Transcript Renal Cell Cancer: Now It’s Getting Complicated – IL

Systemic Therapy of Melanoma:
The Dawn of A New Era
Shailender Bhatia, MD
University Of Washington
Melanoma Incidence And Mortality
(United States 2008)
Estimated New Cases of Melanoma 62,480
Males
Females
Prostate
186,320
25%
Breast
182,460
26%
Lung & bronchus
114,690
15%
Lung & bronchus
100,330
14%
Colon & rectum
77,250
10%
Colon & rectum
71,560
10%
Urinary bladder
51,230
7%
Uterine corpus
40,100
6%
Non-Hodgkin
lymphoma
35,450
5%
Non-Hodgkin lymphoma
30,670
4%
28,410
4%
Melanoma of the skin
34,950
5%
Thyroid
Kidney & renal pelvis
33,130
4%
Melanoma of the skin
Oral cavity & pharynx
25,310
3%
Ovary
Leukemia
25,180
3%
Kidney & renal pelvis
Pancreas
18,770
3%
Leukemia
745,180
100%
All sites
All sites
27,530
21,650
21,260
19,090
4%
3%
3%
3%
690,000 100%
Mortality of Melanoma 8,420
[Jemal et al. CA Cancer J Clin. 2008]
Historically, outcomes of patients with
advanced melanoma have been dismal
10-year survival rate less than 10%
[Balch CM et al. J Clin Oncol 2001]
Systemic therapy is the mainstay of
metastatic melanoma.
US-FDA approved
therapies for metastatic
melanoma
Dacarbazine
(1975)
High-dose IL-2
(1998)
Treatment of Metastatic Melanoma: An Overview
Bhatia S et al. ONCOLOGY. 2009; 23:6; 488-500
E-mail: [email protected]
How can we cure patients with
advanced melanoma?
Immunotherapy
versus
Chemotherapy / Targeted therapy
COMBINATION THERAPIES
Immunotherapy Works
(Albeit only in a small subset of melanoma patients)
n=17 (6%)
n=26 (10%)
Pooled analysis of 270 Melanoma patients treated with High-dose Interleukin-2
[Atkins MB et al. JCO 1999 113:293]
High-dose Interleukin-2 is very toxic
and requires administration in the ICU
[Google images]
CTLA-4 blockade leads to
immune stimulation
[Halama N et al Journal of Oncology 2010]
Ipilimumab is active in melanoma;
although responses are infrequent.
[Wolchok JD et al Lancet Oncology 2010]
Stay Tuned for Major Ipi Update!!
Ipilimumab is available, through an expanded-access trial, for
SCCA patients with metastatic melanoma.
Targeting Cytokine Delivery
To Tumors: ALT-801
ALT-801
[Belmont et al. 2006 Clin. Immunol. 121:29
Wen et al. 2008 Cancer Immunol Immunother. 57:1781]
ALT-801 phase I/IIa trial:
Tumor shrinkage seen in several patients
Cohort 1 - 0.015mg/kg
Patient
Tumor
Cancer type
ID
response
NeuroSD -0.2%
2002
endocrine
@ w11
2001
Colon
PD
1002
Melanoma
PD
Cohort 2 - 0.04mg/kg
Tumor
Patient ID Cancer type
response
SD 5.6%
1004
Prostate
@ w 11
Head and
SD -3.3%
2004
Neck
@ w 11
SD 8.3%
1005
Renal
@ w 11
1012
Renal
4005
Melanoma
1003
1006
1010
1011
3002
3003
4002
4003
4004
4006
Renal
Prostate
Renal Pelvis
Renal
Melanoma
Melanoma
Melanoma
Melanoma
Melanoma
Melanoma
2003
Lymphoma
SD -2.2%
@w8
SD -3.5%
@ w 11
PD
PD
PD
PD
PD
PD
PD
PD
PD
N/A (PD)
N/A
(Withdrawal)
Cohort 3 - 0.08mg/kg
Tumor
Patient ID Cancer type
response
SD 6.2%
1007
Renal
@w7
SD -22.7%
4001
Melanoma
@ w 11
SD -12.5%
3001
Melanoma
@ w 11
SD -3.5%
@
w 11
Subsequently
2005
Melanoma
converted to
Complete
Response
1008
Renal
PD
1009
Renal
PD
[Courtesy: Hing Wong.
Altor Biosciences]
Phase Ib/II Study of ALT-801 With Cisplatin in Patients With
Metastatic Melanoma is open and enrolling at SCCA.
Melanomas arising in different
locations have unique biologic features
V600E mutant BRAF present in 60% of NonCSD cutaneous melanoma patients;
Mutant NRAS in another 20%
CSD= Chronic Sun Damaged-skin
[Curtin JA et al. J Clin Oncol. 2006]
Mutations in BRAF and NRAS are
frequent in cutaneous melanomas
and contribute to tumorigenesis
60%
V600E
20%
[Curtin JA et al. NEJM 2005]
Early attempts at BRAF inhibition with
Sorafenib were disappointing.
Non-selective BRAF
inhibitor.
BRAF wild-type
BRAF V600E
22 nmol/L
38 nmol/L
CRAF, VEGFR-2, PDGFR-β,
Flt-3, c-KIT
[Hauschild A. et al. J Clin Oncol; 2009]
Selective inhibitor of BRAFV600E had
potent anti-melanoma activity in
preclinical models
Structure-based discovery
Selectivity for B-rafV600E
Effective inhibition of target
Anti-tumor activity in mice
[Tsai J et al. PNAS 2008]
RO5185624 (PLX4032) led to tumor
regressions in majority of melanoma
patients with V600E mutation in BRAF
Expansion Cohort patients at MTD (960 mg BID)
[Chapman P et al. ECCO/ESMO. 2009]
Progression-free survival data
looks promising as well.
Median PFS not yet reached in patients treated at 960 mg PO BID
(as of 08/2009)
[Chapman P et al. ECCO/ESMO. 2009]
Several patients had significant
reductions in tumor size and metabolism
.
Pre-treatment
Day 15
Pre-treatment
Pre-treatment
Cycle 2
Post-treatment
Cycle 4
A Roller Coaster Chase for a Cure
After Long Fight, Drug Gives Sudden Reprieve
A Drug Trial Cycle: Recovery, Relapse, Reinvention
By AMY HARMON
Published: February, 2010
RAF inhibitors in clinical trials in
Melanoma
[Shepherd C et al. Curr Oncol Rep. 2010]
RO5185426 vs Dacarbazine for Untreated Metastatic Melanoma (RO5185426)
BRIM 3: A Randomized, Open-label, Controlled, Multicenter, Global Study on Progression-free and Overall
Survival in Previously Untreated Patients With Unresectable Stage IIIC or Stage IV Melanoma With V600E
BRAF Mutation Receiving RO5185426 or Dacarbazine
Status: Open and enrolling at SCCA
Aberrations in Kit are relatively more
frequent in uncommon melanoma subtypes
36%
39%
28%
CSD= Chronic Sun Damaged-skin
[Curtin JA et al. J Clin Oncol. 2006]
Imatinib, an oral inhibitor of KIT,
works in melanoma patients harboring
somatic alterations of KIT.
31 out of 145 melanoma patients (21%) had KIT aberrations.
CSD
12% (4/34)
Mucosal
24% (14/59)
Acral
30% (13/43)
Unknown
0% (0/9)
Objective response rate - 33% (4/12)
Complete remission
- 17% (2/12)
Stable Disease
- 50% (6/12)
[Carvajal RD et al. 2009 ASCO Abstract 9001]
Until CURE happens, participation in
well-designed clinical trials should be
considered Standard of Care
Therapeutic Trials at SCCA (not including the T-cell Therapy trials)
Disease Status
Immunotherapy
Targeted therapy
Chemotherapy
RO5185426
(BRAF inhibitor)
vs
Dacarbazine
Abraxane
vs
Dacarbazine
MAGE-A3 Vaccine vs Placebo
Adjuvant
Ipilimumab vs Placebo
1st Line
Metastatic
2nd Line or
beyond
Cisplatin + ALT-801
MAGE-A3 Vaccine
Ipilimumab
(expanded access)
BRAF inhibitor
(coming soon)
MLN4924 (Nedd-8
enzyme inhibitor)
Tasisulam
vs
Paclitaxel
Personalized therapy of melanoma
is finally picking up speed.
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