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NEW THERAPEUTIC OPTIONS FOR THE TREATMENT OF MALIGNANT
MELANOMA
Gary C. Doolittle, MD Capitol Federal Masonic Professor Clinical Oncologist University of Kansas Cancer Center
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… there ARE therapeutic options for the treatment of malignant melanoma!
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Overview
Therapeutic Options:
• Adjuvant Therapy
– Interferon
– Chemotherapy
• Metastatic melanoma
– Targeted treatment
– Immunotherapies
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THERAPY FOR MELANOMA IN THE ADJUVANT SETTING
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TNM 5-year
Stage classification Definition survival rate
IIB T3b N0M0 T 2.01-4.0 mm, ulceration 63% T4a N0M0 T >4.0 mm, no ulceration 67%
IIC T4b N0M0 T >4.0 mm, ulceration 45%
IIIA AnyTN1a M0 1 micro node, no ulceration 69%
AnyTN2a M0 2-3 micro nodes, no ulceration 63%
IIIB AnyTN1a M0 1 micro node, ulceration 53%
AnyTN2a M0 2-3 micro nodes, ulceration 50%
AnyTN1b M0 1 macro node, no ulceration 59%
AnyTN2b M0 2-3 macro nodes; no ulceration 46%
IIIC AnyTN1b M0 1 macro node, ulceration 29%
AnyTN2b M0 2-3 macro nodes, ulceration 24%
AnyTN3 M0 4 nodes, matted nodes or nodes + in-transit 27% metastasis
J Clin Oncol. 2001;19:3635-3648.
Rationale for Adjuvant Treatment
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Adjuvant Treatment of High Risk Primary Disease
• High risk:
– Greater than 4 mm primary
– 2-4 mm with the presence of ulceration (Stage IIB)
– Lymph node positive (Stage III) disease
• Treatment options:
– High Dose Interferon
– Pegylated Interferon
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Mocellin et al, , JNCI, 2010; 102: 493-501
What Do We Know About IFN in the Adjuvant Setting?
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Adjuvant Therapy for High Risk Disease
• High dose interferon improves relapse free and overall survival
– Traditional dose schedule:
• Four weeks of high dose intravenously
• Forty eight weeks, thrice weekly subcutaneously
– High dose IFN versus Intermittent IFN:
• ‘standard’ versus four weeks of HDI three times in one year
• Most studies for cutaneous melanoma
– One adjuvant study for mucosal primaries
• Side effects with interferon are substantial
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Adjuvant Treatment—Pegylated Interferon
• Pegylated Interferon randomized trial
– Induction 6ug/kg/week; maintenance 3 ug/kg/week
– Dose reduction to 2, 3, 1 to maintain performance status
• for node + patients
• Treatment Schema:
- Induction: 8 weeks: 6ug/kg per week
- Maintenance: 3ug/kg per week
- Five year treatment course
- Doses reduced to maintain ECOG PS of 0 or 1
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Adjuvant Treatment—Pegylated Interferon
• Results:
- Improved relapse-free survival
- No improvement in overall survival
• Who benefits?
- Ulcerated primary lesions
- Lower disease burden, N1 patients
Eggermont, Suciu, Testori et al: Long-Term Results of the Randomized Phase III Trial EORTC 18991 of Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation in Resected Stage III Melanoma. JCO 30: 3010-3818, 2012
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Adjuvant Therapy for High Risk Disease
High dose interferon versus biochemotherapy—SWOG S0008 – Phase III trial, Cisplatin, Velban, DTIC, IL-2 and interferon
– RFS: 47% versus 39%, BCT vs. IFN, statistically significant
– Overall survival: 56%, no difference
Toxicity: – BCT: more hematologic, GI and metabolic toxicity
– IFN: more hepatic, neuro/ psych toxicity
BCT - Does not replace IFN as standard of care
BCT - for selected patients
- RFS longer
Flaherty, et al, ASCO Annual Meeting, 2012
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Adjuvant Avastin for Resected High-Risk Melanoma: AVAST-M
• Prospective, randomized trial of 1320 patients
• Stages IIB,, IIC or III subjects with cutaneous melanoma
• SLNB recommended but not mandatory
• Treatment:
• Bevacizumab (7.5mg/ kg, IV every three weeks for one year) versus observation
• Primary endpoint: overall survival
• Secondary endpoints: DFS, safety, toxicity, QOL
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Adjuvant Avastin for Resected High-Risk Melanoma: AVAST-M
• Baseline characteristics balanced for age, gender, performance status, stage, Breslow thickness, presence of ulceration, SLNB performed and N classification
• 54% completed planned treatment
• Discontinued due to disease recurrence, toxicity, patient choice, death, other
• Findings:
No improvement in OS, DFS did improve, well tolerated
Corrie, et al, ASCO, 2013, UK NCRI Melanoma Clinical Studies Group
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Disease-free Interval (DFI)
Presented By Philippa Corrie, PhD, MRCP, FRCP at 2013 ASCO Annual Meeting
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Overall Survival
Presented By Philippa Corrie, PhD, MRCP, FRCP at 2013 ASCO Annual Meeting
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Adjuvant Therapy for Resected High-Risk Melanoma
• High-dose IFN-α2b and peg-IFN are both FDA approved as adjuvant therapy for resected stage IIB/III melanoma
• High-dose IFN may be best for stages IIIb/IIIc resected disease; peg-IFN may be more useful for ulcerated stage II disease and stage IIIa microscopic disease
• For both treatments, prolonged RFS but only modest evidence of increased OS has been observed
• Avastin?
• Biochemotherapy?
RFS = recurrence-free survival Mocellin et al, 2010; NCCN, 2011; Kaehler et al, 2010; Okuyama et al, 2010.
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Future Study in the Adjuvant Population?
• Standard of care is still interferon
• Questions to address:
– Immune versus targeted versus chemotherapy
– What should the control arm be?
– What is the end point? RFS? OS
• Clinical trial participation is essential!
– ECOG 1609 Study
• Ipilimumab versus standard interferon
– Roche/ Genentech
• Vemurafenib versus placebo
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THERAPY FOR MELANOMA IN THE METASTATIC SETTING
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Treatment of Metastatic Melanoma Chemotherapy
– DTIC
– Biochemotherapy
– Temozolamide
– Temozolamide/ Thalidomide
– Carboplatin/ Taxol
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Treatment of Metastatic Melanoma
Targeted agents – Vemurafenib
– Dabrafenib
– Trametinib
– Vemurafenib and trametinib
Immunotherapy – High dose IL-2
– Ipilimumab
– Ipilimumab + GM CSF
– PD 1 inhibitors
– PD-1 inhibitor (Nivolumab) and Ipilimumab
– Anti-PD-1 antibodies: Lambrolizumab
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Targeted Agents
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Treatment of Metastatic Melanoma The RAS/RAF/MEK Pathway
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Distribution of BRAF/NRAS/cKIT Mutations by Site of Primary
A New Way to Classify Melanomas
CSD = chronic sun-damaged skin Curtin et al, 2006
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BRIM 3: The Vemurafenib Story
• Phase III Trial of metastatic patients with no prior treatment
• Vemurafenib (960 mg BID) versus dacarbazine (1000mg/ M2 every three weeks)
• 675 patients randomized
• Primary endpoints: – Progression free survival
– Overall survival
• Secondary endpoints: – Response rate
– Response duration
– Safety
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BRIM 3: Progression-free Survival
Chapman PB et al. N Engl J Med 2011;364:2507-2516
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BRIM 3: Overall Survival
Chapman PB et al. N Engl J Med 2011;364:2507-2516
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BRIM3: Selected Adverse Events
Vemurafenib, n= 336 Dacarbazine, n= 282
Adverse events All Grade 3 Grade≥ 4 All Grade 3 Grade ≥4
Arthralgia 49 3 - 3 <1 -
Rash 36 8 - 1 - -
Fatigue 33 2 - 31 2 -
Photosensitivity 30 3 - 4 - -
LFTs 18 7 <1 5 1 -
Cutaneous SCC 12 12 - <1 <1 -
Keratoacanthoma 8 6 - - - -
Skin papilloma 18 <1 - - - -
Nausea 30 1 - 41 2 -
Neutropenia <1 - <1 11 5 3
Discontinuations due to AE: 6% Vemurafenib; 4% Dacarbazine Chapman PB et al. N Engl J Med 2011;364:2507-2516
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Vemurafenib and the Skin
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Vemurafenib and the Skin
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BREAK-3: The Dabrafenib Story
• Dabrafenib inhibits BRAF V600e kinase
• Phase III, randomized study in which patients received dabrafenib (150 mg BIS) or Dacarbazine (1000mg/ M2 IV every three weeks)
• Stratified, unresectable Stage III, IVa, IVb, and IVc
• Primary endpoint: progression free survival
Hauschild, et al. Lancet 2012; 380:358-65
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BREAK-3: The Dabrafenib Story
Hauschild, et al. Lancet 2012; 380:358-65
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BREAK-3: the Dabrafenib Story Progression-Free Survival
Hauschild, et al. Lancet 2012; 380:358-65
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BREAK-3: The Dabrafenib Story
Adverse events with dabrafenib:
• Arthralgias
• Asthenia
• Fatigue
• Headache
• Pyrexia (8%)
• Skin: – Hyperkeratosis
– Palmar-plantar hyperkeratosis
– Squamous cell carcinoma/ keratoacanthoma
• Nausea/ vomiting
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METRIC: The Trametinib Story
• MEK Inhibitor
• Phase III, randomized trial treating with trametinib (2mg orally daily) or Dacarbazine (1000mg per M2) or taxol (175 mg/M2 every three weeks)
• Chemotherapy patients crossed over to trametinib upon progression
• Primary endpoint: progression free survival
Flaherty KT et al. N Engl J Med 2012;367:107-114
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METRIC: The Trametinib Story
Flaherty KT et al. N Engl J Med 2012;367:107-114
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METRIC: The Trametinib Story
Flaherty KT et al. N Engl J Med 2012;367:107-114
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METRIC: The Trametinib Story
Flaherty KT et al. N Engl J Med 2012;367:107-114
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METRIC: The Trametinib Story
Flaherty KT et al. N Engl J Med 2012;367:107-114
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METRIC: The Trametinib Story
Flaherty KT et al. N Engl J Med 2012;367:107-114
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What about combination treatment? Dabrafenib and Trametinib
• Theory: resistance to BRAF inhibitors is associated with reactivation of the MAPK pathway
• To address: combine BRAF inhibitor to MAPK MEK inhibitor
• Phase I/ II trial – open-label randomized study of dabrafenib (75mg or 150 mg
twice daily) and trametinib (1 mg or 1.5 mg or 2.0 mg once daily) in eighty five patients
– Randomly assigned to receive combination dabrafenib (150 mg) with trametinib (1 or 2 mg)
Flaherty KT et al. N Engl J Med 2012;367:1694-1703
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What about combination treatment?
Flaherty KT et al. N Engl J Med 2012;367:1694-1703
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Dabrafenib and Trametinib
Flaherty KT et al. N Engl J Med 2012;367:1694-1703
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Dabrafenib and Trametinib
Flaherty KT et al. N Engl J Med 2012;367:1694-1703
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Dabrafenib and Trametinib
Flaherty KT et al. N Engl J Med 2012;367:1694-1703
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Immunotherapies: Anti-CTLA 4 agents
Anti-PD-1 agents
Anti-PD-L1 agents
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Anti-CTLA4 Antibodies
• CTLA-4
– Molecule expressed on the surface of the activated T-lymphocytes
– CTLA-4 can restrict the antitumor immune response of T cells
• CTLA-4 antibodies result in increased T cell activation
• Treatment for at least 12 weeks
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Ipilimumab Is a Member of a Novel Class of Immunotherapeutic Antibodies
.
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Ipilimumab Plus DTIC vs. DTIC Alone (Study 024): Design
Dacarbazine 850 mg/m2 q3wks x8
SCREENING INDUCTION MAINTENANCE
Previously untreated Metastatic Melanoma (N = 502)
Ipilimumab 10 mg/kg q3wks x4
Placebo q3wks x4
Ipilimumab 10 mg/kg q12wks
Placebo q12wks
Dacarbazine 850 mg/m2 q3wks x8
Wk 12 Wk 24
Baseline tumor assessment
First scheduled tumor assessment
R
Wk 1
2In absence of progression. Wolchok et al, 2011.
= blinded
randomization (1:1) R
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Side Effect Profile For Ipilimumab
• Immune-mediated: – Dermatologic
• Rash
– Gastrointestinal
• Colitis/diarrhea
– Endocrine
• Pituitary dysfunction
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Management of Side Effects:
• Patient education for early recognition
• Maintain close contact with patient
• Aggressive work-up and management for moderate/severe events
• Non-specific complaints
– May reflect endocrine (e.g., pituitary) toxicity
• Established therapies (e.g., corticosteroids) are effective, may need other immunosuppressive agents, and reporting
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Summary of Ipilimumab Data
• First agent to show survival improvement in metastatic melanoma
• Survival rates in ipilimumab studies:
– 1 yr: 44%, 46%
– 2 yrs: 22%, 24%
• Consistent superiority of ipilimumab for all secondary efficacy end points
– PFS, BORR, DCR Hodi et al, 2010.
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Can Ipilimumab be Improved by Adding GM-CSF?
• Immunologic rationale
-GM-CSF enhance dendritic cell activation, potentiates antitumor T and B cell responses
- GM-CSF is widely available and may have immunomodulatory properties in melanoma
- Synergy between CTLA4 blockade and GVAX was shown in mice with established melanoma
. Hodi et al, 2013
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Can Ipilimumab be Improved by Adding GM-CSF?
ECOG 1608 Study: Eligibility: measureable disease, ≤1 prior therapy, no CNS mets, ECOG PS 0-1, > 4 wks prior therapy, adequate end organ function, no autoimmune disease, no prior CTLA-4 blockade/CD137 agonist.
Endpoint: overall survival
Randomized to receive: Arm A Ipi 10 mg/kg q3 wks IV x 4 then q12 wks plus GM 250 μg SC days 1-14 of 21 day cycles Arm B Ipi 10 mg/kg as in Arm A alone.
Hodi et al, ASCO 2013
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Can Ipilimumab be Improved by Adding GM-CSF?
Results:
• 245 pts were enrolled. Arms were balanced for demographics. Median follow up 13.3 mos
• IPI + GM-CSF: Response rate 11.3%
Median OS 17.5 months
• IPI Alone: Response rate 14.7% Median OS 12.6 months
• Toxicity? Side effect profile?
Fewer grade 3-5 side effects Hodi et al, 2013
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PD-1/ PD-L1 as Immune Targets
Programmed death-1, or PD-1, is an inhibitory receptor expressed by activated T-cells. It is a member of the CD28 family of receptors, which are involved in T cell regulation. PD-1 is activated by its ligand, PD-L1, which is expressed primarily on lymphoid and restricted non-lymphoid tissues. The physiologic role of the PD-1/PD-L1 interaction is to prevent uncontrolled immune activation during chronic infection or inflammation. However, when PD-1 is bound by PD-L1, the ability of the activated T-cell to produce an effective immune response against cancer cells is downregulated. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167-3175.
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Lambrolizumab (Anti-PD-L1) in the Treatment of Melanoma
Inclusion Criteria: Advanced, unresectable melanoma No restriction on prior therapies ECOG 0 or 1 Adequate Organ Function
Exclusion Criteria
Systemic corticosteroid therapy Active autoimmune disease Active and untreated CNS metastases
CNS metastases eligible if > 2 months Uveal melanoma
Hamid O et al. N Engl J Med 2013;369:134-144
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ANTI-PD-1
Hamid O et al. N Engl J Med 2013;369:134-144
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ANTI-PD-1
Hamid O et al. N Engl J Med 2013;369:134-144
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ANTI-PD-1
Hamid O et al. N Engl J Med 2013;369:134-144
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ANTI-PD-1
Hamid O et al. N Engl J Med 2013;369:134-144
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ANTI-PD-1
Hamid O et al. N Engl J Med 2013;369:134-144
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Lambrolizumab (Anti-PD-L1) in the Treatment of Melanoma
Conclusions:
• Treatment with lambrolizumab resulted in a high rate of tumor regression with a favorable toxicity profile
• Cohort treated at 10 mg/kg every two weeks showed the highest response rate (52%)
• Highest rate of drug-related side effects
• Randomized trial comparing 10mg/kg every 2 versus every 3 weeks
• Caution with cross study comparisons! ….ipilimumab studies
• Fewer immune-related adverse events Hamid O et al. N Engl J Med 2013;369:134-144
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Nivolumab plus Ipilimumab in Advanced Melanoma
Phase I Study: data for 86 patients; PD-1; PD-L1 immunohistochemical testing prior to study entry
• Escalating doses of IV nivolumab and ipilimumab
• Ipilimumab and nivolumab every three weeks four total of four doses
• Combination therapy every 12 weeks for up to eight doses
• Sequential therapy cohort
Hamid O et al. N Engl J Med 2013;369:134-144
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ANTI-PD-1 & IPILIMUMAB
Wolchok JD et al. N Engl J Med 2013;369:122-133
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ANTI-PD-1 & IPILIMUMAB
Wolchok JD et al. N Engl J Med 2013;369:122-133
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ANTI-PD-1 & IPILIMUMAB
Wolchok JD et al. N Engl J Med 2013;369:122-133
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ANTI-PD-1 & IPILIMUMAB
Wolchok JD et al. N Engl J Med 2013;369:122-133
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ANTI-PD-1 & IPILIMUMAB
Wolchok JD et al. N Engl J Med 2013;369:122-133
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ANTI-PD-1 & IPILIMUMAB
Wolchok JD et al. N Engl J Med 2013;369:122-133
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New Treatment Algorithm for Stage IV Melanoma
• Treatment naïve
– High dose IL-2 eligible
– High priority protocol if eligible
– Vemurafenib or imatinib if tumor mutated
– Ipilimumab alone or with other drugs if not mutated
• Previously treated
– High priority protocol if eligible
– High dose IL-2, vemurafenib or imatinib if appropriate
– Standard therapy, or phase I or II protocol
• Low tumor burden: immunoRx; High Burden: BRAF inhibitor
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Metastatic Melanoma: Clinical Trial Prospects - 2013
• Clinical trial preferred for all patients to answer key therapeutic questions
– Ipilimumab dose and schedule, induction and maintenance
– Vemurafenib + ipilimumab
– Addition of MEK inhibitor to mutant BRAF inhibitor
• Addition of agents blocking pathways responsible for resistance
– Targeted agent trials for NRAS mutant and WT population (15% and 35%)
– Combination immunotherapies
– Combination with chemotherapy and anti angiogenic agents
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MELANOMA MONDAY
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