New Targets and New Treatments in Melanoma

Brendan D. Curti, MDDirector, Melanoma ProgramDirector Biotherapy ProgramProvidence Cancer Center

Earle A. Chiles Research Institute

Disclaimers

• Earle A. Chiles Research Institute accepted grants of from BMS, Medarex, and Roche to cover costs of clinical trials.

• I am neither employed nor do I have equity in any company or entity whose products/drugs will be discussed today.

• Research Support: NIH, Prostate Cancer Foundation, Safeway Foundation, Kuni Foundation, Prometheus Pharmaceuticals

• Speakers Bureau: Genentech, Prometheus• Advisory Board: BMS, Prometheus

Melanoma Statistics

• More than 70,000 people in the United States will get melanoma 2011.

• About 8,800 patients die per year from melanoma. • During the 1970s, the rate of new cases of melanoma each year

increased at about 6% per year. Since the 1980s, the rate of increase has slowed to a little less than 3% per year.

• Melanoma is more often found in whites who are about 10X more likely to develop melanoma than African Americans.

• Men are slightly more likely than women to have melanoma. • Melanoma rates are highest in older people, but occur in all

ages. In fact, melanoma is one of the most common cancers in people under age 30.

Copyright © American Society of Clinical Oncology

Balch, C. M. et al. J Clin Oncol; 27:6199-6206 2009

Survival curves from the AJCC Melanoma Staging Database

Copyright © American Society of Clinical Oncology

Balch, C. M. et al. J Clin Oncol; 27:6199-6206 2009

Survival of 7,635 patients with metastatic melanomas (stage IV) by (A) the site of metastatic disease and (B) serum (LDH) levels

TREATING METASTATIC MELANOMA

The Long Dark Tunnel• No documented improvement in survival

over the past 30 years• No new FDA-approved drugs for

melanoma from 1992 until 2011.• Until this year, first-line therapy of

questionable value over supportive care, no established second-line therapy at all, no proven value of combination regimens

• Treatment of choice is a clinical trial

Vern Sondak ASCO 2010

TREATING METASTATIC MELANOMA

Not Just Bad, Consistently Bad

Korn et al. J Clin Oncol 2008;26:527-534

DECADE TRIAL PERFORMED 1st LINE VS PRETREATED

PROGRESSION-FREE SURVIVAL ON COOPERATIVE GROUP PHASE II TRIALS BY DECADE AND PRETREATMENT ALLOWED

MHC-I/II TCR

4-1BBL

B7-DC/PD-L2

OX40

B7-2(CD86)

OX40L

4-1BB

PD-1

AntigenPresenting Cell

T Cell

CTLA-4

-

+

B7-H1/PD-L1

+

TNFR family TNF family B7 family CD28 family

Adapted from: Melero et al. Nature Rev Cancer. 2007;7:95.

Targets of novel immunotherapy

CTLA-4: The Brake on T-Cell Activation

CTLA-4 B7

Vaccine?

CD28 B7

T-cell receptor: antigen/MHC

IL-2

Original Article Improved Survival with Ipilimumab in Patients with

Metastatic Melanoma

F. Stephen Hodi, M.D., Steven J. O'Day, M.D., David F. McDermott, M.D., Robert W. Weber, M.D., Jeffrey A. Sosman, M.D., John B. Haanen, M.D., Rene Gonzalez, M.D.,

Caroline Robert, M.D., Ph.D., Dirk Schadendorf, M.D., Jessica C. Hassel, M.D., Wallace Akerley, M.D., Alfons J.M. van den Eertwegh, M.D., Ph.D., Jose Lutzky, M.D.,

Paul Lorigan, M.D., Julia M. Vaubel, M.D., Gerald P. Linette, M.D., Ph.D., David Hogg, M.D., Christian H. Ottensmeier, M.D., Ph.D., Celeste Lebbé, M.D., Christian

Peschel, M.D., Ian Quirt, M.D., Joseph I. Clark, M.D., Jedd D. Wolchok, M.D., Ph.D., Jeffrey S. Weber, M.D., Ph.D., Jason Tian, Ph.D., Michael J. Yellin, M.D., Geoffrey M.

Nichol, M.B., Ch.B., Axel Hoos, M.D., Ph.D., and Walter J. Urba, M.D., Ph.D.

N Engl J MedVolume 363(8):711-723

August 19, 2010

MDX-020: Study Design

RANDOMIZE

Pre-treatedMetastaticMelanoma(N=676)

(N=137)

(N=136)

(N=403)

gp100 + placebo

Ipilimumab + placebo

Ipilimumab + gp100

Kaplan-Meier Analysis of Survival

Ipi + gp100 (A)Ipi alone (B)

gp100 alone (C)

1 2 3 4Years

Survival Rate Ipi + gp100 N=403

Ipi + pbo N=137

gp100 + pbo N=136

1 year 44% 46% 25%

2 year 22% 24% 14%

Ipilimumab Improves Best Objective Response Rate (BORR)

Arm AIpi + gp100

N=403

Arm BIpi + pboN=137

Arm Cgp100 + pbo

N=136

BORR, % 5.7 10.9 1.5

P-value: A vs C 0.0433

P-value: B vs C 0.0012

DCR‡, % 20.1 28.5 11.0

P-value: A vs C 0.0179

P-value: B vs C 0.0002

‡: Disease control rate: percentage of patients with CR, PR, or SD

Ipilimumab and DTICversus DTIC (+ placebo)

CTLA-4 Immunotherapy: Toxicity = Immune Response-related Adverse Event (IRAE)

• Most common IRAEs– Rash– Diarrhea (colitis)– Endocrinopathies– Hepatitis

• IRAEs are almost always reversible and manageable with steroids

• Toxicity does not always equal response, but there does appear to be an association

Weber, 2007.

Dermatologic IRAEs

Image courtesy of Jeffrey S. Weber, MD, PhD.

Robinson et al, 2004; Phan et al, 2003.

Ipilimumab-Induced Colitis and Iritis

6/30/04 Baseline(4.5 mm)

12/3/04 Headache/fatigue after 5 doses (10.8 mm)

Ipilimumab-Related Pituitary Swelling and Dysfunction

Blansfield et al, 2005.

Beck et al, 2006.

IRAE Management

• Patient education for early recognition of IRAEs• 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

– Dexamethasone: 4 mg IV q6hrs x 7 days followed by 17 days taper. If ineffective then infliximab 5 mg IV x 1.

• Algorithms established for work-up, treatment, and reporting of IRAEs

• Patient wallet card and/or medical ID bracelet

Conclusions- Ipilimumab• Ipilimumab represents a new class of T-cell

potentiators and a breakthrough for the field of immunotherapy

• Further development of ipilimumab is ongoing

– Treatment of a variety of cancer types

– Alternative combination regimens

– Refinements in dose and schedule

• Approved by the FDA on March 25, 2011

– Price for 4 doses = ~$120,000

Targeted Therapy

Hocker, et al. 2008 The Society for Investigative Dermatology

BRAF mutation location (by amino acid position and

substitution)

% of all BRAF mutations

V600E 97.3%

V600K 1.0%

K601E* 0.4%

G469A* 0.4%

D594G* 0.3%

V600R 0.3%

L597V* 0.2%

*Indicates most common amino substitution, but % represents all amino acid changes reported at that position

Relative frequency of BRAF mutations

Distribution of BRAF/NRAS/c-kit mutations by primary site

Curtin J et al. JCO 2006; 24: 4340

Representative Findings of the Effect of PLX4032 in Patients with Melanoma That Carried the V600E BRAF Mutation

Flaherty KT et al. N Engl J Med 2010;363:809-819

Antitumor Response in Each of the 32 Patients in the Extension Cohort

Flaherty KT et al. N Engl J Med 2010;363:809-819

BRAF and Vemurafenib: Conclusions

• Approximately 50% of melanomas contain an activating mutation in BRAF: glutamic acid for valine at amino acid 600 (the V600E mutation).

• Side effects included rash, arthralgia, fatigue, and keratoacanthoma.

• Treatment of patients with V600E BRAF mutated metastatic melanoma with PLX4032 resulted in complete or partial tumor regression in the majority of patients.

• Remissions do not appear to be durable.

• Approved by the FDA on 8/16/2011

• Bargain price: $9800 per month ($117,600 per year)

Patient 1• 76 year old grandmother diagnosed in

2002 years with TXN3M0 (stage 3) melanoma of left neck s/p RLND

• 2004: Left axillary LN recurrence, 24/28 + on axillary dissection

• May 2010: New onset dyspnea. Found to large left pleural effusion, bulky chest and abdominal adenopathy. Biopsy confirms melanoma. ECOG 2 (on a good day)

• What would you do?

PLX4032 vs DTIC (BRIM3)

Patient has had 16 squamous cell cancers resected in 6 months

Patient 2

• 51 year old salesman with T2bN1M0 melanoma on back in 2005. S/P WLE, SLN and CLND. One year “Kirkwood” IFN.

• Surveillance CT shows new mediastinal and hilar adenopathy, new SQ nodule.

• What would you do?

PLX4032 vs DTIC (BRIM3)

Assigned to DTIC, PR after after 6 cycles, then PD, now responding to IL-2

Patient 3

• 64 year old dentist, presents with acute abdominal pain. CT shows liver mets and adrenal tumors. Additional staging shows lung, LN, adrenal mets. LDH 8000. Biopsy confirms melanoma, PS 2 (and sliding rapidly).

• What would you do?

Before

After

Pt 11 – MelanomaCT PRPET CR

Patient 4

• 56 year old woman presents with cough. Imaging shows mediastinal lymph nodes. Biopsy shows melanoma.

• IL-2: Mixed response. RT to progressing lesion. 6 months later, new SQ, lung and LN disease. SQ nodule harvested for autologous vaccine.

• What would you do?

Ipilimumab

Questions for the future:• How excited should we be with PFS of 6 – 8 months with targeted therapies

(despite the high initial response rate)?• How do we sequence “targeted” therapies?• We have entered the age of personalized medicine to characterize targets

for melanoma treatment. Do we need to enter the age of personalized mechanisms of resistance? (and include physiologic, immunologic and other mechanisms of resistance)

• If BRAF resistance can (in part) be overcome with MEK inhibition, and MEK resistance can be overcome with WNT inhibition (at least in vitro), what will we need for WNT resistance?

• A melanoma “wiring diagram” was shown at a recent meeting with 35 nodes (connections). If we assume that there are 2 interactions from each node, and each interaction represents a path of resistance (or a path of recovery if you take the perspective of a melanoma cell), then there are 235 (= 3.4 x 1010) potential resistance pathways. How easy will it be to address address these several pathways of resistance in an individual? (and even if my estimate is wrong by 99.999999999%, there are 34 resistance pathways to manage).