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New and Emerging Therapies for
metastatic
melanoma
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
CME Information
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
Polling Question 1
Pre-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 2
Case 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 3
Case 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
Tumor
Microenvironment
MHC
B7
B7
TCR
TCR
+++
MHC
+++
CD28
+++
CTLA-4
---
---
PD-1
PD-L1
anti-PD-1
anti-CTLA-4
PD-1
PD-L2
--anti-PD-1
CTLA-4 Blockade
PD-1 Blockade
FDA-approved Checkpoint
Blocking Antibodies
Antibody
Trade name
Target
Ipilimumab
Yervoy
CTLA4
Keytruda
PD1
Opdivo
PD1
Pembrolizumab
Nivolumab
Ipilimumab vs gp100 Vaccine vs Both: OS and ORR
Response rates
Adapted from Hodi FS et al. N Engl J Med. 2010;363:711.
Ipi
alone
Ipi +
vaccine
Vaccine
alone
11%
5.7%
1.5%
Dacarbazine ± Ipilimumab: OS and ORR
Response rates
Ipi + DTIC
DTIC alone
15.2%
10.3%
Adapted from Robert C et al. N Engl J Med. 2011;364:2517.
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
Delayed Response with Ipilimumab Treatment
Pre-treatment
10/06 (Week 12)
4 blinded doses
ipilimumab
12/06
No drug
5/07
4 10 mg/kg doses
ipilimumab
Ipilimumab Toxicities
Toxicity
Signs/symptoms
Treatment
Colitis
Watery diarrhea, bowel wall
edema on CT
Systemic 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
Pembrolizumab
Nivolumab
Trade name
Keytruda
Target
PD1
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 + Nivolumab
Change 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 Toxicities
Same as Ipi Except Less Common, Plus Pneumonitis
Toxicity
Signs/symptoms
Treatment
Pneumonitis
Dyspnea, cough, infiltrates
Systemic steroids
Colitis
Watery diarrhea, bowel wall
edema on CT
Systemic 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 acuity
Ophthalmology consult
Adrenalitis
Fatigue
Systemic steroids
Key Take Away
• Anti-PD1 antibodies (pembrolizumab and nivolumab) have
higher response rates and lower incidences of immunerelated 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.
Ipilimumab vs Nivolumab vs Both:
Adverse Events
Larkin J et al. N Engl J Med 2015;373:23-34
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
3+
1+
1+
4+
Toxicity
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 4
Case 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 5
Case 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
BRAF
Inhibitors
Vemurafenib
Dabrafenib
Encorafenib
Modified from Ribas et al. Nat Rev Clin Oncol. 2011;8:426.
MEK
Inhibitors
Trametinib
Cobimetinib
Binimetinib
FDA-approved Molecularly Targeted
Therapies
Drug
Vemurafenib
Dabrafenib
Trametinib
Trade name
Zelboraf
Tafinlar
Mekinist
Target
BRAF
BRAF
MEK
Treating BRAFV600E Mutant Melanoma with
a BRAF Inhibitor Leads to Rapid Response
Baseline
Day 15
McArthur et al. J Clin Oncol. 2012;30:1628.
Vemurafenib vs Dacarbazine (DTIC):
OS, PFS, and ORR
Vemu
DTIC
ORR
56.9%
8.6%
mPFS
6.9 months
1.6 months
mOS
13.6 months
9.7 months
Chapman et al. N Engl J Med. 2011;364:2507.
*V600E
mutation
only
Antitumor Activity of Vemurafenib vs DTIC
48% confirmed response rate
(2 complete responses)
5% confirmed response rate
(0 complete responses)
Chapman et al. N Engl J Med. 2011;364:2507.
Activity of RAF inhibitor in BRAF-mutated
melanoma with brain metastases
Baseline
Courtesy of Chapman P and Memorial Sloan Kettering Cancer Center.
Week 32
BRAF Inhibitor Toxicity: Cutaneous Squamous
Carcinomas, Keratoacanthoma Type
Median
0
5
10
15
20
25
30
35
Time on vemurafenib (weeks)
• Median time 8 weeks (range 2–36)
• Each dot represents weeks to development of first lesion
Ribas et al. Proc ASCO. 2011; abstract 8509.
40
Dabrafenib ± Trametinib: PFS and ORR
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
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.
Dabrafenib + Trametinib vs Vemurafenib: OS
HR 0.69 (95% CI 0.53-0.89) P=0.005
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
ORR (approx.)
OS
Toxicity
Vemurafenib
Dabrafenib
Trametinib
Dabrafenib +
Trametinib
combination
51%
53%
22%
69%
17 mos median
65% 1 year
19 mos median
68% 1 year
42% 2 years
Not reported
25 mos median
74% 1 year
51% 2 year
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!