Prior to the start of the program, check your syllabus to ensure you have the participant survey and CME evaluation:

• In the front of your syllabus• Remove from your packet• Fill out the demographic information at the top• Throughout the program, please take a moment to answer

the corresponding Activity Survey questions on this form (slides will be marked as “Polling Questions” throughout the deck)

Please Help Us with the Following

melano ma me lano ma

metasta tic metasta tic New and Emerging Therapies for

A CME-certified Oncology Exchange Activity

Jointly provided by Potomac Center for Medical Education and Rockpointe Oncology

This activity is supported by educational grants from Genentech and Novartis Pharmaceuticals Corporation

Please note, all pertinent CME information, statements, and disclosures can be found in your program syllabus, including:

• Faculty/Steering Committee and Non-faculty Planner/Reviewer Disclosures

• Educational Objectives• Accreditation and Credit Designation Statements• Faculty/Steering Committee Bios

CME Information

Polling Question 1Pre-activity Survey

How confident are you in your ability to adopt new and emerging therapies for the management of metastatic melanoma?

A. Not at all confident

B. Slightly confident

C. Confident

D. Very confident

E. Expert

Educational Objectives

• Evaluate the efficacy and safety of approved and emerging therapies for metastatic melanoma

• Explain the value of a multidisciplinary approach for the treatment of melanoma to improve patient outcomes

• Recognize the importance of patients actively participating in their treatment decisions and health management

Checkpoint Blockade for Melanoma

Case 1: BRAF Wild-type Melanoma

• A 42-year-old woman is found to have melanoma metastatic to lung and subcutaneous sites

• Her melanoma does not have a BRAF mutation• She has a KPS of 80%• She is overweight and has type II diabetes controlled with

metformin• No other significant medical history

Polling Question 2Case Study 1

Which of the following FDA-approved therapies is associated with the highest response rate for a patient like this?

A. Dacarbazine

B. Vemurafenib

C. High-dose interleukin-2 therapy

D. Either nivolumab or pembrolizumab

E. Ipilimumab

Polling Question 3Case Study 1

The patient is treated with a PD-1 inhibitor and develops diarrhea up to 8 times per day. She otherwise feels well except for a mild rash and fatigue. The best recommendation for this patient is:

A. Imodium and close monitoring

B. Intensive oral hydration until diarrhea resolves

C. Urgent colonoscopy as an outpatient

D. High-dose steroids and close monitoring

Blocking CTLA-4 and PD-1

T cellTumor cell

MHCTCR

PD-L1PD-1- - -

T cell

Dendriticcell

MHCTCR

CD28

B7 CTLA-4- - -

Activation(cytokines, lysis, proliferation,

migration to tumor)

B7+++

+++

CTLA-4 Blockade PD-1 Blockade

anti-CTLA-4 anti-PD-1

Tumor Microenvironment

+++

PD-L2PD-1

anti-PD-1

- - -

FDA-approved Checkpoint Blocking Antibodies

Antibody Trade name Target

Ipilimumab Yervoy CTLA4

Pembrolizumab Keytruda PD1

Nivolumab Opdivo PD1

Ipilimumab vs gp100 Vaccine vs Both: OS and ORR

Adapted from Hodi FS et al. N Engl J Med. 2010;363:711.

Ipi alone

Ipi + vaccine

Vaccine alone

11% 5.7% 1.5%

Response rates

Dacarbazine ± Ipilimumab: OS and ORR

Adapted from Robert C et al. N Engl J Med. 2011;364:2517.

Response rates Ipi + DTIC DTIC alone

15.2% 10.3%

Ipilimumab: Pooled OS Data from Multiple Trials

Schadendorf D et al. J Clin Oncol. 2015;33:1889-1894.

Key Take Away

• Ipilimumab improves overall survival compared to chemotherapy alone

12/06 5/07

4 blinded doses ipilimumab

4 10 mg/kg doses ipilimumab

No drug

Delayed Response with Ipilimumab TreatmentPre-treatment 10/06 (Week 12)

Ipilimumab Toxicities

Toxicity Signs/symptoms TreatmentColitis Watery diarrhea, bowel wall

edema on CTSystemic steroids

Rash/itching Rash/itching Usually antihistamines or topical steroids

Hypophysitis Headache, fatigue, enlarged pituitary on brain MRI

Systemic steroids. Usually will need chronic cortisol and thyroid hormone replacement

Hepatitis Usually asymptomatic; Elevated transaminases

Systemic steroids

Thyroiditis Fatigue Systemic steroids

Uveitis Decreased visual acuity Ophthalmology consult

Adrenalitis Fatigue Systemic steroids

Key Take Away

• Immunotherapy requires close follow-up for immune-related adverse events

FDA-approved Anti-PD1 Antibodies

Antibody Trade name TargetPembrolizumab Keytruda PD1

Nivolumab Opdivo PD1

Antitumor Activity of Pembrolizumab

Hamid O et al. N Engl J Med. 2013;369:134.

Best Overall Response to Nivolumab

Robert C et al. N Engl J Med. 2015;372:320.

Nivolumab vs Dacarbazine: OS and PFS

Robert C et al. N Engl J Med. 2015;372:320.

Pembrolizumab vs Ipilimumab OS and PFS

Robert C et al. N Engl J Med 2015;372:2521

Ipilimumab vs Ipilimumab + NivolumabChange in Tumor Burden, Durability of Tumor Regressions, and Progression-free Survival

Postow MA et al. N Engl J Med. 2015;372:2006.

Ipilimumab vs Nivolumab vs Both: PFS

Larkin J et al. N Engl J Med. 2015;373:23.

Ipi alone Ipi + Nivo Nivo alone

2.9 mos 11.5 mos 6.9 mos

Anti-PD1 Antibody ToxicitiesSame as Ipi Except Less Common, Plus Pneumonitis

Toxicity Signs/symptoms TreatmentPneumonitis Dyspnea, cough, infiltrates Systemic steroidsColitis Watery diarrhea, bowel wall

edema on CTSystemic steroids

Rash/itching Rash/itching Usually antihistamines or topical steroids

Hypophysitis Headache, fatigue, enlarged pituitary on brain MRI

Systemic steroids. Usually will need chronic cortisol and thyroid hormone replacement

Hepatitis Usually asymptomatic. Elevated transaminases

Systemic steroids

Thyroiditis Fatigue Systemic steroidsUveitis Decreased acuity Ophthalmology consultAdrenalitis Fatigue Systemic steroids

Key Take Away

• Anti-PD1 antibodies (pembrolizumab and nivolumab) have higher response rates and lower incidences of immune-related adverse events compared to ipilimumab

Response of a Large Chest-wall Melanoma Metastasis to One Dose of Ipilimumab Plus Nivolumab

Chapman PB et al. N Engl J Med. 2015;372:2073.

Larkin J et al. N Engl J Med 2015;373:23-34

Ipilimumab vs Nivolumab vs Both: Adverse Events

FDA-approved Checkpoint Blocking Antibodies: SUMMARY

Ipilimumab Nivolumab Pembrolizumab Ipi + Nivo combination

ORR (approx.) 11-19% 40-44% 34% 58-61%

OS 11.4 mo ND ND ND

Toxicity 3+ 1+ 1+ 4+

Key Take Away

• Combination ipilimumab + nivolumab have a higher response rate than either drug alone, but much higher incidence of adverse events

Targeted Therapy for Melanoma

Case 2: BRAF-Mutated Melanoma

• A 42-year-old woman is found to have melanoma metastatic to lung and subcutaneous sites

• Her melanoma is found to have a BRAF V600E mutation • She has a KPS of 80%• She is overweight and has type II diabetes controlled with

metformin• No other significant medical history

Polling Question 4Case Study 2

Which of the following FDA-approved therapies is associated with the highest response rate for this patient?

A. Dacarbazine

B. Either vemurafenib or dabrafenib

C. Dabrafenib plus trametinib

D. Either nivolumab or pembrolizumab

E. Ipilimumab

Polling Question 5Case Study 2

Which of the following FDA-approved therapies has been shown to improve overall survival for a patient with metastatic melanoma harboring BRAF V600E mutation:

A. Dabrafenib plus trametinib, nivolumab, IL-2

B. Vemurafenib, dabrafenib plus trametinib, nivolumab

C. Dacarbazine, vemurafenib, pembrolizumab

D. IL-2, vemurafenib, dabrafenib

Blocking BRAF and MEK

Modified from Ribas et al. Nat Rev Clin Oncol. 2011;8:426.

BRAF Inhibitors

VemurafenibDabrafenibEncorafenib

MEK Inhibitors

TrametinibCobimetinibBinimetinib

FDA-approved Molecularly Targeted Therapies

Drug Trade name TargetVemurafenib Zelboraf BRAFDabrafenib Tafinlar BRAFTrametinib Mekinist MEK

Treating BRAFV600E Mutant Melanoma with a BRAF Inhibitor Leads to Rapid Response

McArthur et al. J Clin Oncol. 2012;30:1628.

Day 15

Baseline

Vemurafenib vs Dacarbazine (DTIC):OS, PFS, and ORR

Chapman et al. N Engl J Med. 2011;364:2507.

Vemu DTIC

ORR 56.9% 8.6%mPFS 6.9 months 1.6 monthsmOS 13.6 months 9.7 months

*V600E mutation

only

48% confirmed response rate (2 complete responses)

5% confirmed response rate (0 complete responses)

Antitumor Activity of Vemurafenib vs DTIC

Chapman et al. N Engl J Med. 2011;364:2507.

Activity of RAF inhibitor in BRAF-mutated melanoma with brain metastases

Baseline Week 32

Courtesy of Chapman P and Memorial Sloan Kettering Cancer Center.

• Median time 8 weeks (range 2–36)• Each dot represents weeks to development of first lesion

BRAF Inhibitor Toxicity: Cutaneous Squamous Carcinomas, Keratoacanthoma Type

Ribas et al. Proc ASCO. 2011; abstract 8509.

0 5 10 15 20 25 3530 40

Time on vemurafenib (weeks)

Median

SCC/KAs 9% in monotherapy arm vs 2% in combination arm

Response rate 51% in monotherapy arm vs 67% in combination arm, P=0.002

Dabrafenib ± Trametinib: PFS and ORR

Long et al. N Engl J Med. 2014;371:1877.

Dabrafenib ± Trametinib: PFS – Elevated LDH Patients

Long et al. N Engl J Med. 2014;371:1877.

Vemurafenib ± Cobimetinib: PFS

Larkin et al. N Engl J Med. 2014;371:1867.

Dabrafenib ± Trametinib : OS

Long et al. N Engl J Med. 2014;371:1877.

Dabrafenib ± Trametinib: OS – Elevated LDH Patients

Long et al. N Engl J Med. 2014;371:1877.

HR 0.69 (95% CI 0.53-0.89) P=0.005

Dabrafenib + Trametinib vs Vemurafenib: OS

Robert et al. N Engl J Med. 2015;372:30.

Vemurafenib ± Cobimetinib : OS

Larkin et al. N Engl J Med. 2014;371:1867.

FDA-approved Molecularly Targeted Therapies: SUMMARY

Vemurafenib Dabrafenib TrametinibDabrafenib + Trametinib

combination

ORR (approx.) 51% 53% 22% 69%

OS 17 mos median65% 1 year

19 mos median68% 1 year42% 2 years

Not reported25 mos median

74% 1 year51% 2 year

Toxicity 2+ 2+ 2+ 1+

Based on recent phase III trial data

Key Take Away

• Dabrafenib + trametinib has a higher response rate and better overall survival than dabrafenib alone. The combination regimen also has a higher incidence of fever and fatigue.

Questions?

Participant Survey and CME Evaluation

• CME Evaluation

– If you’re seeking credit, ensure you’ve filled in your name and demographic information on page 1 and complete the CME Evaluation part of your form (after the In-Activity Survey)

– Your answers are important and will help us identify remaining educational gaps and shape future CME activities

– Return all forms to on-site CME staff

Thank you for joining us today!