Transcript PowerPoint slides - Research To Practice

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Oncology Grand Rounds
Melanoma
Nurse and Physician Investigators
Discuss New Agents, Novel Therapies
and Actual Cases from Practice
Saturday, April 30, 2016
6:00 AM – 7:30 AM
Faculty
Katherine Benchich, MSN, ANP, OCN
Adil Daud, MD
Rene Gonzalez, MD
Jason J Luke, MD
Kathleen Madden, MSN, FNP,
AOCNP, APHN
Moderator
Neil Love, MD
Oncology Grand Rounds Series
Oncology Grand Rounds: Themes
• New agents and treatment strategies: Benefits and risks
• Counseling patients about side effects
– Practical implementation
• End-of-life care
• Psychosocial issues in patient care
• Supporting the supporters
• Job satisfaction and burnout in oncology professionals
• The oncology professional just entering practice
• The bond that heals
Courtesy of Christiana Care Health System
Module 1:
Overview of Melanoma;
Surgery and Adjuvant
Therapy for Localized
Disease
60-Year-Old Man with In-Transit Metastatic
Melanoma (Ms Madden)
• 2013: Diagnosed with melanoma on his mid back
• Wide-margin surgical excision
• Sentinel lymph node biopsy: Negative
• 2015: Biopsy/PET-CT — melanoma on right scapula
– Wide excision of in-transit metastasis and splitthickness skin graft from the right thigh
• Adjuvant ipilimumab
– Gastrointestinal toxicity after the third dose
• A pastor with many resources, but his sister and wife
need much emotional support
Case discussion points (Ms Madden)
• How did the patient tolerate the surgical
procedures that accompanied the original
melanoma diagnosis?
• How does this presentation compare to how most
patients present with melanoma?
Risk Factors for Melanoma
• Sun exposure
• Pigmentary characteristics
• Multiple nevi
• Family and personal history of melanoma
• Immunosuppression
• Environmental exposures
PDQ Cancer Information Summaries 2002-2016 Feb 2
Ipilimumab: Mechanism of Action
T-cell activation
T cell
T-cell inhibition
T cell
T cell
CTLA4
TCR
CD28
MHC
B7
APC
T-cell potentiation
CTLA4
TCR
TCR
CD28
MHC
APC
CTLA4
X
CD28
B7 CD28
MHC
B7
IPILIMUMAB
binds
CTLA-4
APC
TCR = T-cell receptor; MHC = major histocompatibility complex; APC = antigen presenting
cell; CTLA-4 = cytotoxic T-lymphocyte associated antigen-4
Fong et al, 2008.
Courtesy, Kathy Madden, MSN, FNP, AOCNP, APHN
Module 2:
Intralesional Therapy for
Subcutaneous Dermal and
Nodal Disease — Use of
Talimogene Laherparepvec
(T-VEC)
Discussion Topics
• Clinical spectrum of subcutaneous, dermal and
nodal involvement of melanoma
• Mechanism of action of T-VEC, an injectable
herpes simplex virus 1-based oncolytic virus
• Review of efficacy and safety data with T-VEC,
including the pivotal trial that led to the recent FDA
approval
• Local and systemic effects of T-VEC; integration
into the management of malignant melanoma
Discussion Topics
• Patient identification and selection for therapy with
T-VEC: Contraindications, precautions and
recommendations pertaining to concomitant
antiviral therapy
• Practical considerations for storage, handling,
administration and dosing of T-VEC
• Active trials of T-VEC and other investigational
injectable agents, such as PV-10 and SCIB1
58-Year-Old Man with BRAF V600R-Mutant
Metastatic Melanoma (Ms Benchich)
• 2011: Primary melanoma on the scalp
– Widely excised
– Sentinel lymph node biopsy: Negative
• 4/2015: Multiple bilateral pulmonary metastases
– Fine needle aspiration of a scalp nodule was positive for
melanoma with a BRAF V600R mutation
• Clinical trial: Ipilimumab and T-VEC
– 1 subcutaneous nodule on the scalp was injected, with
initial clinical response, before ipilimumab was
administered
– Grade 3 diarrhea after the first ipilimumab infusion, which
was treated with prednisone and infliximab
• He lives alone and owns a business
Determination of T-VEC Injection Volume Based
on Lesion Size
Lesion size
(longest dimension)
Injection volume
>5 cm
Up to 4 mL
>2.5 cm to 5 cm
Up to 2 mL
>1.5 cm to 2.5 cm
Up to 1 mL
>0.5 cm to 1.5 cm
Up to 0.5 mL
≤0.5 cm
Up to 0.1 mL
Talimogene laherparepvec package insert
T-VEC: An HSV-1-Derived Oncolytic Immunotherapy
Designed to Produce Local and Systemic Effects
Local Effect:
Virally-Induced Tumor Cell Lysis
Selective viral
replication in
tumor tissue
Tumor cells
rupture for an
oncolytic effect
Systemic Effect:
Tumor-Specific Immune Response
Systemic
tumor-specific
immune response
Courtesy, Jason J Luke, MD
Death of distant
cancer cells
Kaufman et al. ASCO (2014);Abstract LBA9008
Talimogene Laherparepvec: Proposed
Mechanism of Action for Systemic Immunologic
Effect
1
Inside a healthy cell, the
virus ( ) is unable to
replicate, leaving the cell
unharmed.
2
Inside a cancer cell, the
virus replicates and
secretes GM-CSF ( ) until
the cells lyses, releasing
more viruses, GM-CSF
and antigens ( ).
3
GM-CSF attracts dendritic
cells to the site, which
process and present the
antigens to T cells. The
T cells are now
“programmed” to identify
and destroy cancer cells
throughout the body.
T cells destroy
cancer cells
throughout the
body, including
those not
directly injected
with the virus.
T cells
Dendritic cell
T cells destroy
noninjected
cancer cells
Adapted from Kaufman H et al. Ann Surg Oncol 2010;17(3):718-30.
Recommended T-VEC Dose and Schedule
Treatment
interval
Max.
injection
volume/vis
it
—
Second
All
subsequent
treatments
Treatment
Initial
Dose
strength
Prioritization of
lesions for injection
4 mL
106
PFU/mL
• Largest lesion(s) first
• Prioritize remaining
lesions by size until max.
injection volume reached
or all lesions treated
3 wk after
initial
4 mL
108
PFU/mL
• New lesions since initial
treatment
• Prioritize remaining
lesions as above
2 wk after
previous
4 mL
108
PFU/mL
• New lesions since
previous treatment
• Prioritize remaining
lesions as above
Talimogene laherparepvec package insert
T-VEC Injection Procedure
1. Intralesional injection using a single insertion point, along
multiple tracks as far as the radial reach of the needle
allows.
a. Multiple insertion points may be used if a lesion is larger
than the needle’s radial reach.
2. Inject evenly and completely within the lesion by pulling the
needle back without exiting the lesion.
a. Redirect the needle as needed while injecting the
remainder of the dose.
b. Continue until the full dose is evenly and completely
dispersed.
3. Withdraw the needle from the lesion slowly to avoid leakage
at the insertion point.
Talimogene laherparepvec package insert
Practical Considerations for the Preparation
and Handling of T-VEC
• Pregnant or immunocompromised healthcare
professionals should avoid exposure
• Proper thawing and storage important
• Biohazard precautions for preparation, administration and
handling necessary
– Personal protective equipment
– Avoidance of accidental exposure
– Proper disposal of materials (both for healthcare
providers and patients)
Talimogene laherparepvec package insert
Locoregional Responses to T-VEC
Baseline
12 months
Andtbacka RHI et al. Proc ASCO 2013;Abstract LBA9008.
Locoregional Responses to T-VEC
Baseline
Andtbacka RHI et al. Proc ASCO 2013;Abstract LBA9008.
1 year
T-VEC Injection Sites
1 month
Andtbacka RHI et al. Proc ASCO 2013;Abstract LBA9008.
12 months
Phase III Trial of T-VEC versus GM-CSF
Overall Survival (ITT)
T-VEC
189/295 (64)
23.3
GM-CSF
101/141 (72)
18.9
Overall Survival (%)
Events/n (%)
Median (95% CI)
OS in months
Stage IIB, IIC, or IVM1a
Log-rank P = .051
Hazard ratio, 0.79
Andtbacka RHI et al. J Clin Oncol 2015;33(25):2780-8.
Treatment-naïve
T-VEC
41.1
33.1
GM-CSF
21.5
17.0
Phase III Trial of T-VEC versus GM-CSF
Duration of Response
CR
PR
Censored
Durable response rate
T-VEC:
16.3%
GM-CSF:
2.1%
15
12
9
6
3
0
3
6
9
12
Duration of Response (months)
GM-CSF
Andtbacka RHI et al. J Clin Oncol 2015;33(25):2780-8.
Talimogene laherparepvec
15
T-VEC Side Effects
Most Common AEs
• Fatigue
• Chills
• Pyrexia
Grade 3 or 4 AEs
• Only cellulitis (2.1%)
No fatal treatment-related AEs
Andtbacka RHI et al. J Clin Oncol 2015;33(25):2780-8.
Module 3:
Management of Metastatic
Disease (Part 1) — Use of
BRAF and MEK Inhibitors
Discussion Topics
• Biologic rationale and current indications for combined
BRAF and MEK inhibition in metastatic melanoma
• Selection of a BRAF and MEK inhibitor combination for
patients with metastatic melanoma:
Dabrafenib/trametinib versus vemurafenib/cobimetinib
• Incidence of photosensitivity reactions and
dermatotoxicities with available BRAF inhibitors and
combinations
• Prevalence and management of pyrexia associated with
dabrafenib/trametinib
• Choosing between immunotherapy and anti-BRAF
therapy for patients with BRAF tumor mutations
Systemic Therapy for Metastatic Melanoma
Historical Standards
•
Dacarbazine (DTIC)
•
Biochemotherapy with IL-2
•
High-dose bolus IL-2
•
Carboplatin/paclitaxel
•
Temozolomide
Recently Approved —
Immunotherapy
Recent Approved —
Targeted Therapy
•
Ipilimumab
•
Dabrafenib
•
Pembrolizumab
•
Vemurafenib
•
Nivolumab
•
Trametinib
•
Nivolumab-ipilimumab
•
Dabrafenib-trametinib
•
Vemurafenib-cobimetinib
52-Year-Old Woman with BRAF V600E-Mutant
Metastatic Melanoma (Ms Madden)
• Ulcerated melanoma on the right calf
– Workup: BRAF V600E mutation-positive
metastatic disease in the stomach, bowel and
brain
• 6/2014: Dabrafenib 150 mg BID and trametinib 2
mg daily
– Complete clinical response with minimal
tolerability issues
– Remains on treatment
• Works full time as a pediatric nurse
• Married with 3 young children
BRAF Inhibitor Mechanism of Action
Webber, 2011
Courtesy, Kathy Madden, MSN, FNP, AOCNP, APHN
“Best Practices”
Patient Education and AE Management
• Educational sessions
– Review specific mechanisms of selected treatment
– Pre-treatment and at each office visit/encounter
• Assess patients ability to communicate symptoms
– Language barrier
– Access to phone; computer
• Provide a calendar or treatment schedule
– Follow-up visits
– Important time points
• Encourage patients to keep a treatment diary
• Provide prescription medications and encourage having medications on
hand for anticipated AEs
Ledezma, 2009, Rubin 2012.
Courtesy, Kathy Madden, MSN, FNP, AOCNP, APHN
“Best Practices”
Patient Education and AE Management (cont.)
• Thorough physical assessment and evaluation of adverse
effects
– Baseline and at each office visit
• Educate patients to contact provider at the onset of adverse
effects or changes in condition from baseline
• At each office visit review the relevant potential adverse
effects of therapy
• Provide support for patients experiencing the unique patterns
of adverse events associated with new novel therapies
Ledezma, 2009, Rubin 2012.
Courtesy, Kathy Madden, MSN, FNP, AOCNP, APHN
Dabrafenib/Trametinib in Untreated V600E or
V600K BRAF-Mutant Metastatic Melanoma
Overall survival (%)
Similar rates of AEs between groups
• Except less hyperkeratosis,
cutaneous squamous cell carcinoma,
new primary melanomas and noncutaneous treatment-emergent
cancers for the combination
Dabrafenib and trametinib
Dabrafenib and placebo
OS
Dabrafenibtrametinib
(n = 211)
Dabrafenib
(n = 212)
Hazard
ratio
P-value
25.1 mo
18.7 mo
0.71
0.01
Time (months)
Long GV et al. Lancet 2015;386:444-51.
Select Adverse Events Associated with the
Dabrafenib-Trametinib Combination
Dabrafenib/trametinib
(n = 209)
Dabrafenib/placebo
(n = 211)
Any grade
Grade 3
Any grade
Grade 3
Pyrexia
52%
7%
25%
2%
Fatigue
27%
2%
28%
<1%
AST (aspartate
aminotransferase) increase
11%
3%
3%
<1%
Peripheral edema
11%
1%
2%
0
ALT (alanine aminotransferase) increase
10%
2%
3%
0
Adverse event
Long GV et al. Lancet 2015;386:444-51.
Survival Distribution Function (%)
coBRIM: Updated Survival Analyses of
Cobimetinib with Vemurafenib in BRAF-Mutated
Advanced Melanoma
ITT population
PFS events, n (%)
Median PFS, months
HR*
Cobi + vem
n = 247
Pbo + vem
n = 248
143 (57.9)
180 (72.6)
12.25
7.20
0.58
* Stratified HR
+
Cobimetinib + vemurafenib (n = 247)
Placebo + vemurafenib (n = 248)
Censored
Time
The final OS analysis demonstrated that cobimentib + vemurafenib reduced the risk of death
by 30% compared to vemurafenib + placebo (median OS, 22.3 mo vs 17.4 mo).
Larkin JMG et al. Proc ASCO 2015;Abstract 9006; Atkinson V et al. Abstract presented at the 12th
International Congress of the Society of Melanoma Research.
coBRIM: Select Adverse Events Associated with
Cobimetinib/Vemurafenib
Vemurafenib/cobimetinib
(n = 254)
Adverse event
Vemurafenib/placebo
(n = 239)
Grade 1/2
Grade 3/4
Grade 1/2
Grade 3/4
Diarrhea
50%
6%
28%
0
Rash
33%
6%
30%
5%
Photosensitivity reaction
26%
2%
15%
0
Pyrexia
24%
2%
22%
0
Hyperkeratosis
10%
0
27%
2%
Larkin J et al. N Engl J Med 2014;371(20):1867-76.
Module 4:
Management of Metastatic
Disease (Part 2) — Use of
Checkpoint Inhibitors
Discussion Topics
• Biology of the immune system; mechanisms of
action of various immunotherapy agents
• Efficacy and tolerability/toxicity of anti-CTLA-4
antibodies, anti-PD-1/PD-L1 antibodies and the
combination in melanoma: Current approved
indications
• Sequencing immunotherapy and other systemic
therapies for patients with metastatic disease
• Role of immunotherapeutic approaches for patients
with underlying autoimmune disorders (eg, Crohn’s
disease, rheumatoid arthritis)
63-Year-Old Woman with BRAF Wild-Type
Metastatic Melanoma (Ms Benchich)
• 2011: 2-cm thick desmoplastic melanoma on the
scalp
– Excision and postoperative radiation therapy
– Sentinel lymph node biopsy: Negative
• 2013: Multiple BRAF wild-type pulmonary nodules
• Ipilimumab  disease progression
• Pembrolizumab with a complete response
– Remains on treatment
• Before her diagnosis her daughter died of
metastatic melanoma
KEYNOTE-006: OS with Pembrolizumab versus
Ipilimumab in Advanced Melanoma
Pembrolizumab Q3W
Overall Survival (%)
Pembrolizumab Q2W
Ipilimumab
1-year survival
Pembrolizumab q2wk
Pembrolizumab q3wk
Ipilimumab
74.1%
68.4%
58.2%
Months
Robert C et al. N Engl J Med 2015;372:2521-32.
HR = 0.63, p<0.0005
HR = 0.69, p=0.0036
KEYNOTE-002: PFS with Pembrolizumab versus
Chemotherapy for Ipilimumab-Refractory
Melanoma
Pembro 2mg/kg
(n = 180)
Pembro 10mg/kg
(n = 181)
Chemo
(n = 179)
HR (PFS)
0.57, p<0.0001
0.50, p<0.0001
Reference
6-month PFS
34%
38%
16%
Months
Ribas A et al. Lancet Oncol 2015;16:908-18.
Nivolumab
#
ORR=32%
ICC
Patients (responders)
CheckMate-037: Time to and Duration of
Response with Nivolumab versus
Chemotherapy in Advanced Melanoma
ORR=11%
Time (weeks)
Weber JS et al. Lancet Oncol 2015;16(4):375-84.
On treatment
Off treatment
First response
Censored
Death
69-Year-Old Woman with BRAF Wild-Type
Metastatic Melanoma (Ms Benchich)
• 2011: Diagnosed with primary melanoma
• 6/2015: Lumbar mass, diagnosed with metastatic
BRAF wild-type disease
• Ipilimumab/nivolumab
– Rapid clinical complete response
– Adrenal insufficiency and hypothyroidism
– Continues to receive single-agent nivolumab
CheckMate-067: Nivolumab, Ipilimumab or the
Combination in Untreated, Unresectable or
Metastatic Melanoma
Median tumor burden change = -51.9%
Nivo alone = -34.5%
Ipi alone = 5.9%
Nivo/Ipi
(n = 314)
Nivolumab
(n = 316)
Ipilimumab
(n = 315)
Best ORR (all pts)
58%
44%
19%
PD-L1+
72%
58%
21%
11.5 mo
6.9 mo
2.9 mo
14 mo
14 mo
3.9 mo
Median PFS (all pts)
PD-L1+
Larkin J et al. N Engl J Med 2015;373:23-34.