Treatment of Advanced Melanoma: Myths, Facts and Clinical Trials
Jedd D. Wolchok, MD, PhD Melanoma-Sarcoma Oncology Service Ludwig Center for Cancer Immunotherapy Memorial Sloan-Kettering Cancer Center
Adjuvant Therapy: What to do after surgery?
• Careful observation- CT scans, physical exams, blood tests • Clinical trials- mainly of investigational immunotherapies (vaccines and antibodies) • High dose interferon alfa (Intron A)
Interferon• Approved in 1995 based on results of ECOG-1684 (9 % survival benefit) • 20 MU/m2 IV, 5 days/week x 4 weeks, then 10 MU/m2 SC, TIW x 11 months • Hepatic, cardiac, constitutional and psychiatric toxicities necessitating dose reduction in 2/3 of patients • ECOG-1690: a confirmatory trial?
ECOG-1690
ECOG-1690: OS
EORTC Overall Survival from randomization 18961 ITT Population
100 90 80 70 60 50
May 2007
Observation
GMK vaccine
HR (99.99% CI) 1.57 (0.68,3.64) 1.66 (0.69,3.99) P-value 0.03 0.02
40
30 20
10
0
Stratified for Breslow thickness, LND, ulceration, sex
(years)
0
O 35 56
1
477 478
2 Number of patients at risk :
214 221
3
51 57
4
3 4
5 Treatment
N
657 657
Observation GMK vaccine
High Dose IFN versus GMK (ECOG 1694)
OS HR 1.38 P = 0.023
18961 HR 1.66 P = 0.02
What to do if recurrence happens?
• • • • Surgery Radiation Therapy Chemotherapy Immunologic Therapy
Metastatic Melanoma—2009
Approved Therapies (USA) Date • DTIC • High-dose interleukin-2 1970s 1998
Many patients will receive both agents
Myth: Chemotherapy doesn’t work in melanoma
Single Agent DTIC Activity*
• Response rate
• Median response duration • Median survival • 6-year survival
19%
4 mos 6–9 mos <2%
DTIC has never been compared with observation or best supportive care
*Hill et al. Cancer 53:1299; 1984 (n=580)
Activity of single agents in melanoma
Early phase II trials of Dartmouth regimen
No. of patients 20 45 32 47 20 147 319 PR 7 18 10 11 11 41 100 CR 4 5 5 6 0 17 40 Resp. Rate 55% 51% 47% 36% 55% 39% 44%
Del Prete, et al. McClay, et al. Fierro, et al. Reintgen, et al. Richards, et al. Berd, et al.
Total
More Recent Phase III Trials
DTIC +/- IFN +/- Tam
1.0
Dacarbazine Dacarbazine + TMX Dacarbazine + IFN + TMX
DTIC vs Dartmouth
1.0
Proportion Surviving
Proportion Surviving
0.8 0.6 0.4 0.2 0.0
Dacarbazine + IFN
0.8
0.6 0.4 0.2 0.0
Dartmouth DTIC
0
10
20
30
Months
40
50
60
0
12
24
36
48
60
72
84
Months
Falkson et al. JCO, 1997
Chapman et al. JCO, 1999
Cytotoxic Chemotherapy: Conclusion
There is currently no evidence that combination chemotherapy or the addition of IL-2 or IFN is superior to chemotherapy alone.
Combinations of minimally active drugs yield minimal activity.
High-Dose IL-2 Therapy*
1.0 Probability of continuing response 0.8 CR (n = 17) PR (n = 26) CR + PR (n = 43)
• •
RR: 16% (43/270) Durable responses – Median 8.9 mos – CR: not reached
0.6
0.4
0.2
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Duration of response, months
*Atkins et al. JCO, 1999 (n=270)
IL-2 Toxicity: Constitutional
• Rigors/fevers
• Myalgias/arthralgias
• Fatigue
• Nausea/vomiting/anorexia • Diarrhea • Skin rash/pruritis
T-cell receptor: Antigen-MHC
CD28: B7
CTLA-4: B7
Vaccine?
Regulation of T cell activation is a Complex Process
TCR Antigen MHC
~
CD28 B7
TCR CD28 Antigen
CTLA-4
CTLA-4 : B7 suppression Termination of response
~
B7
Antigen-specific T cell Activation
TCR : Antigen MHC CD28 : B7 Co-stimulation
MHC
TCR CD28 Antigen
CTLA-4
~
B7
Activated T cell
IL-2 secretion Proliferation Effector function Induction of CTLA-4
MHC
CTLA-4 Blockade Activates Antigen Specific T-cell Responses
Anti-CTLA-4 mAb
TCR CD28 Antigen MHC
CTLA-4
TCR
~
B7
CD28
Antigen MHC
CTLA-4
~
B7
Oct 2006
April 2009
Pre-Treatment
After 4th dose
PLX4032, XL281, Sorafenib
AZD6244
Important New Findings in Genes Altered in Melanoma- Therapeutic Implications
• B-raf: mutations occur in this gene in 70% of melanomas, mainly those on intermittently sun exposed skin. Several new drugs being tested to inhibit B-raf with responses observed. • C-kit: mutations in in this gene in a small subset of patients with melanoma on internal surfaces, the face or the bottom of the foot. Imatinib (Gleevec) has shown efficacy in people preselected with mutations.