Advance Non-Small Cell Lung Cancer final

Tauhid Ahmed Bhuiyan, PharmD
Pharmacy Practice Resident (R2)
King Faisal Specialist Hospital &
Research Center (KFSH&RC)
Advanced Non-Small Cell Lung Cancer:
An Evidenced-Based Review of Targeted
Therapies With Case Presentation
King Faisal Specialist Hospital and Research Center (KFSHRC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing
pharmacy education. (UAN# 0833-0000-15-039-L01-P, 0833-0000-15-039-L01-T)

Objectives
 To discuss general overview of lung cancer
 To recognize available molecular targets of Non-
Small Cell Lung Cancer (NSCLC) and their
implications in therapy
 To identify diagnostic measures for diagnosing
NSCLC
 To evaluate available targeted therapies for
management of NSCLC
I do not have financial relationship and no actual or potential conflict of interest in relation to this activity

Terminology
 Onco-gene:
 “A gene that is a mutated (changed) form of a gene involved in
normal cell growth”
 Tumor suppressor gene:
 “A type of gene that makes a protein called a tumor suppressor
protein that helps control cell growth. Also called anti-oncogene”
 Disease free survival:
 “The length of time after primary treatment for a cancer ends that
the patient survives without any signs or symptoms of that
cancer. Also called DFS, relapse-free survival, and RFS.”
 Progression free survival:
 “The length of time during and after the treatment of a disease
that a patient lives with the disease but it does not get worse.
Also called PFS.”
NCI Dictionaries. National Cancer Institute. Accessed from:
http://www.cancer.gov/publications/dictionaries

Lung Cancer
 Second leading cause of cancer related deaths in both
sex
 Majority of the new cases occur in the developing
countries (55%)
 Projection disease burden for 2015,
 221, 200 new cases
 158,040 deaths
 Incidence increases with age, ̴ 2/3 cases diagnosed in
age between 60-79 years
 Despite medical advancement, the 5-year survival rate is
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015

(World)
per 100,000
WHO: International Agency for Research on Cancer. Accessed: June 26, 2015.

Epidemiology in Saudi Arabia
 Based on Saudi Cancer Registry (SCR) [1994-
2008]:
Khalid Al-Ahmadi & Ali Al-Zahrani. Int. J. Environ. Res. Public Health 2013. 10:7207-7228

Epidemiology in Saudi Arabia
 Age specific incidence rate:
 25 per 100 000 population
Maghfoor. I et al. Ann Saudi Med 2005; 25(1): 1-12

Classification
(Histologically)
Lung Cancer
Small Cell Non-Small Cell Combined Typical
Carcinoid
Atypical
Carcinoid
Adenocarcinoma Squamous cell
carcinoma
Large Cell
carcinoma
80-
87%
37-
47%
25-
32%
10-
18%

Etiology/Pathogenesis
 Alteration of normal bronchial epithelial cells
 Multiple genetic lesions
 Activation of proto-oncogene
 Inhibition or mutation of tumor suppressor gene
 Production of autocrine growth factors contribute
to cellular proliferation and malignant
transformation

Risk Factors
 Tobacco smoking ( ̴ 80% of all lung cancer
caused by cigarette smoking)
 Family history (first degree relatives with
cancer)
 Respiratory history (asthma, COPD)
 Environmental exposure to carcinogens
(e.g. asbestos, benzene, arsenic, etc.)

Smoking & Lung Cancer Risks
 From UK data, mortality risk of active smoking:
 Male smoker: 22-fold
 Female smoker: 12-fold
 Passive smoking increases mortality risks for non-
smokers by 1.5-fold
 Spouses of smokers found to have higher risk (~25%) of
lung cancer than spouses of non-smokers
 Smoking cessation:
 Measurable difference at 5 years
 80-90% reduction after 15 years
 Cutting the number smoked per day by half of heavy
smokers (≥ 15 cigarettes per day) mortality decreases
by 25%
Peto R et al. BMJ 2000; 321:323-9
Godtfredsen NS. et al. JAMA 2005; 294:1505-10

NSCLC
 Slow growing than small cell better prognosis
 Adenocarcinoma: most common type in non-
smokers
 Squamous cell carcinoma: common in smokers
 Mutations in KRAS, EGFR & EML4-ALK  more
targeted therapies
EGFR: Epidermal Growth Factor Receptor
EML4-ALK: Echinoderm Microtubule-
associated protein-Like 4-Anaplastic
Lymphoma kinase

KRAS
 Most common
mutation: ~25% of all
adenocarcinoma
 Exclusive to smoker
 Mutation has lack of
therapeutic efficacy
shorter survival
 No targeted therapy
established so far
https://sangakukan.jp/journal/journal_contents/2013/01/articles/1301-02-1/1301-02-
1_earticle.html

EGFR
 Mutation cause receptor
deregulation or over
expression
 Overall frequencies in
NSCLC = 10-15%
 Most common forms:
 Deletions in exon 19 and
exon 21 [sensitizing EGFR
mutation]
 Sensitive to small
molecule tyrosine kinase
inhibitor (TKI) (Erlotinib,
Gefitinib)
Brambilla E. et al. Eur Respir J. 2009; 33(6): 1485–1497
Erlotinib

EML4-ALK
 Estimates 2-7% of
patients with NSCLC and
common in young men
(median: 52 years)
 Due to inversion in
chromosome 2 that links
EML4 to ALK cancer
cell proliferation
 Does not occur
concurrently with EGFR or
KRAS
 Sensitive to TKI,
Crizotinib
https://sangakukan.jp/journal/journal_contents/2013/01/articles/1301-02-1/1301-02-
1_earticle.html

Prevention & Screening
 Prevention:
 No known effective method of chemoprevention at this time
 No survival benefit or reproducible results of agents like β-
carotene, retinoic acid, selenium, α-tocopherol, etc.
 Early lung cancer screening studies failed to demonstrate a
survival advantage
Screening:
 In 2010, National Lung Cancer Screening Trial (NLST) [RCT,
N= 53,000]:
 Comparison: CXR vs. Low dose CT (LDCT)
 Results: 20% relative risk reduction of death from lung cancer
using LDCT
 Current recommendation (agreement between all the
guideline bodies):
 Annual screening with LDCT for selected (55-80 years) high
risk current (30 PPY) or former (quit within 15 years) smokers

Clinical Presentations
 In general, location and extent of the tumor determine the
presenting signs and symptoms
 Common initial signs and symptoms:
 Cough with or without hemoptysis, dyspnea, and chest pain or
discomfort
 Systemic symptoms of malignancy:
 Anorexia, weight loss, and fatigue
 Extra-pulmonary signs and symptoms:
 Neurologic deficits, bone pain or pathological fracture, abnormal
liver function, etc.
 Paraneoplastic syndromes
 May involve any systems, e.g. endocirne, neuromuscular or
muscoskeletal, cardiovascular, GI, or renal
A group of symptoms that may develop when
substances released by some cancer cells disrupt
the normal function of surrounding cells and
tissue

Diagnosis
 Thorough history and physical examination
 Detecting signs and symptoms of primary tumor, regional
spread of the tumor, distant metastases, and paraneoplastic
syndrome
 Laboratory tests:
 CBC, serum electrolytes, LFTs, renal and bone profile
 Tissue sampling:
 Sputum cytology, bronchoscopy, transthoracic needle biopsy,
thoracentesis (depends on location of tumor)
 Molecular studies and biomarker analysis:
 Cobas® EGFR Mutation Test
 Fluorescence in situ hybridization (FISH) test: Alk mutation
 Other diagnostic tests:
 Chest radiograph, endobronchial ultrasound, CT scans, and
PET scans DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014

TNM Staging
 Estimate prognosis and guidance of therapy
 Staging system established by American Joint
Committee on Cancer (AJCC)
T N M
Size of
the tumor
Extent of
Nodal
Involvement
Presence of
metastatic sites

QuickReference
Guide
Lababede O. et al. CHEST 1999; 115:233–2

Goals of Therapy
 Limited Stage (I & II)
 Complete remission
 Advanced Stage (III & IV)
 Prolong progression free survival
 Improve quality of life
 Minimizing side effects due to the treatment

Treatment Approaches
 Resectable (Stage I, II, IIIA)
 Surgery: treatment of choice
 Radiation therapy: when medically inoperable
 Chemotherapy: adjuvant
 Cisplatin-based regimen in resected Stage II and IIIA
 Vinorelbine/cisplatin (VC) most data on survival benefit

Treatment Approaches
(Unresectable/Advanced Stages)
 Reports by Non-Small Cell Lung Cancer
Collaboration Group on 52 pivotal studies of
patients with advance stage showed that:
 Chemotherapy ± surgery/radiotherapy improves
 median survival by 2-4 months
 1-year absolute survival rate improved by 10%
 Treatment depends on patient-specific factors
such as age, performance status, and co-
morbid conditions

Eastern Cooperative Oncology
Group (ECOG) Performance Score
Status 0-2: consistent predictor of better response and improved
survival following chemotherapy
Status 2 + comorbidities: require less intensive therapy
Status ≥3: do not respond to chemotherapy
http://www.cancernews.com/data/Article/273.asp

Targeted Therapies
 “Newer type of cancer treatment that uses drugs
or other substances to more precisely identify and
attack cancer cells, while doing little damage to
normal cells”—American Cancer Society
 FDA approved specific targeted therapies
 Erlotinib: EGFR positive mutation
 Crizotinib: EML4-ALK positive mutation
 Bevacizumab*: if neither positive
*In combination with chemotherapy: carboplatin +
paclitaxel

Erlotinib (Tarceva®)
 Small molecule TKI used as:
 First-line: patient with EGFR mutation
 Second line: locally advanced/metastatic
NSCLC after progression on at least one prior
chemotherapy
 Dose: 150 mg by mouth daily until disease
progression or unacceptable toxicity
 Drug-drug interaction: strong CYP3A4
(inducers/inhibitors); proton pump inhibitors
 Side effects:
 Dermatologic: skin rash (49% to 85%; grade 3:
5% to 13%; grade 4: <1%; median onset: 8 days)
 Gastrointestinal: diarrhea (20% to 62%; grade
3: 2% to 6%; grade 4: <1%; median onset: 12
days)
 Respiratory: Cough (33% to 48%), dyspnea
(41% to 45%; grades 3/4: 8% to 28%)Kristen NG. et al. Biologics: Targets & Therapy 2007:1(4)
335–346

Dose Adjustments: Toxicity
 Discontinuation of therapy:
 Bullous, blister or exfoliative
 GI perforation
 Corneal perforation or severe ulceration
 Withhold and reinitiate with 50 mg dose
reduction:
 Severe rash
 Dehydration due to diarrhea
 Acute or worsening ocular toxicities or keratitis
Erlotinib. Lexi-Drugs Multinational [Internet]. Accessed: June 06 2015

Landmark Trials
Trial Study Design
Patient
Population
Results
OPTIMAL
n = 83
Multicenter, open-label,
randomized, phase III.
Oral erlotinib (150 mg/d)
vs. chemotherapy
(GEM+CIS)
Adults >18
years with
confirmed
Stage IIIB or IV
NSCLC +
EGFR positive
mutation
Median progression-free survival
(PFS): 13.1 months vs. 4.6
months; p<0.0001. Grade 3 and 4
side effects were less in erlotinib
group
EURTAC
n = 174
Multicenter,
multinational, open-
label, randomized,
phase III. Oral erlotinib
(150 mg/d) vs. chemo
(DTX+CIS)
Adults >18
years with
confirmed
Stage IIIB or IV
NSCLC +
EGFR positive
mutation
Median PFS: 9.7 months vs. 5.2
months; p<0.0001. Grade 3 & 4
hematologic toxicity was higher in
chemo group (22% vs. none),
whereas, erlotinib has higher rash
(13%), and ↑ of LFTs (2%)

Crizotinib (Xalkori®)
 Small molecule tyrosine kinase inhibitor of c-MET, ALK, or ROS 1
and indicated for:
 ALK-positive metastatic NSCLC
 Dose: 250 mg orally twice daily, continue treatment until disease
 Drug-drug interaction: strong CYP3A4 inhibitors/inducers
 Side effects:
 Cardiovascular: edema (28% to 39%), bradycardia (5% to 11%)
 Metabolic: hypophosphatemia (28%), hypokalemia (18%)
 Gastrointestinal: Diarrhea (43% to 60%), nausea (51% to 55%),
vomiting (40% to 47%)
 Hematologic: lymphocytopenia (51%; grades 3/4: 9% to 11%),
neutropenia (49%; grades 3/4: 5% to 12%)
 Hepatic: Increased serum ALT (13% to 76%; grades 3/4: 5% to
17%), AST (9% to 61%; grades 3/4: 2% to 9%)
 Ophthalmic: Visual disturbance (55% to 62%; onset: <2 weeks)
Ingnateus SH. et al. Drug Design, Development and Therapy
2011:5 471–485

Dose Adjustments: Toxicity
 Discontinuation of therapy:
 Pulmonary toxicity: Interstitial lung disease (any grade)
 Grade 4 hematologic toxicity despite lowest dose (250
mg once daily)
 QTc >500 msec or ≥60 msec change from baseline with
life-threatening symptoms
 Dose reduction necessary, if patient develops grade 3
or 4 cardiac, hematologic, and hepatotoxicity
 Dose reduction scheme:
 Step1: reduce dose to 200 mg orally twice daily; if not
tolerable
 Step2: reduce to 250 mg once daily. If not tolerable
 Step3: reduce to 250 mg once daily

Landmark Trials
• FDA approval as a second line from phase I and II studies
(PROFILE 1001 phase I, PROFILE 1005 phase II)
 Tumor response 60%
 PFS 7-10 months
 PROFILE 1007 [2012]: Phase 3, open-label,
randomized, two-arm study (n=318) between crizotinib vs.
standard chemotherapy
 Results (favoring crizotinib):
 Response rate: 65% vs. 20%; p<0.0001
 PFS: 7.7 months vs. 3 months; p<0.0001
 Fewer side effects mainly
 Diarrhea (53%), nausea (52%), vomiting (44%),
elevation of LFTs (36%)
Kwak EL et al. N Engl J Med 2010;363:1693-1703
Shaw AT. et al. Vienna, Austria: European Society for Medical Oncology, September
7.7
3

Landmark Trials
 PROFILE 1014 [2014]:
Randomized, open-label, phase III trial between crizotinib 250 mg twice
daily, or intravenous chemotherapy (pemetrexed, at a dose of 500 mg/m2 of
body-surface area or carboplatin, target area under the curve of 5 to 6 mg per
milliliter per minute) every 3 weeks for 6 cycles

Bevacizumab
 Anti VEGF, FDA approved indication (2006):
 Unresectable, locally advanced, recurrent, or metastatic, non-squamous
NSCLC who are not positive for EGFR or ALK
 First targeted agent that improved outcomes compared to chemotherapy,
however, not commonly used in most of the counties
 Dose:
 15 mg/kg IV every 3 weeks + chemotherapy X 6 cycles
 Maintenance: 15 mg/kg every 3 weeks as monotherapy until disease
 Side effects:
 Cardiovascular: hypertension (12% to 34%; grades 3/4: 5% to 18%)
 Renal: increased serum creatinine (16%) & proteinuria (≥2 g
proteinuria/24 hours)
 Hematologic: hemorrhage (40%; grades 3/4: ≤7%), leukopenia (grades
3/4: 37%), pulmonary hemorrhage (4% to 31%)
 Respiratory: upper respiratory tract infection (40% to 47%), epistaxis
(17% to 35%), dyspnea (25% to 26%), rhinitis (3% to >10%)
VEGF: Vascular Endothelial Growth
Factor

Landmark Trials
Results:
1. Compared to control arm, adding bevacizumab (15 mg/kg) resulted
in
a) Higher response rate (31.5% v 18.8%)
b) longer median time to progression (7.4 v 4.2 months)
c) modest increase in survival (17.7 v 14.9 months)
2. Bleeding was the most prominent adverse event (minor
mucocutaneous hemorrhage and major hemoptysis)

AVAiL:
Results
6.7
6.1
6.5
6.1

Evaluation of Therapeutic
Outcome
 For patients who have undergone surgery ±
radiotherapy/chemotherapy or both:
 Physical examination + chest radiography every 3-4
months X 2 years, then every 6 months for 3 years,
then annually
 Low dose chest CT annually to monitor local
recurrence
 Evaluation of tumor response to chemotherapy
 End of 2nd or 3rd cycle

Pharmacist’s Role
 Educating patient, caregiver, and health care
providers on managing complications of cancer
treatments
 Comprehensive medication therapy management
 drug-drug, drug-food or nutrition interactions
 optimizing appropriate dosing plans
 minimize the chance of significant adverse drug
reactions
 Ensuring safe and effective cancer and
supportive care medication therapies using
knowledge on evidence based medicine

Summary
 Lung cancer is the second leading cause of cancer
related deaths in both sex with overall 5-year survival
rate of ~16%
 Cigarette smoking is responsible for most lung
cancers (~80%), therefore, smoking cessation plays a
major role in therapeutic management
 NSCLC is diagnosed in most (~80%) lung cancer
patients which typically has a slower growth with
better prognosis
 Available molecular and biomarker studies in the
market include: Cobas® EGFR Mutation Test, and
FISH test for detection of ALK mutation

Summary
 Surgery is the treatment of choice for resectable
stages (I, II, IIIA), whereas, advance stages (IIIB
& IV) requires intensification of management (with
chemotherapy or targeted therapies)
 Currently, FDA approved targeted therapies with
better prognosis include:
 Erlotinib: EGFR positive mutation
 Crizotinib: EML4-ALK positive mutation
 Bevacizumab: if neither positive

Patient Case
 QA, is a 95 year old male, k/c of Stage IV EFGR positive
ALK negative NSCLC (adenocarcinoma subtype)
diagnosed in 2014 presented to pharmacotherapy clinic with
severe skin rash (face & scalp)
 HPI:
 Since 2013, QA had multiple visits to cardiology clinic c/o SOB
& compresive CP on exertion X 3 months. No history of weight
loss. Echo (2007) showed large lateral wall ischemia with EF
>55%. At the time, he also did not have any clinical signs of HF
 He was put on anti-failure medication, however, no
improvement in symptoms
 CT (03/2014): Scattered bilateral pulmonary nodules highly
suspicious for metastatic disease, no intrathoracic adenopathy
 PET scan (04/2014): finding related to Rt. lower lobe lung
cancer with metastatic pulmonary nodules + pericarinal
lymphadenopathy
 Tissue biopsy (06/2014): moderately differentiated
adenocarcinoma
 Molecular genetics (06/2014): positive for EGFR mutation in
exon 19
 On July 2014, patient was admitted to a local hospital with
massive pleural effusion that was drained
 Since then, he was started on Erlotinib at a dose of 150 mg by

Patient Case
 PMHx:
 BPH (stopped medication on his own in 2003), DM, HTN, IHD, OA s/p
bilateral total knee replacement
 SHx: unknown
 Allergy: NKA
 Home Medications:
 Vitals:
 Stable; HR: 74 bpm, BP: 159/89 mmHg
 Labs at baseline:
 CBC
 Chemistry:
 Hormone/tumor marker
 PSA: 5.02.63
Metoprolol 50 mg
daily
Isosorbide
dinit. 20 mg
daily
Aspirin 81
mg daily
Clopidogrel 75
mg by mouth
daily
Finasteride 5
mg daily
Tamsulosin
0.4 mg daily
Furosemide 40
mg daily as
needed
Simvastatin 20
mg daily
Omeprazol
e 20 mg
daily
WBC:
7.24
Hgb:
154
Hct:
0.419
Plt:
151
BUN:
7.1
SCr:
110
K: 4.5 Na: 141 Cl: 102 CO2 30
Alb:
40.6
ALT:
9.5
AST:
15.3
Bill (T):
9.5
Trig:
1.03
LDL:
1.97

Oncology Clinic Visit (Sep 2014)
 Subjective:
 c/o severe skin rash (scalp & face)
 Cough with sputum without hemoptysis
 Performance status: 2 (on wheelchair)
 Objective:
 Vital: stable; HR: 82 bpm, BP: 107/64 mmHg
 CBC: WNL except Hgb: 122, HCT: 0.357
 Chemistry: WNL except Scr: 110152 (within a month); BUN: 13.9
 Chest X-ray & CT: slow progression of disease manifested as
increase in the number of metastatic disease + pleural effusion
 Assessment:
 Drug induced skin rash & possible kidney injury
 Slow progression of the primary disease
 Plan:
 Repeat labs
 Hold erlotinib until reviewed in pharmacotherapy clinic in 2 weeks
 Start on Doxycycline/Clindamycin topical cream for rash

Pharmacotherapy Clinic Visit (Sep
2014)
 Subjective:
 c/o dry cough, no blood or sputum
 Acne form rash resolved
 No chest pain or diarrhea
 Objective:
 Vital: stable; HR: 71 bpm, BP: 105/61 mmHg
 CBC: WNL except Hgb: 105, HCT: 0.306
 Chemistry: WNL; SCr: 15296
 LFTs: WNL
 Assessment:
 Erlotinib induced increase Scr or due to dehydration secondary to
diuretics use
 Drug-drug interaction between omeprazole and erlotinib
 Plan:
 Start erlotinib 100 mg PO daily
 Discontinue omeprazole
 Continue clindamycin 0.1% topical solution for skin rash
 RTC in 4 weeks with Dr. Hamid

Oncology Clinic Visit (Oct 2014 -
Apr 2015)
 Subjective:
 No skin rash, mild cough with no hemoptysis
 No SOB, fever, N/V/D; mild constipation
 Objective:
 WNL; except Mg: 0.62 (consistently low)
 CT: Mild progression of the right lower lobe lung cancer as well
as right middle lobe masses
 Assessment:
 Tolerating change in therapy
 Slow progression of the disease
 Plan:
 Continue same & start patient on Magnesium Oxide 400 mg by
mouth TID

Pharmacotherapy Clinic Visit (July
2015)
 Subjective:
 No skin rash,
 No cough, SOB, CP
 No N/V/D or constipation
 Objective:
 WNL; SCr: 97, Mg: 0.66
 Assessment:
 Tolerating erlotinib; dose escalation (?)
 No drug-drug interaction
 Plan:
 Continue same management & RTC in 4 months

Current Medication Profile
Medication I ndication
1. Metoprolol XL 50 mg PO daily IHD, HF
2. Isosorbide dinitrate 20 mg PO
BID
IHD
3. Furosemide 40 mg PO daily Symptomatic management of HF
4. Clopidogrel 75 mg PO daily TNR
5. Aspirin 81 mg PO daily Secondary cardiovascular
prophylaxis
6. Finasteride 5 mg PO daily BPH
7. Tamsulosin 0.4 mg PO daily BPH
8. Erlotinib 100 mg PO daily NSCLC
9. Clindamycin 0.1% topical lotion Acne-form rash
10. Lubriderm lotion Dry skin
11. Simvastain 20 mg PO daily Dyslipidemia

Advance Non-Small Cell Lung Cancer final

Advance Non-Small Cell Lung Cancer final

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