Transcript PowerPoint slides - Research To Practice

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Oncology Grand Rounds
Non-Small Cell Lung Cancer
Nurse and Physician Investigators
Discuss New Agents, Novel Therapies
and Actual Cases from Practice
Thursday, April 28, 2016
6:00 PM – 8:00 PM
Faculty
Sarah B Goldberg, MD, MPH
John V Heymach, MD, PhD
Amanda E Magnoli, MSN, RN,
ANP-BC, AOCNP
Wendi J Stone, MSN, RN, NP-C
Moderator
Neil Love, MD
Oncology Grand Rounds Series
Recently Approved Agents
November 21, 2012 – April 26, 2016
Immunotherapy
• Nivolumab
• Pembrolizumab
• Ipilimumab
• Blinatumomab
Ovarian Cancer
• Olaparib
• Bevacizumab
Gastrointestinal Cancers
• Liposomal irinotecan (MM-398)
• TAS-102
• Ramucirumab
Lymphomas and CLL
• Belinostat
• Idelalisib
• Ibrutinib
Non-Small Cell Lung Cancer
Melanoma
• Osimertinib
• Afatinib
• Ceritinib
• Necitumumab
• Nivolumab
• Ramucirumab
• Talimogene laherparepvec
• Cobimetinib/vemurafenib
• Nivolumab
• Pembrolizumab
• Crizotinib
• Alectinib
Breast Cancer
• Palbociclib
• T-DM1
• Pertuzumab
www.fda.gov; www.centerwatch.org
Bladder Cancer
• Obinutuzumab
• Ofatumumab
• Venetoclax
• Pembrolizumab
• Dabrafenib
• Trametinib
• Ipilimumab
Recently Approved Agents
November 21, 2012 – April 26, 2016
Non-Small Cell Lung Cancer
• Osimertinib
• Afatinib
• Ceritinib
• Necitumumab
• Nivolumab
• Ramucirumab
• Pembrolizumab
• Crizotinib
• Alectinib
www.fda.gov; www.centerwatch.org
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
Overview of Lung Cancer
• Estimated number of new cases and deaths in 2016:
– New cases = 224,390
– Deaths = 158,080
• Stage at diagnosis (percent of patients who present
with):
– Stage I disease = 13%
– Stage II disease = 7%
– Stage III disease = 25%
– Stage IV disease = 55%
• 53% men, 47% women
• Five-year survival estimates (2005-2011) = 18%
Cancer Facts and Figures 2016; cruk.org/cancerstats
2016: Evolving Identification of Molecular
Subsets in Lung Adenocarcinoma
Large cell
No mutations
detected
38%
Squamous
KRAS 24%
Small cell
Adenocarcinoma
AKT1
NRAS
ALK 8%
MEK1
HER2
MET
AMP PIK3CA
DOUBLE
BRAF MUTANTS
Kris MG et al. JAMA 2014;311(19):1998-2006.
EGFR 17%
Module 1:
Management of EGFR
Mutation-Positive NSCLC
Discussion Topics
• Overview of lung cancer: Histologic subtypes and genomic
assays, tumor mutations and gene rearrangements;
algorithms for tissue testing
• Types of EGFR mutations and clinical implications (exon
19 deletion, exon 21 L858R mutation, exon 20 insertion)
• Options for first-line treatment
• Side effects of EGFR tyrosine kinase inhibitors
• Relevance of T790M mutations and considerations for
rebiopsy
• Next-generation tyrosine kinase inhibitors: osimertinib,
rociletinib
64-Year-Old Man with EGFR T790M MutationPositive Metastatic NSCLC (Ms Magnoli)
• October 2012: A retired funeral home director and nonsmoker
developed dyspnea and was found to have metastatic
adenocarcinoma
• Carboplatin/paclitaxel/bevacizumab
• Testing revealed EGFR tumor mutation
– Switched to erlotinib with 17-month response
– T790M tumor mutation detected on disease progression
• December 2015: Osimertinib initiated after several other
treatments were received
• Clinical improvement observed with osimertinib
64-Year-Old Man with EGFR T790M MutationPositive Metastatic NSCLC (Ms Magnoli)
11/20/2015
1/14/ 2016
Osimertinib initiated on 12/2015
Common EGFR Mutations at First Diagnosis
Exon Exon 18
T790M G719X
Other
Exon
20 INS
Exon 21
L858R
40%
Exon 19
50%
http://www.egfr-mutation.com/how-to-test/mutation-testing-methods.html
Tissue Testing in NSCLC
• Squamous vs nonsquamous
• Smokers vs nonsmokers
• Women vs men
• Asians vs other
• Adequate tissue?
• Multiplex vs individual assays (EGFR, ALK)
• ROS1
• ASCO, CAP, NCCN recommendations
Case discussion points (Ms Magnoli)
• What were some of the key patient education
points that you addressed when the patient was
started on erlotinib?
• What are the most common toxicity/tolerability
issues with erlotinib?
• How did the patient tolerate treatment with
erlotinib?
First-Line Treatment Options in EGFR MutationPositive NSCLC
• Erlotinib
– 150 mg/d (PO) until disease progression (PD) or
unacceptable toxicity1-3
• Afatinib
– 40 mg/d (PO) until PD or unacceptable toxicity4-5
• Gefitinib
• 250 mg/d (PO) until PD or unacceptable toxicity6
1Zhou
C et al. Lancet Oncol 2011;12(8):735-42; 2Rosell R et al. Lancet Oncol 2012;13(3):23946; 3Seto T et al. Lancet Oncol 2014;15(11):1236-44; 4Sequist LV et al. J Clin Oncol
2013;31(27):3327-34; 5Wu YL et al. Lancet Oncol 2014;15(2):213-22; 6Ichiihara E et al.
J Thorac Oncol 2015;10(3):486-91.
IPASS Trial: Progression-Free Survival (PFS)
Results
Gefitinib (n = 66)
Carboplatin/paclitaxel
(n = 74)
HR (95% CI) = 0.55 (0.35 to 0.87)
Probability of PFS
Probability of PFS
HR (95% CI) = 0.38 (0.26 to 0.56)
Time since random assigment
(months)
EGFR Exon 19 deletion
Fukuoka M et al. J Clin Oncol 2011;29(21):2866-74.
Gefitinib (n = 64)
Carboplatin/paclitaxel
(n = 47)
Time since random assigment
(months)
EGFR L858R mutation
LUX-Lung 3 and 6: Combined Overall Survival
Analysis by Mutation Category
L858R
Del19
Afatinib Chemo
n = 236 n = 119
Median, mo
31.7
20.7
HR
0.59
p-value
p = 0.0001
0.8
0.6
0.4
0.2
0
Chemo
n = 93
22.1
26.9
HR
p-value
1.0
Estimated OS probability
Estimated OS probability
1.0
Median, mo
Afatinib
n = 183
1.25
p = 0.1600
0.8
0.6
0.4
0.2
0
0
3 6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
Yang CH et al. Lancet Oncol 2015;16:141-51.
0
3 6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
Phase IIb LUX-Lung 7 Trial: First-Line Afatinib
versus Gefitinib in Advanced EGFR-Mutant NSCLC
Afatinib
(n = 160)
Gefitinib
(n = 159)
Median PFS
18-mo PFS
24-mo PFS
11.0 mo
27%
18%
10.9 mo
15%
8%
0.73
Median TTF
13.7 mo
11.5 mo
NR
70%
56%
NR
ORR
HR
TTF = time to treatment failure; ORR = objective response rate; NR = not reported
• Overall survival data: not mature at 27.3-mo follow-up
• Serious adverse events occurred more frequently with afatinib
Park K et al. Proc ESMO 2015;Abstract LBA2 PR.
Skin Rash with Tyrosine Kinase Inhibitors
• Most frequent dermatologic
side effect reported is
acneiform eruption.
• Affects mainly face, upper
chest and/or back.
• Also known as acne,
acneiform skin reaction/rash,
follicular rash and
maculopapular skin rash.
Ricciardi S et al. Clin Lung Cancer 2009;10(1):28-35.
Prophylaxis of Dermatologic Toxicities
with EGFR Inhibitors
Within first 6 weeks of EGFR TKI administration
• Employ proactive approach
• Thick, alcohol-free emollient cream
• Sunscreen ≥SPF15, preferably with zinc oxide or
titanium dioxide
• Good hygiene
Lynch TJ et al. Oncologist 2007;12:610-21.
Management of Dermatologic Toxicities with
EGFR Inhibitors
• Hydrocortisone 1% or 2.5% cream
• Clindamycin 1% gel
• Pimecrolimus 1% cream
• Doxycycline 100 mg BID
• Minocycline 100 mg BID
• Methylprednisolone dose pack
• Dose reduction, interruption or discontinuation
Lynch TJ et al. Oncologist 2007;12:610-21.
T790M: Incidence in NSCLC
• Tissue biopsy is the gold standard and the basis
upon which FDA approvals for “T790M-specific”
EGFR TKIs were made
• Baseline rate of EGFR T790M (EGFR TKI-naïve):
– All lung cancers: 0.5%
– EGFR-mutant NSCLC: 2%
• Acquired resistance to EGFR TKIs (incidence of a
second-site EGFR T790M mutation): 62%
Yu HA et al. Ann Oncol 2014;25(2):423-8.
Yu HA Clin Cancer Res 2013;19(8):2240-7.
Case discussion points (Ms Magnoli)
• What were some of the key patient education
points that you addressed when the patient was
started on osimertinib?
• What are the most common toxicity/tolerability
issues with osimertinib?
• How did the patient tolerate treatment with
osimertinib?
New Agent Profile: Osimertinib
• Mechanism of action:
– An orally available, irreversible, third-generation, mutantselective epidermal growth factor receptor (EGFR) inhibitor that
selectively and covalently binds to and inhibits the activity of the
mutant forms of EGFR, including the T790M EGFR-mutant form
• Indication:
– For the treatment of patients with metastatic EGFR T790M
mutation-positive non-small cell lung cancer (NSCLC), as
detected by an FDA-approved test, who have progressed on or
after EGFR tyrosine kinase inhibitor therapy
• Recommended dose:
– 80 mg orally once daily, with or without food
www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=747632
Osimertinib package insert, April 2016
AURA: Osimertinib (AZD9291) in EGFR TKIResistant NSCLC: Response in Individual Patients
Best percentage change from
baseline in target-lesion size
Evaluable patients with T790M+ NSCLC, expansion cohorts only (N = 127)
ORR: 61%
Most Common ≥Grade 3 AEs:
• Diarrhea
• Fatigue
• Interstitial lung disease-like events
Janne PA et al. N Engl J Med 2015;372(18):1689-99.
Case discussion points (Ms Magnoli)
• What is your general experience with rociletinib
and the hyperglycemia associated with it? How
common is the hyperglycemia? How is it managed
clinically?
Rociletinib (CO-1686) in EGFR Mutation-Positive
NSCLC
Change from baseline (%)
Centrally confirmed T790M+ disease in patients
within therapeutic dose range (N = 40)
900 mg BID FB/500 mg HBr
625 mg BID HBr
750 mg BID HBr
* Ongoing
1000 mg BID HBr
ORR to date: 58%
Most Common ≥Grade 3 AEs:
• Hyperglycemia and impaired glucose
tolerance
• QT prolongation
Sequist LV et al. Proc ASCO 2014;Abstract 8010.
FDA Denies Accelerated Approval for
Rociletinib
“April 12, 2016: The oral agent rociletinib, an
experimental treatment for a subset of lung cancer
patients, has not been recommended for accelerated
approval from the US Food and Drug Administration
(FDA).
Instead, the FDA's Oncologic Drugs Advisory
Committee (ODAC) voted 12 to 1 in favor of waiting for
the results of an ongoing Phase III randomized clinical
trial to be submitted before a regulatory decision is
made.”
http://www.medscape.com/viewarticle/861848
Case discussion points (Ms Magnoli)
• How do you think this patient’s experience
as a funeral home director has affected his
perspective on being diagnosed with cancer?
Module 2:
ALK, ROS1 and Other
Genetic Mutations in NSCLC
Discussion Topics
• ALK and ROS1 tumor rearrangements: Indications
for testing
• Efficacy of crizotinib in patients with ALK and ROS1
rearrangements; unique toxicities associated with
crizotinib — vision abnormalities, hypogonadism
• Next-generation ALK inhibitors: ceritinib, alectinib and
others in development; optimal sequencing of
available ALK inhibitors; tolerability issues and dosing
• Other tumor mutations: BRAF, RET, HER2
54-Year-Old Man with ALK-Positive Metastatic
NSCLC (Ms Stone)
• 2011: Multiple systemic and local therapies for
metastatic adenocarcinoma of the lung
• October 2013: Right pleural biopsy again revealed
adenocarcinoma
– Molecular profiling identified an ALK gene fusion
• Crizotinib for almost 2 years
• Ceritinib initiated on disease progression
• Imaging has revealed a response to treatment
54-Year-Old Man with ALK-Positive Metastatic
NSCLC (Ms Stone)
6/26/15 – Progression
on crizotinib
1/18/16 – Response
to ceritinib
Case discussion points (Ms Stone)
• What were some of the key patient education
points that you addressed when the patient was
started on crizotinib?
• How did you explain how it works?
• What are the most common toxicity/tolerability
issues with crizotinib?
• How did the patient tolerate treatment with
crizotinib?
ALK Rearrangement in Cancer
• Chromosomal
translocation: Most
common ALK
abnormality in cancer
• Rearrangement of
genetic info: Parts of one
chromosome break off
and fuse with another or
flip around (inversion)
• Result: New gene and
expression of fusion
protein
Cancer Genome Atlas, National Cancer Institute
EML4-ALK Alterations in NSCLC
• In ~4% of NSCLC cases
• Enriched in younger, never or light smokers with
adenocarcinoma
• Rarely overlaps with EGFR and KRAS mutations
Soda M et al. Nature 2007;448(7153):561-6.
Decrease or increase from baseline (%)
Activity of Crizotinib in ALK-Positive NSCLC
Update of the Phase II Study (N = 240)
100
80
60
PD
SD
PR
CR
40
20
0
-20
-40
-60
-80
-100
-120
Kim DW et al. Proc ASCO 2012;Abstract 7533.
+
+
++
Visual Disorders with Crizotinib
“Trails” coming off lights in peripheral vision, in low light conditions
Also at edges of vision in low light conditions:
• Image persistence
• Flashes of light, which don’t appear to be connected to a real light source
• High contrast images (eg, stripes) flip registration
Camidge DR. The International Journal of Targeted Therapies in Cancer 2012;6.12:30-3.
Case discussion points (Ms Stone)
• What were some of the key patient education points
that you addressed when the patient was started on
ceritinib?
• What are the most common toxicity/tolerability issues
with ceritinib?
• How did the patient tolerate treatment with ceritinib?
New Agent Profile: Ceritinib
• Mechanism of action:
– An orally available inhibitor of the receptor tyrosine kinase
activity of anaplastic lymphoma kinase (ALK)
• Indication:
– For the treatment of patients with ALK-positive metastatic
NSCLC who have progressed on or are intolerant to
crizotinib
• Recommended dose:
– 750 mg orally once daily on an empty stomach (ie, do not
administer within 2 hours of a meal)
www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=694589
Ceritinib package insert, April 2016
Ceritinib (LDK378) Induces Responses in the
Majority of Patients with Crizotinib-Resistant
Disease
Common Side Effects
• Diarrhea
• Nausea and vomiting
• Dehydration
• Elevated ALT/AST
Shaw AT et al. N Engl J Med 2014;370(13):1189-97.
49-Year-Old Woman with ALK-Positive
Metastatic NSCLC (Ms Stone)
• March 2015: Diagnosis of adenocarcinoma of the
lung metastatic to the brain and T7
– Possible leptomeningeal disease
– ALK gene fusion
• Crizotinib
– Vision problems and headache
– Workup results equivocal for leptomeningeal
disease
• Optic nerve radiation therapy and continued crizotinib
• October 2015: Alectinib on an expanded access
program
Case discussion points (Ms Stone)
• What were some of the key patient education points
that you addressed when the patient was started on
alectinib?
• What are the most common toxicity/tolerability issues
with alectinib?
• How did the patient tolerate treatment with alectinib?
New Agent Profile: Alectinib
• Mechanism of action:
– An orally available inhibitor of the receptor tyrosine
kinase ALK
• Indication:
– For the treatment of patients with ALK-positive, metastatic
NSCLC who have progressed on or are intolerant to
crizotinib
• Recommended dose:
– 600 mg orally twice daily. Administer with food
www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=733572
Alectinib package insert, April 2016
Updated Analysis of Alectinib in Advanced
ALK-Positive, Crizotinib-Resistant NSCLC
Most AEs Grade 1-2
• Fatigue
• Edema
• Myalgia
Grade ≥3: Reduction in neutrophils
Shaw AT et al. Lancet Oncol 2016;17(2):234-42.
ALEX Phase III Study Design
• ALK+
• Stage IIIB/IV or
recurrent
NSCLC
• Chemotherap
y naïve
• ECOG PS 0-2
Alectinib 600 mg BID
(n = 143)
R
1:1
Crizotinib 250 mg
BID (n = 143)
* Determined by investigators, based on RECIST v1.1
Ou SHI et al. Proc ASCO 2015;Abstract 8008.
Until PD* or
premature
withdrawal
(eg, due to
toxicity)
Subsequent
therapy and
survival
follow-up
Case discussion points (Ms Stone)
• What is it like interacting with the patient’s daughter
who is an oncology nurse practitioner?
• What motivated the patient to start the Facebook
group “Living with … ALK Mutation”?
62-Year-Old Woman with BRAF V600E MutationPositive Metastatic NSCLC (Ms Stone)
• February 2012: Diagnosis of metastatic lung
adenocarcinoma
• Carboplatin/pemetrexed/bevacizumab x 6 cycles
– Maintenance bevacizumab/pemetrexed
• September 2012: Bevacizumab discontinued due to
recurrent epistaxis
• October 2014: New biopsy upon disease progression
revealed a BRAF V600E tumor mutation
• Vemurafenib on a clinical trial and no current
evidence of active disease
Case discussion points (Ms Stone)
• What were some of the key patient education
points that you addressed when the patient was
started on vemurafenib?
• What are the most common toxicity/tolerability
issues with vemurafenib?
• How did the patient tolerate treatment with
vemurafenib?
Case discussion points (Ms Stone)
• What is the nature of the clinical responses and
side effects you have observed in your patients
who have BRAF-mutated NSCLC and are receiving
a BRAF inhibitor?
• What is the nature of the clinical responses and
side effects you have observed in your patients
who have BRAF-mutated NSCLC and are receiving
a BRAF inhibitor in combination with a MEK
inhibitor?
Dabrafenib Combined with Trametinib in BRAF
V600E-Mutated Metastatic NSCLC
•
The median duration of response was not reached
Planchard D et al. Proc ASCO 2015;Abstract 8006.
ROS1 Alterations in NSCLC
ROS1 alterations
• In ~1% of NSCLC cases
• Enriched in younger, never or light smokers with
adenocarcinoma
• No overlap with other oncogenic drivers
Bergethon K et al. J Clin Oncol 2012;30(8):863-70; Takeuchi K et al. Nat Med 2012;18(3):37881.
Crizotinib in Advanced ROS1-Positive NSCLC
Disease progression
Stable disease
Change from baseline (%)
Partial response
Complete response
N = 50 evaluable
ORR: 72%
The safety profile of crizotinib was similar to that observed in
ALK-positive advanced NSCLC
Shaw AT et al. N Engl J Med 2014;371(21):1963-71.
Case discussion points (Ms Stone)
• What are some of this patient’s most important
current goals?
• How has this patient being the caregiver for her
mother who has dementia affected how you
approach her cancer care?
Module 3:
Management of Pan-Wild-Type
Metastatic Adenocarcinoma
of the Lung
Discussion Topics
• Systemic treatment of metastatic pan-wild-type
NSCLC: Choice of chemotherapy regimen and role of
bevacizumab
• Recognition and management of hypertension and
proteinuria with bevacizumab; risk of cardiovascular
events
• Maintenance strategies in NSCLC: Biologic therapy,
chemotherapy or both
62-Year-Old Man with Metastatic NSCLC
(Ms Magnoli)
• Stage IV, poorly differentiated metastatic
adenocarcinoma
– Metastases to mediastinum, adrenal gland and
pelvis
• Palliative radiation therapy to the pelvis with
improvement in bone pain
• Carboplatin and pemetrexed
• Carboplatin/nab paclitaxel/bevacizumab followed by
maintenance bevacizumab
Case discussion points (Ms Magnoli)
• What were some of the key patient education
points that you addressed when the patient was
started on carboplatin/pemetrexed?
• What are the most common toxicity/tolerability
issues with carboplatin/pemetrexed?
• How did the patient tolerate treatment with
carboplatin/pemetrexed?
Case discussion points (Ms Magnoli)
• What were some of the key patient education
points that you addressed when the patient was
started on carboplatin/nab paclitaxel/bevacizumab?
• What are the most common toxicity/tolerability
issues with carboplatin/nab
paclitaxel/bevacizumab?
• How did the patient tolerate treatment with
carboplatin/nab paclitaxel/bevacizumab?
Sequencing of Commonly Used
Chemotherapy/Biologic Regimens in Pan-WildType Lung Adenocarcinoma
Pem/carbo/bev
Paclitaxel/carbo/bev
Carbo/pem
Pem/bev OR pem
OR bev maintenance
Bev maintenance
Pem
maintenance
PD-1/PD-L1 antibody
PD-1/PD-L1 antibody
PD-1/PD-L1 antibody
Docetaxel 
ramucirumab
Docetaxel 
ramucirumab
Docetaxel 
ramucirumab
Case discussion points (Ms Magnoli)
• What are some of this patient’s most important
current goals?
• What type of end-of-life planning, if any, have you
discussed with the patient?
Discussion Topics
• Predictors of response and efficacy of newly FDAapproved immune checkpoint inhibitor therapies in
NSCLC
• Current sequencing of immunotherapy
• Pseudoprogression versus disease progression with
checkpoint inhibitors
76-Year-Old Man with Metastatic NSCLC
Receives Nivolumab (Ms Magnoli)
• March 2014: Ex-boilermaker and current smoker
(>100 pack years) is diagnosed with Stage IV panwild-type lung adenocarcinoma
– Family history of lung cancer
• Carboplatin/pemetrexed/bevacizumab
– Maintenance bevacizumab
• Nivolumab
– Major response and improved quality of life with
relief of dyspnea
76-Year-Old Man with Metastatic NSCLC
Receives Nivolumab (Ms Magnoli)
10/21/2015
1/14/ 2016
After nivolumab x 4 cycles (2 months)
Case discussion points (Ms Magnoli)
• What was the time course for the patient’s
response to nivolumab?
• How did he tolerate treatment with nivolumab?
Role of PD-1 in Suppressing Antitumor Immunity
Patient’s T cells
Tumor cell
TCR
MHC
T Cell
PD-L1
PD-1
B7.1
T-cell
inhibition
T Cells
TCR
MHC
Tumor cell
growth
PD-1
PD-L1
Engineered
Fc-domain
B7.1
Tumor cell
death
T-cell
activation
+ Anti-PDL1
Granzymes and perforin
•
Blocking PD-L1 restores T-cell activity, resulting in tumor regression in preclinical models
•
Binding to PD-L1 leaves PD-1/PD-L2 interaction intact and may enhance efficacy and safety
Adapted from Spigel et al. Proc ASCO 2013;Abstract 8008.
New Agent Profile: Nivolumab
• Mechanism of action:
– A fully human immunoglobulin (Ig) G4 monoclonal
antibody directed against the negative immunoregulatory
human cell surface receptor programmed death-1 (PD-1)
• Indication:
– For the treatment of patients with metastatic NSCLC and
progression on or after platinum-based chemotherapy.
Patients with EGFR or ALK genomic tumor aberrations
should have disease progression on FDA-approved
therapy for these aberrations prior to receiving nivolumab
• Recommended dose:
– 3 mg/kg every 2 weeks
www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=539733
Nivolumab package insert, April 2016
CheckMate 057: Duration of Response with
Nivolumab
Borghaei H et al. N Engl J Med 2015;373(17):1627-39.
New Agent Profile: Pembrolizumab
• Mechanism of action:
– A fully human immunoglobulin (Ig) G4 monoclonal antibody
directed against human cell surface receptor PD-1
• Indication:
– For patients with metastatic NSCLC whose tumors express PDL1 as determined by an FDA-approved test and who have
disease progression on or after platinum-containing
chemotherapy. Patients with EGFR or ALK genomic tumor
aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving pembrolizumab
• Recommended dose:
– 2 mg/kg as intravenous infusion over 30 minutes every 3 weeks
www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=695789
Pembrolizumab package insert, April 2016
KEYNOTE-001: OS with Pembrolizumab by PD-L1
Proportion Score (PS) in NSCLC
PS is the percentage of neoplastic cells positive for PD-L1 staining
Garon EB et al. N Engl J Med 2015;372(21):2018-28.
Percentage change from baseline
Response to First-Line Nivolumab Combined
with Ipilimumab in NSCLC
ORR: 13%-39%
mPFS: 4.9-10.6 mo
a Based
PD-L1 expression
N (%)
≥1% PD-L1a
<1% PD-L1a
Unknownb
77 (68)
36 (32)
35 (24)
on patients with known PD-L1 expression; b Based on all treated patients
Rizvi NA et al. Proc IASLC 2015;Abstract ORAL02.05.
New Agent in Development: Atezolizumab
(MPDL3280A)
• Mechanism of action:
– A human, Fc optimized, monoclonal antibody directed against the
protein ligand PD-L1
• Priority Review (April 10, 2016):
– For patients with locally advanced or metastatic NSCLC whose
disease expresses the protein PD-L1, as determined by an FDAapproved test, and who have progressed on or after platinumcontaining chemotherapy
• Breakthrough Therapy Designation (February 2015):
– For patients whose NSCLC expresses PD-L1 and whose disease
progressed during or after standard treatments (e.g., platinum-based
chemotherapy and appropriate targeted therapy for EGFR mutationpositive or ALK-positive disease)
• Investigational Dose:
– 1200-mg intravenous dose every 3 weeks
www.cancertherapyadvisor.com/lung-cancer/lung-cancer-nsclc-fda-atezolizumab-priority-review/article/488800/
www.medscape.com/viewarticle/851625
Module 4:
Management of Metastatic
Squamous Cell Carcinoma
of the Lung
Discussion Topics
• First-line treatment of metastatic squamous cell
NSCLC: Role of nab paclitaxel
• Second-line treatment options for metastatic
squamous cell NSCLC
• Lung-MAP trial and implications for future research
• Incidence and management of immune-related
adverse events associated with checkpoint inhibitor
therapy
• Use of corticosteroids and other immune suppressants
for autoimmune complications of checkpoint inhibitors
• Use of checkpoint inhibitors for patients with a history
of autoimmune disease
68-Year-Old Man with Squamous Cell
Carcinoma of the Lung (Ms Stone)
• August 2014: Diagnosis of bilateral squamous cell
carcinoma of the lung
• Carboplatin/paclitaxel x 6 cycles
• Durvalumab on SWOG-S1400 (Lung-MAP) clinical
trial
S1400: Master Lung-1: Squamous Lung Cancer
Second-Line Therapy
Common Biomarker
Profiling
Biomarker-Driven
Sub-Studies
Non-match
Sub-Studies
S1400B
PI3K
S1400C
CCGA
S1400D
FGFR
Taselisib
Palbociclib
AZD4547
S1400I
Checkpoint
Naive
Durvalumab Nivolumab
+ Ipilimumab
vs
vs
Docetaxel
Nivolumab
www.lung-map.org; www.clinicaltrials.gov; Accessed April 2016; (NCT02154490).
Common Treatment Options for Pan-Wild-Type
Metastatic Squamous Cell NSCLC
First Line
• Carboplatin/gemcitabine
• Carboplatin/paclitaxel
• Carboplatin/nab paclitaxel
• Cisplatin/gemcitabine + necitumumab
Second Line
• Nivolumab
• Pembrolizumab
• Docetaxel ± ramucirumab
• Gemcitabine
NCCN Clinical Practice Guidelines in Oncology – Non-Small Cell Lung Cancer. V4.2016
Nanoparticle Albumin-Bound Paclitaxel (Nab/P) in
Metastatic Squamous Cell Carcinoma of the Lung
• FDA approval October 12, 2012 as first-line therapy
for locally advanced or metastatic NSCLC, in
combination with carboplatin
• Phase III study (N = 1,052) in previously untreated
Stage IIIB/IV NSCLC
– Higher response rate with nab/P in squamous cell
NSCLC
– Overall survival benefit for older patients (≥70
years)
Socinski MA et al. J Clin Oncol 2012;30(17):2055-62. Socinski MA et al. Ann Oncol
2013;24(2):314-21. Socinski MA et al. Ann Oncol 2013;24(9):2390-6.
Common Treatment-Related Grade ≥3 Adverse
Events with Nab Paclitaxel
Nab paclitaxel
(n = 514)
Standard paclitaxel
(n = 524)
Adverse event
Grade 3
Grade 4
Grade 3
Grade 4
p-value
Neutropenia
33%
14%
32%
26%
<0.001
Thrombocytopenia
13%
5%
7%
2%
<0.001
Anemia
22%
5%
6%
<1%
<0.001
Sensory neuropathy
3%
0%
11%
<1%
<0.001
Socinski MA et al. J Clin Oncol 2012;30(17):2055-62.
Differences between Nab Paclitaxel (Nab/P) and
Cremophor®-Based Paclitaxel
• No corticosteroid premedication with nab/P
• Shorter infusion time with nab/P
• Incidence, severity and reversibility of neuropathy?
• Myelosupression?
• Less Grade ≥3 neutropenia, arthralgias and
neuropathy with nab/P
• More Grade ≥3 thrombocytopenia and anemia with
nab/P
Immune-Related Adverse Events (IRAEs)
Associated with Immune Checkpoint Inhibitors
• Hypophysitis
• Thyroiditis
• Adrenal insufficiency
• Colitis
• Dermatitis
• Pneumonitis
• Hepatitis
• Pancreatitis
• Motor and sensory neuropathies
• Arthritis
Less common: hematologic; cardiovascular; ocular; renal
Courtesy of Julie R Brahmer, MD.