Systemic Therapy of Melanoma:The Dawn of A New Era

Shailender Bhatia, MDUniversity Of Washington

Melanoma Incidence And Mortality (United States 2008)

Estimated New Cases of Melanoma 62,480Males 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%

Melanoma of the skin 34,950 5% Thyroid 28,410 4%

Kidney & renal pelvis 33,130 4% Melanoma of the skin 27,530 4%

Oral cavity & pharynx 25,310 3% Ovary 21,650 3%

Leukemia 25,180 3% Kidney & renal pelvis 21,260 3%

Pancreas 18,770 3% Leukemia 19,090 3%

All sites 745,180 100% All sites 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

[Balch CM et al. J Clin Oncol 2001]

10-year survival rate less than 10%10-year survival rate less than 10%

Systemic therapy is the mainstay of metastatic melanoma.

US-FDA approved therapies for metastatic melanoma

Dacarbazine (1975)

High-dose IL-2 (1998)

US-FDA approved therapies for metastatic melanoma

Dacarbazine (1975)

High-dose IL-2 (1998)

Treatment of Metastatic Melanoma: An OverviewBhatia S et al. ONCOLOGY. 2009; 23:6; 488-500E-mail: sbhatia@u.washington.edu

Treatment of Metastatic Melanoma: An OverviewBhatia S et al. ONCOLOGY. 2009; 23:6; 488-500E-mail: sbhatia@u.washington.edu

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)

[Atkins MB et al. JCO 1999 113:293]

n=17 (6%)n=17 (6%)

n=26 (10%)n=26 (10%)

Pooled analysis of 270 Melanoma patients treated with High-dose Interleukin-2

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][Halama N et al Journal of Oncology 2010]

Ipilimumab is active in melanoma; although responses are infrequent.

[Wolchok JD et al Lancet Oncology 2010][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.Ipilimumab is available, through an expanded-access trial, for SCCA patients with metastatic melanoma.

ALT-801

Targeting Cytokine Delivery To Tumors: ALT-801

[Belmont et al. 2006 Clin. Immunol. 121:29Wen et al. 2008 Cancer Immunol Immunother. 57:1781]

ALT-801 phase I/IIa trial:Tumor shrinkage seen in several patients

Phase Ib/II Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma is open and enrolling at SCCA.Phase Ib/II Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma is open and enrolling at SCCA.

Patient ID

Cancer typeTumor

responsePatient ID Cancer type

Tumor response

Patient ID Cancer typeTumor

response

2002Neuro-

endocrineSD -0.2%

@ w111004 Prostate

SD 5.6% @ w 11

1007 RenalSD 6.2%

@ w 7

2001 Colon PD 2004Head and

NeckSD -3.3% @ w 11

4001 MelanomaSD -22.7%

@ w 11

1002 Melanoma PD 1005 RenalSD 8.3% @ w 11

3001 MelanomaSD -12.5%

@ w 11

1012 RenalSD -2.2%

@ w 82005 Melanoma

SD -3.5% @ w 11

Subsequently converted to

Complete Response

4005 MelanomaSD -3.5% @ w 11

1008 Renal PD

1003 Renal PD 1009 Renal PD1006 Prostate PD1010 Renal Pelvis PD1011 Renal PD3002 Melanoma PD3003 Melanoma PD4002 Melanoma PD4003 Melanoma PD4004 Melanoma PD4006 Melanoma N/A (PD)

2003 LymphomaN/A

(Withdrawal)

Cohort 1 - 0.015mg/kg Cohort 2 - 0.04mg/kg Cohort 3 - 0.08mg/kg

[Courtesy: Hing Wong. Altor Biosciences][Courtesy: Hing Wong. Altor Biosciences]

Melanomas arising in different locations have unique biologic features

[Curtin JA et al. J Clin Oncol. 2006] CSD= Chronic Sun Damaged-skin

V600E mutant BRAF present in 60% of Non-CSD cutaneous melanoma patients;

Mutant NRAS in another 20%

V600E mutant BRAF present in 60% of Non-CSD cutaneous melanoma patients;

Mutant NRAS in another 20%

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 22 nmol/L

BRAF V600E 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

[Tsai J et al. PNAS 2008]

Structure-based discoveryStructure-based discovery

Selectivity for B-rafV600ESelectivity for B-rafV600E

Effective inhibition of targetEffective inhibition of target

Anti-tumor activity in miceAnti-tumor activity in mice

RO5185624 (PLX4032) led to tumor regressions in majority of melanoma

patients with V600E mutation in BRAF

[Chapman P et al. ECCO/ESMO. 2009]

Expansion Cohort patients at MTD (960 mg BID)Expansion Cohort patients at MTD (960 mg BID)

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)

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-treatmentPre-treatment Post-treatmentPost-treatmentPre-treatmentPre-treatment Day 15Day 15

Pre-treatmentPre-treatment Cycle 2Cycle 2 Cycle 4Cycle 4

A Roller Coaster Chase for a Cure

After Long Fight, Drug Gives Sudden Reprieve

A Drug Trial Cycle: Recovery, Relapse, Reinvention

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

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

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

[Curtin JA et al. J Clin Oncol. 2006]

28%

36%

39%

CSD= Chronic Sun Damaged-skin

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)

Imatinib, an oral inhibitor of KIT, works in melanoma patients harboring somatic alterations of KIT.

Imatinib, an oral inhibitor of KIT, works in melanoma patients harboring somatic alterations of KIT.

[Carvajal RD et al. 2009 ASCO Abstract 9001][Carvajal RD et al. 2009 ASCO Abstract 9001]

Until CURE happens, participation in well-designed clinical trials should be

considered Standard of CareTherapeutic Trials at SCCA (not including the T-cell Therapy trials)

Disease Status Immunotherapy Targeted therapy Chemotherapy

AdjuvantMAGE-A3 Vaccine vs Placebo

Ipilimumab vs Placebo

1st Line Metastatic

Cisplatin + ALT-801

MAGE-A3 Vaccine

RO5185426 (BRAF inhibitor)

vs Dacarbazine

Abraxane vs

Dacarbazine

2nd Line or beyond

Ipilimumab (expanded access)

BRAF inhibitor (coming soon)

MLN4924 (Nedd-8 enzyme inhibitor)

Tasisulam vs

Paclitaxel

25

Personalized therapy of melanoma is finally picking up speed.