1. 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)
2. 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
3. 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
4. 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
6. 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
7. 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
8. 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%
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
9. 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
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
10. 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.)
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
11. 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
12. 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
13. 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
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
https://sangakukan.jp/journal/journal_contents/2013/01/articles/1301-02-1/1301-02-
1_earticle.html
14. 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)
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
Brambilla E. et al. Eur Respir J. 2009; 33(6): 1485–1497
Erlotinib
15. 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
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
https://sangakukan.jp/journal/journal_contents/2013/01/articles/1301-02-1/1301-02-
1_earticle.html
16. 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
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
17. 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
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
A group of symptoms that may develop when
substances released by some cancer cells disrupt
the normal function of surrounding cells and
tissue
19. 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
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
20. 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
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
23. 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
24. 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
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
25. 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
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
26. 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
27. 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
28. 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
29. 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
30. 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%)
31. 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
progression or unacceptable toxicity
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
32. 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
Erlotinib. Lexi-Drugs Multinational [Internet]. Accessed: June 06 2015
33. 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
34. 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
38. 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
progression or unacceptable toxicity
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%)
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
Erlotinib. Lexi-Drugs Multinational [Internet]. Accessed: June 06 2015
VEGF: Vascular Endothelial Growth
Factor
39. 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)
43. 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
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
44. 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
45. 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
46. 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
47. 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
48. 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: 5.02.63
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
49. 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: 110152 (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
50. 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: 15296
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
51. 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
52. 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
53. 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
Hinweis der Redaktion
PET: A positron emission tomography (PET) scan is a type of imaging test. It uses a radioactive substance called a tracer to look for disease in the body. A PET scan shows how organs and tissues are working
Stomatitis inflammation of the mucous membrane of the mouth