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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.


Survival curves from the AJCC Melanoma Staging Database

Balch, C. M. et al. J ClinOncol; 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

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


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.


T-cell receptor: antigen/MHC

CD28 B7

CTLA-4 B7

Vaccine?

CTLA-4: The Brake on T-Cell Activation

IL-2


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


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)


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


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 Adverse Event (IRAE)

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


Ipilimumab induced colitis and iritis
Ipilimumab Adverse Event (IRAE)-Induced Colitis and Iritis

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


Ipilimumab related pituitary swelling and dysfunction
Ipilimumab-Related Pituitary Swelling and Dysfunction Adverse Event (IRAE)

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 Adverse Event (IRAE)

  • 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 Adverse Event (IRAE)

  • 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 Adverse Event (IRAE)


Hocker Adverse Event (IRAE), et al. 2008 The Society for Investigative Dermatology


Relative frequency of BRAF mutations Adverse Event (IRAE)

*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 Adverse Event (IRAE)by primary site

Curtin J et al. JCO 2006; 24: 4340


Representative Findings of the Effect of PLX4032 Adverse Event (IRAE)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 Extension CohortVemurafenib:

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 Extension Cohort

  • 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) Extension Cohort

Patient has had 16 squamous cell cancers resected in 6 months


Patient 2
Patient 2 Extension Cohort

  • 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) Extension Cohort

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


Patient 3
Patient 3 Extension Cohort

  • 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 Extension Cohort

Pt 11 – Melanoma

CT PR

PET CR

After


Patient 4
Patient 4 Extension Cohort

  • 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 Extension Cohort


Questions for the future
Questions for the future: Extension Cohort

  • 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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