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Challenging Cases in
Lung Cancer
Oncologist and Nurse Investigators
Consult on Actual Patients from the
Practices of the Invited Faculty
Friday, May 2, 2014
6:00 AM – 7:30 AM
Faculty
Geoffrey R Oxnard, MD
Karen L Reckamp, MD, MS
Rebecca Lynn Sipples, MSN,
APRN, ACNP, AOCNP
Alison J Holmes Tisch, MSN,
RN, ANP-BP, AOCNP
Moderator
Neil Love, MD
Oncology 6-Part Case Series: Key Themes
• Mechanisms of action of novel agents and tissue
assays to predict response
• Side effects and toxicities of novel agents; dose
adjustments
• Assessment and management of adherence
• Specific goals of therapy and likely outcomes;
sequencing of agents in advanced disease
• Local and systemic complications of cancer: Fatigue,
pain, CNS involvement
• Care of older, frail patients and those with comorbidities
Oncology 6-Part Case Series: Key Themes
• Clinical trials as a means to access new treatments earlier
• Management of anxiety and depression
• Key determinants of patient satisfaction: What do people
with cancer want and need?
• Quality, value and cost: Investing resources optimally
• End-of-life care and planning
• Impact of the cancer experience on family and loved
ones, including minor children
• Impact of the oncology experience on oncology health
professionals
Agenda
Two Patients with Adenocarcinoma and EGFR Tumor
Mutations
•54 yo woman with advanced EGFR-mutant NSCLC with
progressive disease after responding to erlotinib
(Ms Sipples)
•36 yo Afghani woman with advanced EGFR-mutant NSCLC
currently receiving afatinib/cetuximab (Ms Tisch)
A Patient with Metastatic Adenocarcinoma Who
Received Front-Line Chemobiologic Therapy Followed
by Maintenance
•41 yo woman with advanced “pan-wild-type” NSCLC with 2
young children (Ms Tisch)
Agenda
A Patient Who Received Immunotherapy on a Clinical
Trial
• 77 yo woman with advanced NSCLC who went on a
clinical trial of nivolumab and is currently receiving
nanoparticle albumin-bound (nab) paclitaxel
(Ms Sipples)
Two Patients with Tumor Mutations: ROS1 and HER2
• 70 yo man with advanced, ROS1-mutant NSCLC
receiving crizotinib (Ms Sipples)
• 64 yo woman with advanced NSCLC with a HER2
insertion who has requested help with assisted suicide
(Ms Tisch)
Two Patients with Adenocarcinoma and EGFR
Tumor Mutations
• 54 yo woman with advanced EGFR-mutant NSCLC
with progressive disease after responding to
erlotinib (Ms Sipples)
• 36 yo Afghani woman with advanced EGFR-mutant
NSCLC currently receiving afatinib/cetuximab
(Ms Tisch)
Case 1 (from the practice of Ms Sipples)
• A 54-year-old woman was diagnosed 9 months ago
with advanced non-small cell lung cancer (NSCLC)
(adenocarcinoma with EGFR L858R exon 21 point
mutation) and multiple ring-enhancing brain
metastases
• She responded to erlotinib but then developed
progressive disease
Discussion Point
Incidence of tumor driver mutations
in patients with NSCLC; algorithms
for tissue testing
Incidence of Single Driver Mutations in
Metastatic Lung Adenocarcinoma
N = 733
Kris MG et al. JAMA 2014;311(19):1998-2006.
Discussion Point
Selection of first-line therapy for
patients with EGFR activating
mutations; similarities and differences
between erlotinib and afatinib
Select Trials of First-Line Treatment with EGFR
TKIs vs Chemotherapy in EGFR-Mutant NSCLC
Study
Treatment
N
RR, %
PFS, mo
OS, mo
IPASS1,2
Gefitinib vs
Carbo/pac
261
71.2 vs
47.3
9.5 vs
6.3
21.6 vs
21.9
NEJ0023
Gefitinib vs
Carbo/pac
230
73.7 vs
30.7
10.8 vs
5.4
30.5 vs
23.6
OPTIMAL4,5
Erlotinib vs
Carbo/gem
165
83 vs
36
13.1 vs
4.6
22.7 vs
28.9
Erlotinib vs Platinumbased chemo
174
58 vs
15
9.7 vs
5.2
19.3 vs
19.5
EURTAC6
1 Mok
TS et al. N Engl J Med 2009;361(10):947–57. 2 Fukuoka M et al. J Clin Oncol
2011;29(21):2866–74. 3 Maemondo M et al. N Engl J Med 2010;362(25):2380–8.
4 Zhou C et al. Lancet Oncol 2011;12(8):735–42. 5 Zhou C et al. Proc ASCO
2012;Abstract LBA7520. 6 Rosell R et al. Lancet Oncol 2012;13(3):239–46.
Possible Erlotinib-Associated Side Effects
Most Common AEs
• Rash
• Fatigue
• Diarrhea
• Appetite loss
Afatinib: An Irreversible ErbB Family Blocker
EGF ligands
Heregulins
EGFR inhibitors
ErbB Family Blockade
EGFR (ErbB1)
HER2 (ErbB2)
ErbB3
ErbB4
Afatinib is an orally available, irreversible ErbB family blocker, with high
efficacy potential
• Inhibition of ErbB family receptor heterodimerization
• In vitro activity against EGFR-resistant T790M mutation
Adapted from Li D et al. Oncogene 2008;27:4702-11.
Phase III LUX-Lung 3 Study for Patients with
Treatment-Naïve Advanced Lung Cancer
Stage IIIB/IV lung
adenocarcinoma
EGFR mutation in tumor
R
2:1
Afatinib
Cisplatin + Pemetrexed
Primary endpoint: PFS
Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS,
patient-reported outcomes, safety, PK
Yang JC et al. Proc ASCO 2012;Abstract LBA7500.
LUX-Lung 3: Response and PFS
(Independent Review)
Afatinib
(n = 230)
Cis/pem
(n = 115)
56%
23%
11.1 mo
6.9 mo
Response rate
Median progression-free
survival
Sequist LV et al. J Clin Oncol 2013;31(27):3327-34.
Possible Afatinib-Related AEs
Most Common AEs
• Diarrhea
• Rash/acne
• Stomatitis/mucositis
• Paronychia
• Dry skin
Sequist LV et al. J Clin Oncol 2013;31(27):3327-34.
Discussion Point
Mechanisms of resistance to EGFR TKI
therapy
LUX-Lung 1 Phase IIb/III Study of Afatinib After
Failure of Erlotinib, Gefitinib or Both and
Chemotherapy
• N = 585 patients with Stage IIIB/IV adenocarcinoma
of the lung
• Afatinib/best supportive care (BSC) vs placebo/BSC
• All received prior EGFR TKI and chemotherapy
Afatinib
Placebo
Median OS
10.8 mo
12.0 mo
Median PFS
3.3 mo
1.1 mo
7%
<1%
ORR
No complete responses
Miller VA et al. Lancet Oncol 2012;13(5):528-38.
Phase II Study of Afatinib/Cetuximab
• EGFR mutant
• Advanced NSCLC
Afatinib +
Cetuximab
• Progressing on
erlotinib or gefitinib
• N = 100
ORR: 30%
Median PFS: 4.7 mo
Median DoR: 8 mo
Grade 3 Rash: 18%
Grade 3 Diarrhea: 7%
Janjigian YY et al. Proc ESMO 2012;Abstract 1227O.
Afatinib + cetuximab at MTD:
Responses by T790M mutation
Maximum percentage decrease
from baseline (%)
T790M+
T790M–
EGFR wt
Uninformative for T790M
50
40
30
20
10
0
–10
–20
–30
–40
–50
–60
–70
–80
–90
–100
–110
0
5
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Patient index sorted by maximum % decrease
With permission from Janjigian YY et al. Proc ESMO 2012;Abstract 12007O.
Best Response Rates
T790 Mutation Status
T790M+
(n = 53)
T790M(n = 39)
Total
(n = 96)
Clinical benefit rate
81%
64%
75%
Median duration of
response
6.4 mo
9 mo
8 mo
Response
Janjigian YY et al. Proc ESMO 2012;Abstract 12007O.
Case 2 (from the practice of Ms Tisch)
• A 36-year-old Afghani woman was initially diagnosed in
June 2005 with bronchoalveolar carcinoma that has since
been categorized as adenocarcinoma with lepidic features
• The patient’s disease has progressed through multiple
treatments including chemotherapy, erlotinib,
bevacizumab and 2 clinical trials, one of a single-agent
investigational tyrosine kinase inhibitor (TKI) and one of
erlotinib combined with cabozantinib
• She was later enrolled on a clinical trial of CO-1686 and
experienced a life-threatening tumor flare reaction after
discontinuation of the drug, which was reversed by
restarting erlotinib
• She is currently receiving cetuximab and afatinib
• The patient is a married mother of young children
• Her Muslim faith plays a strong role in her desires
concerning possible future end-of-life care
Progressive Disease on a Trial of CO-1686
Partial Response After Retrial with Erlotinib
Progressive Disease After Retrial of Erlotinib
Partial Response to Cetuximab and Afatinib
CO-1686
• Mutation-specific TKI targeting activating mutations
and T790M
• Theoretically offers key advantage by not inhibiting
wild-type EGFR
• 45 2nd-line TKI patients, 74% T790M+
• Notably absent was rash and diarrhea
• Clinical responses have been observed in 3 of 4
patients who received the highest dose
• Phase II and III studies are under development
Soria JC et al. Proc WCLC 2013;Abstract O03.06.
Skin Rash from 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.
Clinical Grades of Erlotinib-Induced Rash
• Mild
– Generally localized papulopustular reaction
– Minimally symptomatic
– No impact on daily activities
– No sign of superinfection
• Moderate
– Generalized papulopustular reaction
– Mild pruritus or tenderness
– Minimal impact on daily activities
– No sign of superinfection
• Severe
– Generalized papulopustular reaction
– Severe pruritus or tenderness
– Significant impact on daily activities
– Potential for or has become superinfected
Saif MW et al. JOP 2008;9(3):267-74.
Case 3 (from the practice of Ms Tisch)
• A 41-year-old woman was diagnosed in 2010
with a Stage IIIA adenocarcinoma that was
treated with cisplatin/pemetrexed followed by
right upper lobectomy and then consolidative
chemoradiation therapy
• In 2011 she experienced systemic disease
recurrence and was started on
carboplatin/paclitaxel/bevacizumab followed by
maintenance bevacizumab
• The patient is married with 2 young children
2011: Systemic Disease Recurrence
Response to
Carboplatin/Paclitaxel/Bevacizumab Prior to
Maintenance Therapy
Discussion Point
Systemic treatment of metastatic
“pan-wild-type” NSCLC: Choice of
chemotherapy regimen and role of
bevacizumab
Chemotherapeutic Regimens Commonly
Employed in the Front-Line Management of
Metastatic Pan-Wild-Type NSCLC
• Carboplatin/paclitaxel ± bevacizumab
• Carboplatin/nab paclitaxel ± bevacizumab
• Carboplatin/pemetrexed ± bevacizumab
• Cisplatin/chemotherapy ± bevacizumab
NCCN NSCLC Clinical Practice Guidelines v 3.2014
ECOG-E4599: Bevacizumab in Nonsquamous
NSCLC
Paclitaxel/carbo
platin/bevacizum Paclitaxel/carbo
ab
platin
(n = 443)
(n = 444)
Median progression-free
survival (PFS)
6.2 months
4.5 months
Median overall survival (OS)
1-yr OS
2-yr OS
12.3 months
51%
23%
10.3 months
44%
15%
Sandler A et al. N Engl J Med 2006;355(24):2542-50.
Discussion Point
Recognition and management of
hypertension and proteinuria with
bevacizumab; risk of cardiovascular
events
Discussion Point
Maintenance strategies in NSCLC:
biologic therapy, chemotherapy or
both
What Is Maintenance Therapy?
• Use of systemic therapy following 1st-line therapy,
for patients with CR/PR/SD, before documentation
of progression
– Continuation of a targeted agent
– Continuation of one of the agents used in the
1st-line combination regimen
– Switch to a new agent after 1st-line therapy
Rogerio C Lilenbaum, MD, Winter Lung Cancer Conference 2014
PointBreak: Phase III Trial Design
Induction Phase
Maintenance Phase
Pemetrexed
+ Carboplatin
+ Bevacizumab
Pemetrexed
+ Bevacizumab
Inclusion:
- No prior systemic
therapy for lung cancer
- PS 0/1
- Stage IIIB-IV NS-NSCLC
- Stable tx’t brain mets
Exclusion:
- Peripheral neuropathy
≥Grade 1
- Uncontrolled pleural
effusions
R
Paclitaxel
+ Carboplatin
+ Bevacizumab
Patel JD et al. J Clin Oncol 2013;31(34):4349-57.
Bevacizumab
ECOG-E5508: A Phase III Study of Maintenance
Bevacizumab, Pemetrexed or the Combination
in Advanced NSCLC
Target Accrual: 1,282
Study is currently recruiting participants
Study Start Date: August 2010
Maintenance therapy
Eligibility
Bevacizumab
• Stage IIIB/IV
nonsquamous NSCLC
• No brain metastases
• Stable or better
response after 4
courses of carbo,
paclitaxel and bev
R
Pemetrexed
Bevacizumab + Pemetrexed
Primary Endpoint: Overall survival
Induction therapy: Carboplatin, paclitaxel and bevacizumab
www.clinicaltrials.gov, May 2014
Case 4 (from the practice of Ms Sipples)
• A 77-year-old woman diagnosed in 1982 with earlystage NSCLC experienced disease recurrence in the
right upper lobe in 2011, for which she underwent a
segmentectomy followed by adjuvant
cisplatin/pemetrexed
• Her disease recurred in May 2012, at which time she
received carboplatin/gemcitabine
• After further disease progression, in April 2013 she was
enrolled on a clinical trial of an immune checkpoint
inhibitor but 2 months later developed brain metastases,
which were resected
• Since June 2013 she has been receiving nab paclitaxel
3 out of 4 weeks and has responded well but has
developed neuropathy within the past month
Discussion Point
Adjuvant therapy for NSCLC: Choice
of platinum doublet in older patients
Discussion Point
Available data with nab paclitaxel in
lung cancer
Phase III Nab P/C vs P/C Study Design
Chemo-naïve
PS 0-1
Stage IIIb/IV
NSCLC
N = 1,052
Nab Paclitaxel 100 mg/m2 d1, 8, 15
Carboplatin AUC 6 d1 q3wk
No Premedication
n = 521
1:1
Stratification factors:
• Stage (IIIb vs IV)
• Age (<70 vs >70)
• Histology (squamous vs nonsquamous)
Socinski MA et al. J Clin Oncol 2012;30(17):2055-62.
Paclitaxel 200 mg/m2 d1 q3wk
Carboplatin AUC 6 d1 q3wk
With Premedication of
Dexamethasone +
Antihistamines
n = 531
Common Treatment-Related ≥Grade 3 Adverse
Events
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.
Objective Responses by Histology
Squamous
P < 0.001
P = 0.060
Nonsquamous
P = 0.808
P = 0.069
Percent Responses
Nab P/C
P/C
n = 228
n = 221
Socinski MA et al. J Clin Oncol 2012;30(17):2055-62;
Socinski MA et al. ASCO 2010;Abstract 7511.
n = 292
n = 310
Response and Survival in Elderly Patients (≥70)
Nab P/C
(n = 74)
P/C
(n = 82)
Overall response rate
34%
24%
Median progression-free survival
8 mo
6.8 mo
19.9 mo
10.4 mo
Endpoint
Median overall survival
Adverse events similar in both groups
• Nab paclitaxel
- Less neuropathy
- Less neutropenia
- Less arthralgia
- More anemia
Socinski MA et al. Ann Oncol 2013;24(2):314-21.
Discussion Point
Anti-PD-1 and anti-PD-L1 antibodies:
Mechanisms of action, predictors of
response, time sequence of antitumor
benefit, side effects and toxicities
Role of PD-1 in Suppressing Antitumor Immunity
Patient’s T cells
Tumor cell
MHC
TCR
T cell
PD-1
PD-L1
B7.1
MHC
T-cell
blockade
T cells
TCR
Tumor
cell
growth
PD-1
PD-L1
Engineered
Fc-domain
B7.1
T-cell
activation
+ Anti-PD-L1
Granzymes and perforin
Tumor
cell
death
•
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.
Activity of Nivolumab in Patients with
Treatment-Refractory Cancer
• Two patients with lung cancer who received 10 mg/kg of
nivolumab experienced unconfirmed responses, and 8
additional patients with melanoma, lung cancer or renal cell
cancer had a persistent reduction in baseline target lesions in
the presence of new lesions, a finding consistent with an
immune-related response pattern.
• In patients with lung cancer, 14 objective responses were
observed.
• All 14 patients with objective responses started treatment 24
weeks or more before data analysis, and 8 of these patients had
a response that lasted 24 weeks or more. Five of 14 patients
with objective responses started treatment 1 year or more
before data analysis, 2 of whom had a response that lasted 1
year or more. Stable disease lasting 24 weeks or more was
observed in 5 patients with lung cancer.
Topalian SL et al. N Engl J Med 2012;366(26): 2443-54.
Clinical Development of Inhibitors of PD-1
Immune Checkpoint
Target
PD-1
PD-L1
Antibody
Molecule
Development
stage
Nivolumab (BMS936558/MDX1106/ONO-4538)
Fully human IgG4
mAb
Phase II multiple
tumors
Pidilizumab (CT-011)
Humanized IgG1 mAb
Phase II multiple
tumors
Lambrolizumab (MK3475)
Humanized IgG4 mAb
Phase I
AMP-224
B7-DC/IgG1 fusion
protein
Phase I
MDX-1105/BMS936559
Fully human IgG4
mAb
Phase I
Giaccone G. Proc ASCO Clinical Science Symposium.
Two Patients with Tumor Mutations: ROS1 and
HER2
• 70 yo man with advanced, ROS1-mutant
adenocarcinoma of the lung receiving crizotinib
(Ms Sipples)
• 64 yo woman with advanced NSCLC with a HER2
insertion (Ms Tisch)
Case 5 (from the practice of Ms Sipples)
• A 70-year-old man with a history of Stage IIB lung
adenocarcinoma treated in 2006 with resection and
adjuvant cisplatin/vinorelbine experienced local
recurrence 4 years ago and received chemoradiation
therapy
• In 2013 the patient developed biopsy-confirmed
metastatic lung adenocarcinoma positive for ROS1
mutation
• He is currently receiving crizotinib but experienced
acute renal injury that led to a treatment interruption
• The patient is married and is well known by the
medical staff because his daughter was a patient for
breast cancer in the past
Discussion Point
ALK and ROS tumor rearrangements:
Indications for testing
EML4-ALK and ROS1 Alterations in NSCLC
EML4-ALK alterations1
• In ~4% of NSCLC cases
• Enriched in younger, never or light smokers with
adenocarcinoma
• Rarely overlaps with EGFR and K-ras mutations
ROS1 alterations2-3
• In ~1% of NSCLC cases
• Enriched in younger, never or light smokers with
adenocarcinoma
• No overlap with other oncogenic drivers
1 Soda
M et al. Nature 2007;448(7153):561-6; 2 Bergethon K et al. J Clin Oncol 2012;30(8):86370; 3 Takeuchi K et al. Nat Med 2012;18(3):378-81.
ALK Rearrangement in Cancer
• Chromosomal translocation most common ALK
abnormality in cancer
• Rearrangement of genetic info when parts of one
chromosome break off and fuse with another or flip
around (inversion)
• Results in new gene and expression of fusion protein
Cancer Genome Atlas, National Cancer Institute
Discussion Point
Efficacy of crizotinib in patients with
ALK and ROS rearrangements; unique
toxicities associated with crizotinib:
Vision abnormalities, hypogonadism
Activity of Crizotinib in ALK+ NSCLC
Update of the Phase II Study
Variable (n = 259)
Crizotinib 250 mg, n (%)
Objective response rate
155 (59.8)
Complete response
4 (1.5)
Partial response
151 (58.3)
Stable disease
69 (26.6)
Objective progression
19 (7.3)
Kim DW et al. Proc ASCO 2012;Abstract 7533.
FDA NEWS RELEASE
April 29, 2014
“The US Food and Drug Administration today granted
accelerated approval to ceritinib for patients with a
certain type of late-stage (metastatic) non-small cell
lung cancer (NSCLC).
“Ceritinib is an anaplastic lymphoma kinase (ALK)
tyrosine kinase inhibitor that blocks proteins that
promote the development of cancerous cells. It is
intended for patients with metastatic ALK-positive
NSCLC who were previously treated with crizotinib,
the only other approved ALK tyrosine kinase
inhibitor.”
www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm395299.htm
Ceritinib (LDK378) Induces Responses in the
Majority of Crizotinib-Resistant Patients
• A total of 114 patients with NSCLC received at least 400
mg of ceritinib daily
• Overall response rate (ORR) was 58%
• Confirmed complete response: 1(1%)
• Confirmed partial response: 65 (57%)
• The majority of patients with NSCLC who received
ceritinib had previously received crizotinib: 83/122 (68%)
• Among patients who previously received crizotinib,
ORR = 56%
• Among patients who had not received crizotinib
previously and who received ceritinib at ≥400 mg daily,
ORR = 21/34 (62%)
Shaw AT et al. N Engl J Med 2014;370(13):1189-97.
Typical Responses to Ceritinib (LDK378)
• In the Phase I study of ceritinib in ALK-rearranged
NSCLC, some patients experienced rapid
responses to crizotinib.
– In one patient with crizotinib-resistant disease,
the comparison of positron emission
tomography scans taken at baseline and 3.5
weeks of ceritinib treatment was dramatic.
– Subsequent computed tomography scans after
6 weeks of ceritinib treatment showed a 52%
reduction in tumor burden in this patient.
Shaw AT et al. N Engl J Med 2014;370(13):1189-97.
Case 6 (from the practice of Ms Tisch)
• A 64-year-old woman diagnosed with Stage IIIA NSCLC
underwent treatment with neoadjuvant chemotherapy
followed by resection and chemoradiation therapy
• Six months later metastases were detected
• The patient’s disease progressed on several lines of
therapy, and interim mutational testing revealed a HER2
insertion
• She began treatment with vinorelbine/trastuzumab and
had a significant clinical response and prolonged benefit
but ultimately experienced clinical worsening and
entered hospice
• The patient repeatedly asked for help with assisted
suicide, which she planned to use near the time of her
death so that she would not suffer
Pre- and Post-vinorelbine and trastuzumab
treatment
Prior to treatment
Post treatment
HER2 in Lung Cancers
Agents Targeting HER2
Amplification and Protein Expression
•
•
•
•
Trastuzumab
Pertuzumab
Lapatinib
Ado-Trastuzumab Emtansine
Trials of Investigational Agents
Targeting HER2 Mutations
•
•
•
•
Dacomitinib
Afatinib
Neratinib
Neratinib + Temsirolimus
Discussion Point
Role of multiplex testing to identify
other lung cancer mutations:
Implications for clinical trial referral
and nonprotocol care
Options for Molecular Profiling
• Actionable Analysis (EGFR, ALK, ROS)
• SNaPshot (Iafrate MGH)
– Genotyping of approx 100 key mutations
• Extensive Mutation Analysis of COSMIC Genes
– Foundation Medicine 400
– Sklar 409
• Whole Exome Sequencing (23,000 genes)
• Whole Genome Sequencing