New targets and new treatments in melanoma
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New Targets and New Treatments in Melanoma. Brendan D. Curti, MD Director, Melanoma Program Director Biotherapy Program Providence Cancer Center Earle A. Chiles Research Institute. Disclaimers.

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New targets and new treatments in melanoma

New Targets and New Treatments in Melanoma

Brendan D. Curti, MD

Director, Melanoma Program

Director Biotherapy Program

Providence Cancer Center

Earle A. Chiles Research Institute


Disclaimers

Disclaimers

  • Earle A. Chiles Research Institute accepted grants offrom 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

Melanoma Statistics

  • More than70,000people in the United States will get melanoma2011.

  • About 8,800 patients die per yearfrom 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.


New targets and new treatments in melanoma

Survival curves from the AJCC Melanoma Staging Database

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


New targets and new treatments in melanoma

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

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


Treating metastatic melanoma the long dark tunnel

TREATING METASTATIC MELANOMAThe 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

TREATING METASTATIC MELANOMANot Just Bad, Consistently Bad

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

DECADE TRIAL PERFORMED

1st LINE VS PRETREATED

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


New targets and new treatments in melanoma

AntigenPresenting Cell

T Cell

B7-DC/PD-L2

PD-1

B7-H1/PD-L1

-

CTLA-4

B7-2(CD86)

+

MHC-I/II TCR

+

OX40L

OX40

4-1BB

4-1BBL

Targets of novel immunotherapy

TNFR family

TNF family

B7 family

CD28 family

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


New targets and new treatments in melanoma

T-cell receptor: antigen/MHC

CD28 B7

CTLA-4 B7

Vaccine?

CTLA-4: The Brake on T-Cell Activation

IL-2


New targets and new treatments in melanoma

Original ArticleImproved 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 Med

Volume 363(8):711-723

August 19, 2010


New targets and new treatments in melanoma

MDX-020: Study Design

Ipilimumab + gp100

(N=403)

Pre-treated

Metastatic

Melanoma

(N=676)

Ipilimumab+ placebo

(N=137)

R

A

N

D

O

M

I

Z

E

gp100+ placebo

(N=136)


New targets and new treatments in melanoma

Kaplan-Meier Analysis of Survival

Ipi + gp100(A)

Ipi alone(B)

gp100 alone(C)

1

2

3

4

Years


Ipilimumab improves best objective response rate borr

Ipilimumab Improves Best Objective Response Rate (BORR)

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


New targets and new treatments in melanoma

Ipilimumab and DTIC

versus DTIC (+ placebo)


Ctla 4 immunotherapy toxicity immune response related adverse event irae

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

Dermatologic IRAEs

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


Ipilimumab induced colitis and iritis

Ipilimumab-Induced Colitis and Iritis

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


Ipilimumab related pituitary swelling and dysfunction

Ipilimumab-Related Pituitary Swelling and Dysfunction

6/30/04 Baseline(4.5 mm)

12/3/04 Headache/fatigue after 5 doses

(10.8 mm)

Blansfield et al, 2005.


Irae management

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

Beck et al, 2006.


Conclusions ipilimumab

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

Targeted Therapy


New targets and new treatments in melanoma

Hocker, et al. 2008 The Society for Investigative Dermatology


New targets and new treatments in melanoma

Relative frequency of BRAF mutations

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


Distribution of braf nras c kit mutations by primary site

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

Curtin J et al. JCO 2006; 24: 4340


New targets and new treatments in melanoma

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


New targets and new treatments in melanoma

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

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


New targets and new treatments in melanoma

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

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?


New targets and new treatments in melanoma

PLX4032 vs DTIC (BRIM3)

Patient has had 16 squamous cell cancers resected in 6 months


Patient 2

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?


New targets and new treatments in melanoma

PLX4032 vs DTIC (BRIM3)

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


Patient 3

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?


New targets and new treatments in melanoma

Before

Pt 11 – Melanoma

CT PR

PET CR

After


Patient 4

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?


New targets and new treatments in melanoma

Ipilimumab


Questions for the future

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).


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