one moment please - ohio state university

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One Moment Please

One Moment PleaseOne Moment Please

Skin Cancer

Thomas Olencki, DO Thomas Olencki, DO

Today’s WebcastFriday, 09/09/11, Noon

,David Carr, MD

,David Carr, MD

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© The Ohio State University Medical Center, 2011© The Ohio State University Medical Center, 2011

The following program is a Continuing Medical Education Activity sponsored by The Ohio State University Medical Center. The design and production of this CME Activity is the sole responsibility of The Ohio State University Medical Center.

Accreditation Statement

The Ohio State University Medical Center, Center for Continuing Medical Education (CCME) is accredited by the Accreditation Council for Continuing Medical Education (ACCME®) to provide continuing medical education for physicians.

AMA Designation Statement

The Ohio State University Medical Center Center for Continuing Medical Education

The following program is a Continuing Medical Education Activity sponsored by The Ohio State University Medical Center. The design and production of this CME Activity is the sole responsibility of The Ohio State University Medical Center.

Accreditation Statement

The Ohio State University Medical Center, Center for Continuing Medical Education (CCME) is accredited by the Accreditation Council for Continuing Medical Education (ACCME®) to provide continuing medical education for physicians.

AMA Designation Statement

The Ohio State University Medical Center Center for Continuing Medical EducationThe Ohio State University Medical Center, Center for Continuing Medical Education designates this educational activity for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

As an enduring material this CME Activity is approved for three years from original release. Original release 09/09/11. Termination date 09/09/14.

CCME Disclosure Statement

As a provider of AMA PRA Category 1 Continuing Medical Education, it is the policy of CCME to adhere to the ACCME Standards for Commercial Support to avoid any

The Ohio State University Medical Center, Center for Continuing Medical Education designates this educational activity for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

As an enduring material this CME Activity is approved for three years from original release. Original release 09/09/11. Termination date 09/09/14.

CCME Disclosure Statement

As a provider of AMA PRA Category 1 Continuing Medical Education, it is the policy of CCME to adhere to the ACCME Standards for Commercial Support to avoid anyCCME to adhere to the ACCME Standards for Commercial Support to avoid any conflict of interest and/or commercial bias and must ensure balance, independence, objectivity and scientific rigor in all its sponsored educational activities. All individuals who are in a position to control content of an educational activity, including presenters, panel members and moderators, must to disclose any relevant financial relationships that create a conflict of interest.

Nothing in this program is intended to imply that any off-label or unapproved product use discussed is reimbursed by any government or private payor or that submission of a claim for such use is proper.

Presentation may include discussion of services and unapproved or off-label usage of commercial products or devices Log on to ccme osu edu for more information

CCME to adhere to the ACCME Standards for Commercial Support to avoid any conflict of interest and/or commercial bias and must ensure balance, independence, objectivity and scientific rigor in all its sponsored educational activities. All individuals who are in a position to control content of an educational activity, including presenters, panel members and moderators, must to disclose any relevant financial relationships that create a conflict of interest.

Nothing in this program is intended to imply that any off-label or unapproved product use discussed is reimbursed by any government or private payor or that submission of a claim for such use is proper.

Presentation may include discussion of services and unapproved or off-label usage of commercial products or devices Log on to ccme osu edu for more information

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The following planning committee members have no relevant financial relationships with commercial interests to disclose:

Planning Committee DisclosuresPlanning Committee Disclosures

Jame Allen, MD

Barbara Berry

Derrick Freeman

The following planning committee members’ educational unit does not have a financial interest or affiliation with an organization that may receive direct benefit from the subject of the proposed CME activity, and they will not be personally compensated for their role in the planning or execution of this proposed CME activity by an

i ti th th Th Ohi St t U i itorganization other than The Ohio State University:

Jame Allen, MD

Barbara Berry

Derrick Freeman

Speaker DisclosuresSpeaker Disclosures• The following presenters for this educational activity disclose that they have the following relationships with commercial interests to disclose.

Thomas Olencki DOThomas Olencki, DO

Advisory Board Membership – GenentechGrants/Research support – Genentech, Bristol Myers-Squibb

David Carr, MD – Consultant – Healthy Advice

D Ol ki’ t ti ill i l d di i f• Dr. Olencki’s presentation will include discussion of unapproved or “off-label” usage of commercial products and/or services

Thomas Olencki, DO

David Carr, MD

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Agenda Disclaimer

CCME presents this activity for educational purposes only. Participants are expected to utilize their own expertise and judgment while engaged in the practice of medicine The

Agenda Disclaimer

CCME presents this activity for educational purposes only. Participants are expected to utilize their own expertise and judgment while engaged in the practice of medicine Thejudgment while engaged in the practice of medicine. The content of the presentations is provided solely by presenters who have been selected for presentations of recognized expertise in their field.

No further reproduction or distribution is permitted by electronic transmission or any other means The presentations during this

judgment while engaged in the practice of medicine. The content of the presentations is provided solely by presenters who have been selected for presentations of recognized expertise in their field.

No further reproduction or distribution is permitted by electronic transmission or any other means The presentations during thistransmission or any other means. The presentations during this webcast are the intellectual property of the presenter and require his/her permission for further use.

This activity will review the treatment of Skin Cancer.

transmission or any other means. The presentations during this webcast are the intellectual property of the presenter and require his/her permission for further use.

This activity will review the treatment of Skin Cancer.

The Ohio State University Medical CenterMedical Center

Arthur G. James Cancer Hospital and Solove Research Institute

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Skin CancerSkin Cancer

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Thomas Olencki, DO David Carr, MD

Jim Allen, MDProfessor of Internal MedicineThe Ohio State University Medical Center

Jim Allen, MDProfessor of Internal MedicineThe Ohio State University Medical Center

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ccme.osu.educcme.osu.eduCME tracking, 24/7, current therapies, post-tests

Madison, WisconsinPhoto by Dori

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Thomas Olencki, DODavid Carr, MD

Thomas Olencki, DODavid Carr, MD

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Melanoma

Photo by

Basal Cell Carcinoma

Squamous Cell Carcinoma

Photo byJames Heilman, MD

Challenges with Challenges with gtreating

melanoma with chemotherapy

gtreating

melanoma with chemotherapychemotherapychemotherapy

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you are invited to participate

you are invited to participate

and email us with your questions

and email us with your questions

EMAILEMAIL

MohsMohs Surgery: Overview & Surgery: Overview & IndicationsIndications

MohsMohs Surgery: Overview & Surgery: Overview & IndicationsIndicationsIndicationsIndicationsIndicationsIndications

David Carr, MDAssistant Professor

Division of DermatologyThe Ohio State University College of Medicine

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Video PresentationVideo Presentation

Mohs Surgery


Q & A with Dr. David Carr

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Dr. David Carr’s Key Point

Prognosis ofPrognosis ofPrognosis of metastatic melanoma

Prognosis of metastatic melanoma

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Review of 2 New Meds for Review of 2 New Meds for Therapy of Therapy of MetasticMetastic

MelanomaMelanoma

Review of 2 New Meds for Review of 2 New Meds for Therapy of Therapy of MetasticMetastic

MelanomaMelanomaMelanoma Melanoma Melanoma Melanoma

Thomas Olencki, DOClinical Professor of MedicineDivision of Medical Oncology

Ohio State University College of Medicine

FDA Approved Drugs For Treatment Of Metastatic Melanoma

FDA Approved Drugs For Treatment Of Metastatic Melanoma

• Dacarbazine (DTIC) – 1975

• Interleukin-2 (IL-2) – Jan 1998

• Yervoy (ipilimumab) – March 2010Yervoy (ipilimumab) March 2010

• Zelboraf (vemurafenib) – August 2011

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MAP Kinase Pathway And Targeted Therapy


growth factor

shc

Grb

SOS

RAS

BRAF

growth factor

tyrosine kinase

MEKCancercellnucleus ERK

DNAtranscription



growth factor

shc

Grb

SOS

RAS

BRAF

growth factor

tyrosine kinase

B raf inhibitors


DNAtranscription

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growth factor

shc

Grb

SOS

RAS

BRAF

growth factor

tyrosine kinase

B raf inhibitors


DNAtranscription

MEK inhibitors

B raf MutationB raf Mutation• Found in 50% of cutaneous melanomas

– Most commonly V600 E B raf mutation

R lt i b tit ti f l t i id f• Results in a substitution of glutamic acid for valine at codon 600

– May also have a B raf V 600K and B raf V 600R

– Present in the entire spectrum of melanoma (primary to mets)

Activating mutation– Activating mutation

– Translocates to mitochondria where it binds to and inactivates Bad

• Net effect is to decrease melanoma apoptosis

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B raf MutationB raf Mutation

• Drugs designed to inhibit site

– Sorafenib (Nexavar®) bound to non-mutated B raf not active in melanoma

– Vemurafenib (Zelboraf®) (RO 5185426, PLX 4032)

– GSK 2118436

Phase III 1st Line Vemurafenib vs Dacarbazine


Open 1/2010 to 12/2010

RANDO

Vemurafenib 960 mg BID PO

DTIC IV

675 pts withB raf

mutationmetastatic melanoma

336 pts

336 ptsMIZE

DTIC IV

Chapman, NEJM 364:2507, 2011

melanoma 336 pts

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vemurafenib

Waterfall Plot of Best Tumor Response Waterfall Plot of Best Tumor Response

d b idacarbazine

Chapman, NEJM 364:2507, 2011



• Results vemurafenib DTIC Kornvemurafenib DTIC Korn

median PFS 5.3 mos 1.6 mos 1.7

median OS not reached 7.9 mos 6.2

12 mos survival 44% 25% 26%

24 mos survival 22% 14%

RR 48% 6%RR 48% 6%

Control rate* 22% 11%

* CR, + PR, + SD

Chapman, NEJM 364:2507, 2011

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Problems With Current Targeted Therapy

Problems With Current Targeted Therapy

• Blocking B raf may up regulate C raf and other pathways

• B raf and MEK inhibitors “work” only if mutation present

• Significant clinical resp. usually of short duration

– alternative signaling pathways take over– alternative signaling pathways take over

• Multiple signal transduction pathways may need to be blocked simultaneously

– but this may increase side effects or “off target” effects

PI3 And MAP Kinase InhibitorsPI3 And MAP Kinase Inhibitors

PI3KPIP-3

growth factor receptor

PI3KAkt

mTOR

p70s6k

Ras

B raf

MEK

PTEN

DNAtranscription

↓ cyclin D(G1S)

HIF Cox-2 angiogenesisand other protein translation

MEK

ERKtumor

nucleus

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PI3KPIP-3


PI3KAkt

mTOR

p70s6k

Ras

B raf

MEK

PTEN

DNAtranscription

↓ cyclin D(G1S)


MEK

ERKtumor

nucleus


PI3KPIP-3


PI3KAkt

mTOR

p70s6k

Ras

B raf

MEK

PTEN

DNAtranscription

C raf

↓ cyclin D(G1S)


MEK

ERKtumor

nucleus

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PI3KPIP-3


PI3KAkt

mTOR

p70s6k

Ras

B raf

MEK

PTEN

DNAtranscription

C raf

↓ cyclin D(G1S)


MEK

ERKtumor

nucleus


PI3KPIP-3


X PI3KAkt

mTOR

p70s6k

X

Ras

B raf

MEK

PTEN

DNAtranscription

C raf

↓ cyclin D(G1S)


MEK

ERKtumor

nucleus

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So, what is all the news about?

ASCO 2010Sunday June 6, 2010

Cytotoxic T Lymphocyte Assoc Protein-4 (CTLA-4)


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Ag presentingDendritic cell

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MHC II Ag




MHC II Ag

CD 80 B 7.1CD 86 B 7.2

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MHC II Ag

CD 80 B 7.1CD 86 B 7.2




MHC II Ag

CD 80 B 7.1

Activated T Cell

CD 86 B 7.2

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MHC II Ag TCR

CD 80 B 7.1

Activated T Cell

CD 86 B 7.2




MHC II Ag TCR

CD 80 B 7.1

Activated T Cell

CD 86 B 7.2

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MHC II Ag TCRCD 28 – T cell stimulation (with IL-2 production)

CD 80 B 7.1

Activated T Cell

(with IL 2 production)CD 86 B 7.2





CD 80 B 7.1

Activated T Cell


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CD 80 B 7.1

Activated T Cell


CTLA-4 – T cell inhibition (induction of tolerance)





CD 80 B 7.1

Activated T Cell



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CD 80 B 7.1

Activated T Cell



CTLA-4 (2)CTLA-4 (2)


MHC II Ag TCRCD 28 – Unopposed T cell stimulationCD 80 B 7.1

Activated T Cell

CD 86 B 7.2 Unopposed autoimmune effects:- uveitis- rash and vitiligo- pan hypo-pituitarism - diarrhea and colitis- hepatitis

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CTLA-4 (3)CTLA-4 (3)

• anti-CTLA-4 MoAbh i d I G1k– humanized IgG1k

– T1/2 20 - 30 days

– BMS/ Medarex - MDX 010 - ipilimumab

• Breaks tolerance – removes the “b k “ T ll“brake “ on T cells– decreases T reg number and function

(↓ IL-10 and TGFβ)

Phase III MDX010-20 – 2nd Line Tx


Open 9/2004 – 8/2008Double blind

All drugs q 3wks x 4 doses(3:1:1; for ipi, ipi & gp100 and

RANDOM

Ipilimumab 3 mg/kg IV

Ipilimumab 3 mg/kg IV & gp 100

gp100 alone)676 pts with prior treatedmetastatic melanoma

70% h d MIZE

Hodi, NEJM 363:711, 2010

70% hadM1c poor risk

visceral disease

gp 100 vaccine

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• Results ipi ipi and gp100 gp100 Korn

PFS 2.8 mos 2.8 mos 2.8 mos 1.7

med OS 10.1 mos 10 mos 6.4 mos 6.2

12 mos 46% 44% 25% 26%

24 mos 24% 22% 14%

RR 11% 6% 2%

Control rate* 29% 22% 11%

* CR, + PR, + SD

Hodi, NEJM 363:711, 2010

MDX010-20 IpilimumabMDX010-20 Ipilimumab• Toxicity

– 60% had immune related adverse events30% diarrhea/colitis (an grade) lasting a– 30% diarrhea/colitis (any grade) lasting a median of 2.3 wks (after steroids begun)

– 10-15% of pts have gr. 3 and 4 immune toxicity

– cutaneous – maculopapular rash and vitiligo

• Deaths – 14 pts (2%) of drug side effects• Unique feature – pts who progress may be re-

challenged and still have a chance of response

Hodi, NEJM 363:711, 2010

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Phase III Ipilimumab +/- Dacarbazine – 1st Line

Phase III Ipilimumab +/- Dacarbazine – 1st Line

R

Open 8/2006 to 1/2008RANDOM

Ipilimumab 10 mg/kg IV + DTIC

DTIC 850 mg/m2

250 pts

252 pts

All drugs q 3wks x 4

502 pt with untreated

metastatic melanoma M

IZE

DTIC 850 mg/m 252 pts

Robert, NEJM 364:2517, 2011

Maintenance givenin pts with stable to responding disease



Results ipi and DTIC DTIC Korn

PFS (stat significant) 2.8 mos 2.6 mos 1.7

med OS 11 mos 9 mos 6.2

12 mos 47% 36% 26%

24 mos 29% 18%

RR (duration) 15% (19 mos)10% (8 mos)

Control rate* 33% 30%

* CR, + PR, + SD

Robert, NEJM 364:2517, 2011

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Which Is Better –High Dose IL-2 Or Ipilimumab?


• HD IL-2– In pt treatment– Side effects stop with drug

infusion– 4% complete response rate (may

be increased with surgery)– Pts need to be in good physical

condition



• Ipilimumab• Ipilimumab– Out pt treatment– Side effects continue for weeks– 0.5 to 1% complete response rate– May be done in a pt with Tx brain

mets or with less physical reserve

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ConclusionsConclusions• Because of short response and short survival

upon progression, B raf inhibitors will need to be given in combination or sequentially with be g e co b at o o seque t a y tother drugs

• Uncertainty remains – re the effect of dacarbazine given in

combination with ipi– whether ipi should be given 1st or 2 nd line

h th i i h ld b i i bi ti– whether ipi should be given in combination or sequentially with other drugs

• As optimal therapy remains lacking, pts should be treated on clinical trials as much as possible

Signs and Signs and gsymptoms of

recurrent melanoma

gsymptoms of

recurrent melanomamelanomamelanoma

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Skin cancer Skin cancer prevention: Advice for patients

prevention: Advice for patientspatientspatients

Immuno-Immuno-Immuno-suppression and

skin cancer

Immuno-suppression and

skin cancer

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Squamous cell carcinoma and

basal cell

Squamous cell carcinoma and

basal cellbasal cell carcinoma: the

role of the

basal cell carcinoma: the

role of the medical

oncologistmedical

oncologist

© The Ohio State University Medical Center, 2011© The Ohio State University Medical Center, 2011

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