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New and Emerging Options in Metastatic Melanoma: Progress and Challenges in
Personalizing Patient Care
Jon M. Richards, MD, PhDOncology Specialists, SC
Director, Biologics Response Modifier ProgramDivision of Hematology/Oncology
General HospitalPark Ridge, IL
MDP Pathology Grand Rounds Lecture Series
Dinner is provided by:
The planners and faculty indicated no relevant financial relationships with any commercial interests.
Jon M. Richards, MD, PhD
ConsultantBristol-Myers Squibb Company
Grant/Research SupportBristol-Myers Squibb CompanyLilly USA, LLCCelgene CorporationGenentech, Inc.
HonorariaBristol-Myers Squibb Company
Ownership InterestsBristol-Myers Squibb Companysanofi-aventis
Incidence and Prognosis
• During 2011, 70,230 new cases of melanoma of the skin are expected
– ~8790 deaths – Majority of all skin cancer deaths
American Cancer Society. Cancer Facts Figures 2011. Atlanta, GA: American Cancer Society; 2011; American Cancer Society. http://www.cancer.org/Cancer/SkinCancerMelanoma/DetailedGuide/melanoma-skin-cancer-survival-rates. Accessed 08/24/11; Rigel. CA Cancer J Clin. 2011;61:212.
Disease Stage
5-Yr Survival (%)
IA 97 IB 92 IIA 81 IIB 70 IIC 53 IIIA 78 IIIB 59 IIIC 40 IV 15-20
Distribution of Stage at Diagnosis
Localized 84%
Distant 4%
Regional 8%
Lifetime Risk of Developing Invasive Melanoma in the United States
1/15001/600
1/250
1/150
1/100
1/741/65
1/58
1/50
PRO
JEC
TED
Rigel. CA Cancer J Clin. 2010;60:301.
1930 1950 1980 1985 1993 2000 2004 2009 2015
Estimated New Cancer Cases by Gender
RankMales Females
Cancer Type New Cases (%) Cancer Type New Cases (%)
1 Prostate 240, 890 (29) Breast 230, 480 (30)
2 Lung and bronchus 115, 060 (14) Lung and bronchus 106, 070 (14)
3 Colon and rectum 71, 850 (9) Colon and rectum 69, 360 (9)
4 Urinary bladder 52, 020 (6) Uterine corpus 46, 470 (6)
5 Melanoma of the Skin 40, 010 (5) Thyroid 36, 550 (5)
6 Kidney and renal pelvis 37, 120 (5) Non-Hodgkin lymphoma 30,300 (4)
7 Non-Hodgkin lymphoma 36, 060 (4) Melanoma of the skin 30, 220 (4)
8 Oral cavity and oral pharynx 27, 710 (3) Kidney and renal pelvis 23, 800 (3)
9 Leukemia 25, 320 (3) Ovary 21, 990 (3)
10 Pancreas 22, 050 (3) Pancreas 21, 980 (3)
Siegel. CA Cancer J Clin. 2011;61:212.
Average Yrs of Life Lost
SEER Cancer Statistics Review 1975-2006. http://seer.cancer.gov/csr/1975_2006/results_merged/ topic_year_lost.pdf. Accessed 08/24/11.
Childh
ood
Breas
t (fem
ale)
Melano
maOva
ry
Oral C
avity
and P
haryn
x
Kidney
and R
enal
Pelvis
Lung
and B
ronc
hus
Pancre
as
Non-H
odgk
in Ly
mphom
a
Colon a
nd R
ectum
Prostat
e
8070605040302010
0
71
18.9 18 17.3 17.1 15.5 15 14.5 14.3 14.29.3
Lack of Chemotherapeutic Efficacy in Patients With Melanoma
• Drug resistance by the tumor cell – Mismatch repair– Alkylguanine; alkyltransferase– Base excision repair
• Specific molecular mechanisms of progression
– BRAF mutated in 66% of melanoma– STAT3 constitutively activated in melanoma
• Resistance of tumor cell to apoptosis– BCL2– Survivin
DeVita. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2005; Koon. Expert Rev Anticancer Ther. 2007;7:79; Kortylewski. Cancer Metastasis Rev. 2005;24:315.
SWOG-9430: Complete Resection of Stage IV Melanoma Prolongs Survival
Reproduced with permission from Sosman. Cancer. March 31, 2011 [Epub ahead of print].CI=confidence interval; SWOG=Southwest Oncology Group.
100%
80%
60%
40%
20%
0%0 2 4 6 8 10
1 yr: 75% (95% CI: 64%-86%)2 yrs: 47% (95% CI: 35%-59%)3 yrs: 36% (95% CI: 24%-48%)4 yrs: 31% (95% CI: 20%-42%)
Patients Completely Resected
At Risk Deaths1-Yr
Estimate64 54 75%
Yrs After Complete Resection
The Evolution of Immunotherapy for Patients With Metastatic Melanoma
Rationale for Immunotherapy in Patients With Melanoma
• Well-documented cases of spontaneous responses in melanoma (<1%) that are immunologically mediated, especially in primary tumors
• 3 immunostimulatory agents approved for use in melanoma– IFN-a– Peg–IFN-α– IL-2– All are associated with significant toxicity
• New understanding of the immunobiology of melanoma allows the development of more rational immunotherapy strategies
– Vaccines– Immune-modulating antibodies (anti–CTLA-4; anti-CD40)– Adoptive transfer of melanoma-specific T cells
Dudley. J Clin Oncol. 2005;23:2346; Queirolo. Cancer Treat Rev. 2006;32:524; Benjamini. Immunology: A Short Course. 3rd ed. New York, NY: Wiley-Liss, Inc. 1996; Pilla. Expert Rev Anticancer Ther. 2006;6:1305; Vonderheide. J Clin Oncol. 2007;25:876; Proleukin [package insert]. Emeryville, CA: Chiron Corporation; 2000; Intron A [package insert]. Kenilworth, NJ: Schering Corporation; 2002; Faries. BioDrugs. 2005;19:247.
CTLA=cytotoxic T-lymphocyte antigen; IFN=interferon; IL=interleukin; Peg=pegylated.
Current Immunotherapeutic Agents for the Treatment of Melanoma
Mocellin. J Natl Cancer Inst. 2010;102:493.
Metaanalysis: Adjuvant Therapy With IFN
• Metaanalysis of 1822 patients treated in randomized trials with IFN vs control (observation, placebo, or vaccine)
• IFN treatment significantly improved RFS (18% increase, P<0.001) and OS (11% increase, P=0.002)
HR=hazard ratio; LL=lower limit of 95% confidence interval; OS=overall survival; RFS=relapse-free survival; UL=upper limit of 95% confidence interval.
EORTC 18991 Phase III Trial of Pegylated IFN- vs Observation in Metastatic Melanoma
• Stratification: microscopic vs palpable nodes; number of nodes; Breslow width; ulceration; gender; site
• Primary endpoint: RFS• Secondary endpoints: DMFS, OS, and safety
Peg–IFN- 6 g/kg/wk for 8 wks;
maintenance 3 g/kg/wk for 5 yrs
(N=627)
Observation(N=629)
RANDOMIZE
Bottomley. J Clin Oncol. 2009;27:2916; Eggermont. Lancet. 2008;372:117.
Stage III metastatic melanoma after full lymphadenectomy
(N=1256)
DMFS=distant metastasis–free survival; EORTC=European Organization for the Research and Treatment of Cancer.
EORTC 18991 Phase III Trial: Efficacy
Eggermont. ASCO. 2011 (abstr 8506).
DMFSRFSHR: 0.87(95% CI: 0.76-1.00)P=0.05
0
20
40
60
80
100
0 2 4 6 8 10Time (Yrs)
Observation (N=629)
Peg–IFN-α (N=627)
HR: 0.93(95% CI: 0.81-1.07)P=0.33
Observation (N=629)
Peg–IFN-α (N=627)
0
20
40
60
80
100
0 2 4 6 8 10Time (Yrs)
EORTC 18991: RFS and DMFS in Patients With Stage III-SN–Positive Melanoma and Ulceration
RFS DMFS
HR: 0.72(95% CI: 0.46-1.13)P=0.06
0
20
40
60
80
100
0 2 4 6 8 10Time (Yrs)
Observation (N=90)
Peg–IFN-α (N=96)
HR: 0.65(95% CI: 0.41-1.04)P=0.02
Observation (N=90)
Peg–IFN-α (N=96)
0
20
40
60
80
100
0 2 4 6 8 10Time (Yrs)
Eggermont. ASCO. 2011 (abstr 8506).
EORTC 18991: OS in Patients With Stage III-SN–Positive Melanoma and Ulceration
HR: 0.59 (99% CI: 0.35-0.97)Median OS: 3.7 yrs vs >9 yrsP=0.006
0
20
40
60
80
100
0 2 4 6 8 10Time (Yrs)
Observation (N=90)
Peg–IFN-α (N=96)
Eggermont. ASCO. 2011 (abstr 8506).
• Common grade 3/4 AEs include fatigue, hepatotoxicity, and depression• Treatment discontinued in 31% of patients due to toxicity • Peg–IFN- treatment resulted in a significant lowering of health-related
quality of life vs observation (P≤0.0004)– Negative impact on social functioning, role functioning, appetite loss,
fatigue, and dyspnea
EORTC 18991 Phase III Trial: AEs
Bottomley. J Clin Oncol. 2009;27:2916; Eggermont. Lancet. 2008;372:117.
AE (Grade 3/4) Peg–IFN- (N=608) Observation (N=613)
Any 605 (99%) 484 (79%)
Fatigue 574 (94%) 252 (41%)
Liver Function Test* 479 (79%) 221 (36%)
Pyrexia 454 (75%) 53 (9%)
Headache 425 (70%) 118 (19%)
Myalgia 408 (67%) 140 (23%)
Depression 360 (59%) 153 (25%)*Alanine and aspartate aminotransferases/bilirubin/alkaline phosphatase.
AE=adverse event.
Novel Immunotherapeutic Agents: Monoclonal Antibodies
CTLA-4 as a Therapeutic Target
• One of the key negative regulators of adaptive immune responses– Central role in shaping T-cell responses and
maintaining peripheral tolerance
– Important in limiting antitumor responses
• Development of CTLA-4 antibodies as therapeutic anticancer agents– Ipilimumab (MDX-010)
– Tremelimumab (CP-675206)
Queirolo. Cancer Treat Rev. 2006;32:524; Benjamini. Immunology: A Short Course. 3rd ed. New York, NY: Wiley-Liss, Inc. 1996.
CTLA-4 Blockade
T-cell inactivation
APC
CTLA-4T cell
APC
T cellT cell
APC
CD28CD28
B7
TCR
HLA
CTLA-4
Adapted from Weber. J Cancer Immunol Immunother. 2009;58:823.
HLA=human leukocyte antigen.
T-cell activation
T-cell activation
• Optimal dose: ipilimumab 10 mg/kg• DCR (CR + PR + SD) also improved with increasing dose• Rates of irAEs higher with increasing dose
CA184-022 Dose-Finding Trial of Ipilimumab inUnresectable Stage III/IV Melanoma
Wolchok. Lancet Oncol. 2010;11:108; Hamid. ASCO. 2008 (abstr 9025).
• 217 patients with previously treated, therapy-refractory or -intolerant, stage III (unresectable) or stage IV melanoma
• Treated with ipilimumab (various doses) q3w x 12 wks then q12w x 48+ wks depending on response
P=0.0015
CR
+ P
R (%
)
CR=complete response; DCR=disease control rate; irAE=immune-related AE; PR=partial response; SD=stable disease.
Ipilimumab 0.3 mg/kg (n=73)Ipilimumab 3 mg/kg (n=72)Ipilimumab 10 mg/kg (n=72)
Hodi. N Engl J Med. 2010;363:711.
Ipilimumab + gp100(N=403)
gp100 + placebo(N=136)
RANDOMIZE
Pretreated metastatic melanoma
(N=676)
Ipilimumab + placebo(N=137)
Phase III Trial of Ipilimumab ± gp100 Vaccine vs gp100 Vaccine Alone: MDX010-20
• Primary endpoint: OS• Secondary endpoints: ORR, DOR, and PFS
DOR=duration of response; gp100=glycoprotein 100; PFS=progression-free survival.
MDX010-20: OS
1 2 3 4Time (Yrs)
Reproduced with permission from Hodi. N Engl J Med. 2010;363:711.
Survival Rate Ipilimumab + gp100 (N=403)
Ipilimumab + Placebo (N=137)
gp100 + Placebo (N=136)
1 yr 44% 46% 25%2 yr 22% 24% 14%
Ipilimumab + gp100 Ipilimumab + gp100 Ipilimumab + placebo Ipilimumab + placebo gp100 + placebo gp100 + placebo
Phase III Trial of Ipilimumab Plus Dacarbazine vs Dacarbazine Alone: Study 024
• Scheduled tumor assessments at baseline, 12 wks, and 24 wks
• Primary endpoint: OS
Ipilimumab 10 mg/kgq3w x 4
Dacarbazine 850 mg/m2
q3w x 8(N=251)
Dacarbazine 850 mg/m2
q3w x 8Placebo(N=251)
RANDOMIZE
Previously untreated metastatic melanoma(N=502)
Ipilimumab 10 mg/kg
q12w
Placeboq12w
Robert. N Engl J Med. 2011;364:2517.
Study 024: OS
• 1-yr survival: 47.3% (ipilimumab) vs 36.6% (placebo)• 2-yr survival: 28.5% vs 17.9%• 3-yr survival: 20.8% vs 12.2%• HR: 0.72; P<0.001
Reproduced with permission from Robert. N Engl J Med. 2011;364:2517.
Study 024: Select AEs
AE
Ipilimumab + Dacarbazine (N=247)
Placebo + Dacarbazine (N=251)
Total Grade 3/4 Total Grade 3/4
Patients (%)
Pruritus 73 (29.6 5 (2.0) 22 (8.8) 0
Rash 61 (24.7) 3 (1.2) 17 (6.8) 0
Diarrhea 90 (36.4) 10 (4.0) 62 (24.7) 0
Colitis 11 (4.5) 5 (2.0) 0 0
Robert. N Engl J Med. 2011;364:2517.
Ipilimumab: Clinical Activity in Brain Metastases
• 28 pts with ≥1 melanoma brain metastases received ipilimumab 10 mg/kg q3w x 4
• No steroids were allowed; prior radiotherapy to nonindex lesions was allowed
• 6 pts achieved CNS DCR (CR + PR + SD): 21.4%• Overall DCR: 17.9% (5 pts)• irAE overall rate: 60.7% (17 pts)• Dose-limiting irAEs occurred in 4 patients: 14.3%• 19 pts had CNS events, all considered disease related• Ipilimumab has activity in melanoma CNS disease
Margolin. ESMO. 2009 (abstr O-9306).
CNS=central nervous system.
Unique Kinetics of Response in Patients Treated With Ipilimumab
• Some patients treated with ipilimumab have been shown to have unique time courses for their antitumor responses
• Patients might have prolonged SD followed by regression
• Some patients have an initial response with slow induction of a CR
• Others have new lesions, meaning PD, but then have either prolonged stability or a subsequent response
• These responses are shown on the next slide
Weber. ASCO. 2008 (abstr 9010).
Objective Response to Ipilimumab After Significant Progression With Tumor Volume Increase
Week 20: Regression Week 36: Still Regressing
Screening Week 12: Progression
Reproduced with permission from Wolchok. ASCO. 2008 (abstr 3020).
Unique Kinetics of Response in Patients Treated With Ipilimumab
ScreeningWeek 12: swelling and
progression Week 12: improved
Week 16: continued improvement
Week 72: complete remission
Week 108: complete remission
Images courtesy of Jedd D. Wolchok, MD.
Ipilimumab Treatment and irAEs
• Blockade of CTLA-4 can lead to the development of irAEs• Treatment results in T cells losing tolerance to self-antigens• Preclinical melanoma tumor models utilizing CTLA-4
blockade have demonstrated enhanced immune-mediated tumor rejection AND irAEs such as depigmentation
• Common autoimmunities in pts treated with anti–CTLA-4 include
– Dermatitis– Enterocolitis– Endocrinopathies
• Toxicity does not always equal response, but there does appear to be an association
Attia. J Clin Oncol. 2005;23:6043; Downey. Clin Cancer Res. 2007;13:6681; Lutzky. ASCO. 2009 (abstr 9034); van Elsas. J Exp Med. 1999;190:355; Weber. J Clin Oncol. 2008;26:5950.
Occurrence of irAEs Is Associated With OS in Patients Treated With Ipilimumab
Pooled Data From CA184-008 and CA184-022
1.0
0.8
0.6
0.4
0.2
0.0
Prop
ortio
n A
live
Any irAE within 12 wksCensored
No irAEs within 12 wksCensored
Time (Mos)
GroupMedian OS
mos (95% CI)Any irAE within 12 wks
No irAEs within 12 wks
14.8 (10.0-21.7)
8.21 (5.29-13.7)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Reproduced with permission from Lutzky. ASCO. 2009 (abstr 9034).
Enteritis Induced by Ipilimumab
• Inflammation can be anywhere in GI tract (eg, mucositis and gastritis, but most commonly colitis)
• Diarrhea: requires attention– New and watery– Increased frequency >50% baseline– Duration– Bloody
• Grade 1 and 2– Treat symptomatically– Rule out other causes– No need for systemic steroids; can use budesonide– Follow closely for resolution
Weber. Cancer Immunol Immunother. 2009;58:823; Weber. Oncologist. 2007;12:864; Ledezma. Oncol Nurs Forum. 2009;36:97.
Endocrinopathy irAEs: Overview
• Symptoms: fatigue, nausea, amenorrhea, impotence, hypotension, hyponatremia, hypoglycemia, and eosinophilia– If strong suspicion for adrenal crisis (dehydration and
hypotension), start stress-dose steroids• Endocrine labs: ACTH, cortisol, and TSH
– Closely follow; if grade 2 toxicity, continue ipilimumab– Hormone replacement; consider trial of high-dose
steroids if needed– If suspect hypophysitis, head MRI with pituitary cuts;
visual field testing
Beck. J Clin Oncol. 2006;24:2283.
ACTH=adrenocorticotropic hormone; TSH=thyroid-stimulating hormone.
Beck. J Clin Oncol. 2006;24:2283; Agarwala. Expert Rev Anticancer Ther. 2009;9:587; Weber. Cancer Immunol Immunother. 2009;58:823.
Management of irAEs
• Patient education for early recognition of irAEs• Aggressive work-up and management for
moderate/severe events• Nonspecific complaints might reflect endocrine (eg,
pituitary) toxicity• Corticosteroids might be effective• Algorithms established for the management of irAEs
Novel Immunotherapeutic Strategies: Adoptive-Cell Therapy
What Is Adoptive-Cell Therapy?
• T cells are isolated from tumor-infiltrating lymphocytes or peripheral blood
• Ex vivo enrichment and expansion of antigen-specific effector T cells utilizing
– IL-2, anti-CD3, feeder cells, and/or antigen-pulsed DCs
• T cells are reintroduced back to the patient
Yee C. 2009 ASCO Educational Book. Alexandria, VA: American Society of Clinical Oncology. 2009;511-515.
T cells isolated
from patient
In vitro expansion
and activation
Adoptive transfer
into patient
DC=dendritic cell.
Adoptive-Cell Therapy and Intensive Myeloablative Chemoradiation
• Rationale for lymphodepletion with NMA and TBI (preclinical evidence)– Elimination of Treg cells– Elimination of homeostatic cytokine “sinks”– Stimulation of TLRs on APCs
• Direct correlation of lymphodepletion extent and antitumor effect in murine models
Dudley. J Clin Oncol. 2008;26:5233; Antony. J Immunol. 2005;174:2591; Gattinoni. J Exp Med. 2005;202:907; Paulos. J Clin Invest. 2007;117:2197; Muranski. Nat Clin Pract Oncol. 2006;3:668; Wrzesinski. J Clin Invest. 2007;117:492.
NMA Chemotherapy:Cyclophosphamide 60 mg/kg for 2 days Fludarabine 25 mg/m2 for 5 days (N=43)
NMA chemotherapy over 5 days2 Gy of TBI (N=25)
NMA chemotherapy over 5 days12 Gy of TBI (2 Gy 2x daily for 3 days) (N=25)
ECOG=Eastern Cooperative Oncology Group; NMA=nonmyeloablative; PS=performance status; TBI=total body irradiation.
Eligibility Criteria
• Pts with metastatic melanoma
• ECOG PS: 0/1 (N=93)
Regimen RR (%)
TBI 12 Gy 72
TBI 2 Gy 52
NMA 48.8
Adoptive-Cell Therapy and Intensive Myeloablative Chemoradiation: Results
Reproduced with permission from Dudley. J Clin Oncol. 2008;26:5233.
RR=response rate.
Novel Immunotherapeutic Strategies: Vaccines
Antitumor Vaccines
• Multiple vaccine approaches are being studied that target molecular mechanisms in immune function and tumor-host interactions
Pilla. Expert Rev Anticancer Ther. 2006;6:1305; Fang. J Invest Dermatol. 2008;128:2596; Lens. Expert Opin Biol Ther. 2008;8:315.
Tumor-derived proteins/fusion proteins
DNA-encoding tumor antigens
Whole cells (autologous or allogeneic)
Tumor-derived peptides
Antigen-pulsed DCs
Viral vectors
Stimulate antitumor
immune response
Peptide-Based Vaccines
• Lineage antigens– Melan-A/MART-1, gp100, and tyrosinase
• Germline (cancer-testis) antigens– MAGE-3
• First cloned human melanoma antigen recognized by CD8+ T cells– NY-ESO-1
• Immunogenic testicular antigen aberrantly expressed in melanoma in a lineage-nonspecific fashion
• Restriction of recognition for CTLs: MHC class I– HLA class I–restricted peptide vaccines are composed of 8-10
amino acids• Restriction of recognition for helper T cells: MHC class II
– HLA class II–restricted peptide vaccines are composed of 12-14 amino acids
Paul, ed. Fundamental Immunology. 3rd ed. New York, NY: Raven Press, Ltd. 1993; Pilla. Expert Rev Anticancer Ther. 2006;6:1305; Reynolds. Int J Cancer. 1997;72:972; Chen. Proc Nat Acad Sci U S A. 1997;94:1914; Maeurer. Melanoma Res. 1996;6:11.
Ant
igen
Cla
ssM
HC
R
estr
ictio
n
CTL=cytotoxic T lymphocyte; MHC=major histocompatibility complex.
Phase III Trial of High-Dose IL-2 ± Peptide Vaccine in Patients With Metastatic Melanoma
• Pts with stage IV or locally advanced stage III cutaneous melanoma
• HLA-A*0201 positive
(N=185)
High-dose IL-2 720K IU/kg/dose IV every 8 hours x 12Repeat every 3 wks
(N=94)
Vaccine ([gp100:209-217(210M)] subcutaneous d1 q3w) +High-dose IL-2 (as above)
(N=91)
• Primary endpoint: RR• Secondary endpoints: toxicity, PFS, quality of life, and
immunologic monitoring• Central HLA typing, pathology review, and blinded response
assessment performed at the National Institutes of Health
Schwartzentruber. N Engl J Med. 2011;364:2119.
Eligibility CriteriaRANDOMIZE
High-Dose IL-2 ± Peptide Vaccine: OS
Reproduced with permission from Schwartzentruber. N Engl J Med. 2011;364:2119.
Ongoing Trials of Adjuvant Therapy in Metastatic Melanoma
Trial Phase Regimen
CA184-029, EORTC 18071 III
Adjuvant ipilimumab vs placebo after complete resection of high-risk stage III
melanoma
DERMA IIIAdjuvant GSK 2132231A (vaccine) vs
placebo after resection of stage IIIB/IIIC melanoma
NCT00028431 I/IIIpilimumab + tyrosinase/gp100/MART-1
peptides in resected stage III/IV melanoma
NCT00199901 II NY-ESO-1 vaccine vs placebo in resected stage IIC, III, or IV melanoma
National Institutes of Health website. http:// www.clinicaltrials.gov. Accessed 08/25/11.
EORTC=European Organization for Research and Treatment of Cancer.
Molecular Approaches to the Treatment for Patients With Metastatic Melanoma
Case 2
• A 61-yr-old woman is diagnosed with metastatic melanoma and receives alkylating agents as frontline therapy. After 20 wks, there has been no measurable response. Testing of the tumor tissue reveals that it harbors a V600E mutation. The patient wishes to discuss treatment options for refractory disease, including the possibility of clinical trial enrollment.– What factors might help to determine an alternative
treatment strategy?– Which late-stage trials might be most promising for pts
with this mutation?– What other molecular approaches might help to direct
potential therapies?
First Melanoma Cell Line Genome Sequenced
Reproduced with permission from Pleasance. Nature. 2010;463:7278.
• 50% of cutaneous melanomas have a BRAF mutation in the 599/600 amino acids—usually in intermittent sun-exposed skin
• N-RAS mutations are present in 20%; no overlap with BRAF mutation
• PTEN deletions are found in the remaining 30%
Lovly . Cancer Res. 2011;71:4920; Curtin. J Invest Dermatol. 2006;126:1660.
Oncogenic Mutations in the MAPK Pathway: BRAF
Phase I Trial of Vemurafenib in Patients With BRAFV600E Mutation: Rapid Response
Day 15Baseline
Reproduced with permission from Flaherty. N Engl J Med. 2010;363:809.
Phase III Trial of Vemurafenib vs Dacarbazine in Patients With Metastatic Melanoma: BRIM-3
Chapman. N Engl J Med. 2011;364:2507.
• Stratification: AJCC stage; ECOG PS 0 or 1; geographic region; serum LDH• Treatment was discontinued on PD• Endpoints: OS, PFS, and confirmed response
• Pts with stage IV or unresectable stage III melanoma
• BRAF V600E mutant positive
• No prior therapy(N=672)
Vemurafenib 960 mg p.o. bid(N=337)
Dacarbazine 1000 mg/m2 IV q3w(N=338)
RANDOMIZE
AJCC=American Joint Committee on Cancer; LDH=lactate dehydrogenase.
BRIM-3: PFS
Reproduced with permission from Chapman. N Engl J Med. 2011;364:2507.
Number at Risk Dacarbazine 274 213 85 48 28 16 10 6 3 0 0 0 0Vemurafenib 275 268 211 122 105 50 35 16 4 3 0 0 0
PFS
(%)
Mos
BRIM-3: OS
Reproduced with permission from Chapman. N Engl J Med. 2011;364:2507.
OS
(%)
Number at RiskDacarbazine 336 283 192 137 98 64 39 20 9 1 1 0 0Vemurafenib 336 320 266 210 162 111 80 35 14 6 1 0 0
Mos
Phase I/II Trial of Combination MEK and BRAF Inhibition in Patients With Solid Tumors
• Study part 1: pharmacokinetic drug-drug interaction study– Objective: determine the effects of the MEK inhibitor
GSK212 on the BRAF inhibitor GSK436 pharmacokinetics
• Study part 2: dose-escalation study followed by expansion cohorts– Objectives: assess safety and tolerability, determine
recommended phase II dose, characterize steady-state pharmacokinetics, and evaluate clinical activity
• Study part 3: randomized phase II trial in untreated stage IV melanoma– Currently accruing pts
Infante. ASCO. 2011 (abstr 8503).
Perc
ent c
hang
e fr
om b
asel
ine
in s
um o
f tum
or d
iam
eter
s >100
50
0
-50
-100
>100
50
0
-50
-100
Dacarbazine: 5.5% response
Vemurafenib: 48.4% response M1c
Best tumor response by individual patient
Chapman et al. 2011
Phase I/II MEK/BRAF Inhibition: Maximum Tumor Response
Infante. ASCO. 2011 (abstr 8503).
GSK436 150 mg bid/GSK212 1.5 mg qdGSK436 150 mg bid/GSK212 1 mg qdGSK436 75 mg bid/GSK212 1 mg qd
GSK436 150 mg bid/GSK212 2 mg qd
Max
imum
% R
educ
tion
From
Bas
elin
e M
easu
rem
ent
Phase I/II MEK/BRAF Inhibition: Tumor Response in Patients With Melanoma With
Prior BRAF Inhibitor
Infante. ASCO. 2011 (abstr 8503).
Max
imum
% R
educ
tion
From
Bas
elin
e M
easu
rem
ent
40302010
0-10-20-30-40-50-60-70-80-90
-100
<6 mos of prior BRAF inhibitor therapy≥6 mos of prior BRAF inhibitor therapy