery) is effective in eliminating the disease in the eye Once it has spread from the eye, treatment is challenging
Timeline for FDA Approved Drugsfor the Adjuvant Treatment of Melanoma 1994 2011 PEG IFN approved for Stage II/III Melanoma HD IFN approved for Stage II/III Melanoma
Interferon-• Approved in 1994 based on results of ECOG 1684• Administered 20 MU/m2 IV, 5 days/week x 4 weeks, then 10 MU/m2 SC, TIW x 11 months• With a median f/u of 7 years, ECOG 1684 demonstrated: – 9% survival benefit at 5 years – Prolongation in median survival from 2.8 to 3.8 years Relapse-free survival Overall survival
ECOG 1690: High Dose vs Low P = 0.05 for HD P = 0.17 for LD Dose vs Observation Relapse-free survival P = NS Overall survival Kirkwood et al. JCO 18:2444, 2000
Adjuvant Interferon in Uveal Melanoma Enrolled 121 patients with high risk ocular melanoma (118 PBI; 3 enucleation) Age > 65, tumor diameter > 15mm, ciliary body involvement, extrascleral extension Treated with 3 MIU IFN-alfa-2a subq 3 times/week x 2 years Compared with historical controls matched for age, tumor diameter, gender, survival time from primary tx to initiation of adjuvant tx Lane et al. Ophthalmology. Volume 117, Issue 9, September 2010.
Adjuvant Uveal Melanoma Trials (03/2012) Agent Phase Sponsor/Lead Center Clinicaltrials.gov IDmRNA Transfected Dendritic Cell Radboud University, II NCT00929019 Vaccination Netherlands DTIC & Interferon Alfa‐2b II Cleveland Clinic NCT01100528 San Diego Pacific Onc & Sunitinib, Tamoxifen, and Cisplatin II NCT00489944 Hematology Challenges of developing effective adjuvant trials: What treatments should be tested? Which patients should be enrolled onto the study? What defines a “positive” study? How many patients are required to prove that a treatment is effective? www.clinicaltrials.gov
www.clinicaltrials.gov• A service of the US National Institutes of Health• Offers up-to-date information on federally and privately supported clinical trials for a wide range of diseases and conditions.• Currently contains 116,889 trials* sponsored by the National Institutes of Health, other federal agencies, and private industry.• Studies listed in the database are conducted in all 50 States and in 178 countries* (* - as of November 2011)
Timeline for FDA Approved Drugs for Melanoma 2011 1975 1994 1998 2011 2011DTIC approved Aldesleukin (IL2) PEG IFN approved for Stage IV approved for for Stage II/III Melanoma Stage IV Melanoma Melanoma HD IFN approved for Stage II/III Vemurafenib Melanoma Ipilimumab
Vemurafenib inhibits BRAFV600E Kinase RTK RAS40-60% of melanomas BRAFV600E RAF ATP VEMURAFENIB (PLX4032, RO5185426) MEK ATP ERK Cellular Proliferation
Vemurafenib Screening 960 mg po bid (N=337) BRAFV600E mutation Randomization Stratification • Stage N=675 • ECOG PS (0 vs 1) Dacarbazine • LDH level (↑ vs nl) • Geographic region 1000 mg/m2 iv q3w (N=338)Courtesy of P Chapman
Maximal tumor shrinkage by individual patient (RECIST 1.1) >100 Vemurafenib Percent change from baseline in sum of tumor diameters CR: 0.9% PR: 47.5% 50 ORR: 48.4% 0 -50 -100 >100 Dacarbazine CR: 0% PR: 5.5% 50 ORR: 5.5% 0 -50 -100Courtesy of P Chapman
Differential Sensitivity of Uveal Melanoma Cell Lines to PLX4720 by Mutational Status Ambrosini et al. AACR 2010, abstr 5035.
Ipilimumab: Mechanism of Action T-cell T-cell T-cell activation inhibition potentiation CTLA4 T cell T cell T cell CD28 CD28 CTLA4 CTLA4 TCR TCR TCR B7 IPILIMUMAB MHC B7 MHC MHC B7 blocks CTLA-4APC APC APC
MDX010-20: Study Design Ipilimumab + gp100 (N=403) R APre-treated NMetastatic DMelanoma Ipilimumab + placebo (N=137) (N=676) O M I Z E gp100 + placebo (N=136) Courtesy of S O’Day
Kaplan-Meier Analysis of Survival Ipi + gp100 (A) Ipi alone (B) gp100 alone (C) Ipilimumab Alone versus GP100 Alone HR 0.66 Median OS 10.1 vs 6.4 months P value 0.003 1 2 3 4 Years Survival Rate Ipi + gp100 N=403 Ipi + pbo gp100 + pbo N=137 N=136 1 year 44% 46% 25% 2 year 22% 24% 14% Courtesy of Steven O’Day
Efficacy of Ipilimumab in Uveal Melanoma Week 1: n = 13 Week 12: n = 9 2 SD; 7 POD Week 24: n = 5 3 SD; 2 POD Week 36: n = 3 1 SD; 2 POD Danielli et al. Cancer Immunol Immunother. 2011.
Response to Systemic Therapy Author Study n RR OS/PFSHomsi et al, 2010 Phase 2 Docosahexaenoic 22 4% 9.8 mo OS acid-Paclitaxel (1/22)Penel et al, 2008 Phase 2 Imatinib 10 0% 10.8 mo OS Schmittel et al, Phase 2 Gem/Treosulfan vs 48 2% 2-3 mo PFS 2006 Treosulfan (1/48)Oneill et al, 2006 Phase 2 DTIC/Treosulfan 15 0% 3 mo PFS Schmittel et al, Phase 2 17 0% 3 mo PFS 2005 Gem/Cis/TreosulfanSchmidt-Hieber et Phase 2 Bendamustine 9 0% NR al, 2004 Bedikian et al, Phase 2 Temozolomide 14 0% 1.8 mo TTP 2004Kivelä et al, 2003 Phase 2 BOLD + IFN 22 0% 1.9 mo PFS 157 1.3% 2/157
More than one disease… Gnaq/11 4%"Wild-type" 28% BRAF 45% KIT Melanoma 3% NRAS 20%
Gq/11 Mutations are Frequent in Primary UM Samples GNAQ Exon 5 Q209P Onken et al, 2008 49% 33% (33/67) Q209LVan Raamsdonk et al, 2008 46% 67% (22/48) GNAQ Ex 4 GNAQ Ex 5 GNA11 Ex 4 GNA11 Ex 5Blue Nevi 1.0% 54.7% 1.0% 6.5% (1/96) (76/139) (1/96) (9/139)Primary UM 2.8% 44.8% 2.1% 31.9% (4/145) (73/163) (3/145) (52/163)Metastatic 5.9% 21.7% 5.9% 56.5% UM (1/17) (5/23) (1/17) (13/23) Onken et al. Investigative Ophthalmology and Visual Science, 2008. Van Raamsdonk et al. Nature, 2008. Van Raamsdonk et al. NEJM, 2010.
The GαPathway Gα Gα PLCβ Gβγ GTP GDP DAG PIP2 GNAQ Q209L PKC IP3 P Raf Raf Akt P MEK MEK P ERK ERK mTOR Tumor growth and proliferation
Differential Sensitivity of Uveal Melanoma Cell Lines to AZD6244 by Mutational Status Ambrosini et al. AACR 2010, abstr 5035.
A Randomized Phase II Trial of Temozolomide versus AZD6244 in Patients with Metastatic Uveal Melanoma (NCI#8443)Part A Temozolomide Cross‐over to AZD6244 Allowed TMZ/DTIC Naïve (n = 60) at Progression Metastatic Uveal Melanoma Stratification by: AZD6244 1. Mutation status (n = 60) 2. M1a/b vs M1c 3. Prior therapy (0 vs ≥1) TMZ (n) AZD6244 (n) TOTAL (n) Gnaq/11 Mut At least 40 At least 40 At least 80 Gnaq/11 Wt Up to 20 Up to 20 Up to 40 Probability is 80% that this design will detect a treatment difference at a one-sided 10% significance level if the true PFS hazard ratio is 0.6 in the Gq/11 mutant only population AND the overall population
Phase I Study of AEB071 in UM• Includes a dose‐escalation portion and a 25 patient dose expansion cohort at the MTD – Starting dose 300 mg BID – Dose escalation using an adaptive Bayesian logistical regression model• Pre‐ and day 15 biopsies in all patients• Primary Endpoint: Estimate the MTD, safety/tolerability• Secondary Endpoints: Overall response rate, PFS, TTP, PK• Exploratory Endpoints: pMARCKS, correlation of PK/PD • Participating Centers: 1. MSKCC (PI: Gary K. Schwartz) 2. DFCI (PI: Stephen F. Hodi) 3. Institut Curie (Sophie Piperno‐Neumann) 4. Leiden Univ (H.W. Kapitejin)
Major Oncogenic Events in Uveal Melanoma 45% Gnaq mutations 30% Gna11 mutations 60% PTEN loss70% IGF1R expression 80% MET expression100% SSTR expression 85% KIT expression 85% ERK activationPatel M et al. Clin Cancer Res 2011;17:2087-2100
Metastatic Uveal Melanoma Trials (03/2012) Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID AEB071 I Novartis NCT01430416 Sorafenib (STREAM Trial) II Essen, Germany NCT01377025 Sunitinib vs DTIC II Clatterbridge Centre, UK NCT01551459 Alberta Health Sciences, CP‐675,206 II NCT01034787 Canada Liposomal vincristine (Marqibo) II Talon Therapeutics, Inc NCT00506142Genasense, Carboplatin & Paclitaxel II MD Anderson NCT01200342 SOM230 & RAD001 II Memorial Sloan‐Kettering NCT01252251 Cixutumumab (A12) II MD Anderson NCT01413191 AZD6244 versus Temozolomide II Memorial Sloan‐Kettering NCT01143402 Paclitaxel Albumin‐Stabilized II Ohio State NCT00738361 Nanoparticle Formulation Temozolomide & Bevacizumab II Institut Curie, Paris, France NCT01217398 STA‐9090 II Dana‐Farber NCT01200238 SAHA II Memorial Sloan‐Kettering pending www.clinicaltrials.gov
Uveal Melanoma Liver Targeted Trials (03/2012)Rational for Liver-Directed Therapy:1. Liver is 1st site of metastasis in >60% of cases and may be the dominant site of disease2. Currently available systemic treatments have limited effectiveness3. Regional tx allows dose escalation to the cancer-bearing organ while minimizing systemic exposure/toxicity via separation of the regional and systemic circulation4. Based on its unique vascular anatomy, the liver is a favorable site for regional therapy (established tumors in liver derive the majority of blood flow from the arterial tree - tumors: 100% versus normal liver: 25%) Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID SIR‐Spheres® 90Y Microspheres II Thomas Jefferson NCT01473004IV versus Hepatic Arterial Infusion of III EORTC NCT00110123 Fotemustine Liver Transplantation II Oslo University NCT01311466 www.clinicaltrials.gov
A Phase-III Random Assignment Trial Comparing Percutaneous HepaticPerfusion with Melphalan (PHP-mel) to Standard of Care for Patients with Hepatic Metastases from Metastatic Ocular or Cutaneous Melanoma H E P A PHP Arm T R Follow-up (n= 44) I A C N Melanoma D Metastatic P O Cross over to PHP R to Liver M (n=27, 55%) O (n = 93) I G Z R E E BAC Arm S Follow-up 1:1 (n = 49) S I Total Accrual: 93 patients O (PHP: 44, BAC: 49, Crossover: 27) N
Outline1. What is uveal melanoma?2. What FDA approved treatment options are available for this disease?3. What clinical trials are currently available specifically for patients with uveal melanoma?4. How do I find and participate in a clinical trial?
Summary• Uveal melanoma is a distinct disease entity from cutaneous melanoma, with a unique biology and response pattern to systemic therapy• Currently available treatments for cutaneous melanoma have limited efficacy in uveal melanoma (although further investigation of ipilimumab in uveal melanoma is warranted)• Hepatic directed therapy has activity in liver metastases from uveal melanoma but the role of this treatment in uveal melanoma must be further defined• Emerging insights into the biology of uveal melanoma have led to the development of a series of clinical trials which hold promise for positive clinical impact in this disease• Patient participation in clinical trials, both in the adjuvant and metastatic setting, remains critical to the successful development of effective treatments
Uveal Melanoma Resources• AIM at Melanoma – http://www.aimatmelanoma.org/en/• Melanoma International Foundation – www.melanomainternational.org• Melanoma Research Foundation: Cure OM – http://www.melanoma.org• Ocular Melanoma Foundation – http://www.ocularmelanoma.org• Melanoma Research Alliance – http://www.melanomaresearchalliance.org• National Cancer Institute – http://www.cancer.gov/cancertopics/pdq/treatment/intraocularmelanoma/Patient/page1