Challenging Cases in Lung Cancer

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Challenging Cases in Lung CancerOncologist and
Nurse Investigators Consult on Actual Patients
from the Practices of the Invited
FacultyFriday, May 2, 2014600 AM 730 AM
Faculty
Rebecca Lynn Sipples, MSN, APRN, ACNP,
AOCNP Alison J Holmes Tisch, MSN, RN, ANP-BP,
AOCNP
Geoffrey R Oxnard, MD Karen L Reckamp, MD, MS
ModeratorNeil Love, MD
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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

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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

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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)

6
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)

7
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)

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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

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Discussion Point

• Incidence of tumor driver mutations in patients
  with NSCLC algorithms for tissue testing

10
Incidence of Single Driver Mutations in
Metastatic Lung Adenocarcinoma
N 733
Kris MG et al. JAMA 2014311(19)1998-2006.
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Discussion Point

• Selection of first-line therapy for patients with
  EGFR activating mutations similarities and
  differences between erlotinib and afatinib

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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
EURTAC6 Erlotinib vs Platinum-based chemo 174 58 vs 15 9.7 vs 5.2 19.3 vs 19.5
1 Mok TS et al. N Engl J Med 2009361(10)94757.
2 Fukuoka M et al. J Clin Oncol
201129(21)286674. 3 Maemondo M et al. N Engl
J Med 2010362(25)23808. 4 Zhou C et al.
Lancet Oncol 201112(8)73542. 5 Zhou C et al.
Proc ASCO 2012Abstract LBA7520. 6 Rosell R et
al. Lancet Oncol 201213(3)23946.
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Possible Erlotinib-Associated Side Effects

• Most Common AEs
• Rash
• Fatigue
• Diarrhea
• Appetite loss

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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 2008274702-11.
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Phase III LUX-Lung 3 Study for Patients with
Treatment-Naïve Advanced Lung Cancer
Stage IIIB/IV lung adenocarcinoma
EGFR mutation in tumor
R21
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 2012Abstract LBA7500.
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LUX-Lung 3 Response and PFS (Independent Review)
Afatinib (n 230) Cis/pem (n 115)
Response rate 56 23
Median progression-free survival 11.1 mo 6.9 mo
Sequist LV et al. J Clin Oncol 201331(27)3327-34
.
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Possible Afatinib-Related AEs

• Most Common AEs
• Diarrhea
• Rash/acne
• Stomatitis/mucositis
• Paronychia
• Dry skin

Sequist LV et al. J Clin Oncol 201331(27)3327-34
.
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Discussion Point

• Mechanisms of resistance to EGFR TKI therapy

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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
ORR 7 lt1
No complete responses
Miller VA et al. Lancet Oncol 201213(5)528-38.
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Phase II Study of Afatinib/Cetuximab
EGFR mutant Advanced NSCLC Progressing on erlotinib or gefitinib N 100
Afatinib Cetuximab
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 2012Abstract 1227O.
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Afatinib cetuximab at MTD Responses by T790M
mutation
T790M
T790M
EGFR wt
Uninformative for T790M
50 40 30 20 10 0 10 20 30 40 50 60 70 80
90 100 110
Maximum percentage decrease from baseline ()
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 8
5 90 95
100
Patient index sorted by maximum decrease
With permission from Janjigian YY et al. Proc
ESMO 2012Abstract 12007O.
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Best Response Rates
Response T790 Mutation Status T790 Mutation Status Total (n 96)
Response 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
Janjigian YY et al. Proc ESMO 2012Abstract
12007O.
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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 patients 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

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Progressive Disease on a Trial of CO-1686
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Partial Response After Retrial with Erlotinib
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Progressive Disease After Retrial of Erlotinib
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Partial Response to Cetuximab and Afatinib
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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 2013Abstract O03.06.
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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
200910(1)28-35.
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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 20089(3)267-74.
31
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/paclitax
  el/bevacizumab followed by maintenance
  bevacizumab
• The patient is married with 2 young children

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2011 Systemic Disease Recurrence
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Response to Carboplatin/Paclitaxel/Bevacizumab
Prior to Maintenance Therapy
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Discussion Point

• Systemic treatment of metastatic pan-wild-type
  NSCLC Choice of chemotherapy regimen and role of
  bevacizumab

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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
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ECOG-E4599 Bevacizumab in Nonsquamous NSCLC
Paclitaxel/carboplatin/bevacizumab(n 443) Paclitaxel/carboplatin(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 2006355(24)2542-50
.
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Discussion Point

• Recognition and management of hypertension and
  proteinuria with bevacizumab risk of
  cardiovascular events

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Discussion Point

• Maintenance strategies in NSCLC biologic
  therapy, chemotherapy or both

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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
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PointBreak Phase III Trial Design
Induction Phase
Maintenance Phase

• Inclusion
• - No prior systemic therapy for lung cancer
• - PS 0/1
• - Stage IIIB-IV NS-NSCLC
• - Stable txt brain mets
• Exclusion
• Peripheral neuropathy
• Grade 1
• - Uncontrolled pleural effusions

Pemetrexed Carboplatin Bevacizumab
Pemetrexed Bevacizumab
R
Bevacizumab
Paclitaxel Carboplatin Bevacizumab
Patel JD et al. J Clin Oncol 201331(34)4349-57.
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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
Stage IIIB/IV nonsquamous NSCLC No brain metastases Stable or better response after 4 courses of carbo, paclitaxel and bev
Bevacizumab
R
Pemetrexed
Bevacizumab Pemetrexed
Primary Endpoint Overall survival Induction
therapy Carboplatin, paclitaxel and bevacizumab
www.clinicaltrials.gov, May 2014
42
Case 4 (from the practice of Ms Sipples)

• A 77-year-old woman diagnosed in 1982 with
  early-stage 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

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Discussion Point

• Adjuvant therapy for NSCLC Choice of platinum
  doublet in older patients

44
Discussion Point

• Available data with nab paclitaxel in lung cancer

45
Phase III Nab P/C vs P/C Study Design
Nab Paclitaxel 100 mg/m2 d1, 8, 15 Carboplatin
AUC 6 d1 q3wk No Premedication n 521
Chemo-naïve PS 0-1 Stage IIIb/IV NSCLC N 1,052
11
Paclitaxel 200 mg/m2 d1 q3wk Carboplatin AUC 6 d1
q3wk With Premedication of Dexamethasone
Antihistamines n 531

• Stratification factors
• Stage (IIIb vs IV)
• Age (lt70 vs gt70)
• Histology (squamous vs nonsquamous)

Socinski MA et al. J Clin Oncol
201230(17)2055-62.
46
Common Treatment-Related Grade 3 Adverse Events
Nab Paclitaxel (n 514) Nab Paclitaxel (n 514) Standard Paclitaxel (n 524) Standard Paclitaxel (n 524)
Adverse event Grade 3 Grade 4 Grade 3 Grade 4 p-value
Neutropenia 33 14 32 26 lt0.001
Thrombocytopenia 13 5 7 2 lt0.001
Anemia 22 5 6 lt1 lt0.001
Sensory neuropathy 3 0 11 lt1 lt0.001
Socinski MA et al. J Clin Oncol
201230(17)2055-62.
47
Objective Responses by Histology
Squamous
Nonsquamous
P lt 0.001
P 0.060
P 0.808
P 0.069
Nab P/C
Percent Responses
P/C
Socinski MA et al. J Clin Oncol
201230(17)2055-62 Socinski MA et al. ASCO
2010Abstract 7511.
48
Response and Survival in Elderly Patients (70)
Endpoint Nab P/C (n 74) P/C (n 82)
Overall response rate 34 24
Median progression-free survival 8 mo 6.8 mo
Median overall survival 19.9 mo 10.4 mo
Adverse events similar in both groups Adverse events similar in both groups Adverse events similar in both groups
Nab paclitaxel Less neuropathy Less neutropenia Less arthralgia More anemia Nab paclitaxel Less neuropathy Less neutropenia Less arthralgia More anemia Nab paclitaxel Less neuropathy Less neutropenia Less arthralgia More anemia
Socinski MA et al. Ann Oncol 201324(2)314-21.
49
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

50
Role of PD-1 in Suppressing Antitumor Immunity
Tumor cell
Patients T cells
MHC
TCR
T cell
PD-1
PD-L1
T-cellblockade
B7.1
Tumor cell growth
T cells
MHC
TCR
PD-1
PD-L1
T-cellactivation
Tumor cell death
EngineeredFc-domain
B7.1
Granzymes and perforin
Anti-PD-L1

• 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
2013Abstract 8008.
51
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 2012366(26)
2443-54.
52
Clinical Development of Inhibitors of PD-1 Immune
Checkpoint
Target Antibody Molecule Development stage
PD-1 Nivolumab (BMS-936558/MDX-1106/ONO-4538) Fully human IgG4 mAb Phase II multiple tumors
Pidilizumab (CT-011) Humanized IgG1 mAb Phase II multiple tumors
Lambrolizumab (MK-3475) Humanized IgG4 mAb Phase I
AMP-224 B7-DC/IgG1 fusion protein Phase I
PD-L1 MDX-1105/BMS-936559 Fully human IgG4 mAb Phase I
Giaccone G. Proc ASCO Clinical Science Symposium.
53
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)

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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

55
Discussion Point

• ALK and ROS tumor rearrangements Indications for
  testing

56
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 2007448(7153)561-6 2
Bergethon K et al. J Clin Oncol
201230(8)863-70 3 Takeuchi K et al. Nat Med
201218(3)378-81.
57
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
58
Discussion Point

• Efficacy of crizotinib in patients with ALK and
  ROS rearrangements unique toxicities associated
  with crizotinib Vision abnormalities,
  hypogonadism

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Activity of Crizotinib in ALK NSCLCUpdate 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 2012Abstract 7533.
60
FDA NEWS RELEASEApril 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
61
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 2014370(13)1189-97.
62
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 2014370(13)1189-97.
63
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 patients 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

64
Pre- and Post-vinorelbine and trastuzumab
treatment
Prior to treatment
Post treatment
65
HER2 in Lung CancersAgents Targeting
HER2Amplification and Protein Expression

• Trastuzumab
• Pertuzumab
• Lapatinib
• Ado-Trastuzumab Emtansine

Trials of Investigational Agents Targeting HER2
Mutations

• Dacomitinib
• Afatinib
• Neratinib
• Neratinib Temsirolimus

66
Discussion Point

• Role of multiplex testing to identify other lung
  cancer mutations Implications for clinical trial
  referral and nonprotocol care

67
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