Non-Small Cell Lung Cancer: Topic Review & Case Presentation

Tauhid Ahmed Bhuiyan, PharmDPharmacy 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)

ObjectivesTo 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 NSCLCI do not have financial relationship and no actual or potential conflict of interest in relation to this activity

TerminologyOnco-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 cases158,040 deaths

Incidence increases with age, 2/3 cases diagnosed in age between 60-79 years

Despite medical advancement, the 5-year survival rate is about 16.8%DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015

Estimated Age-Standardized Rates (World) per 100,000

WHO: International Agency for Research on Cancer. Accessed: June 26, 2015. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx

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 CancerSmall CellNon-Small CellCombinedTypical CarcinoidAtypical CarcinoidAdenocarcinoma Squamous cell carcinomaLarge Cell carcinoma80-87%37-47%25-32%10-18%DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014

Etiology/PathogenesisAlteration of normal bronchial epithelial cellsMultiple 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

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

Smoking & Lung Cancer RisksFrom 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-foldSpouses of smokers found to have higher risk (~25%) of lung cancer than spouses of non-smokers

Smoking cessation: Measurable difference at 5 years80-90% reduction after 15 yearsCutting the number smoked per day by half of heavy smokers ( 15 cigarettes per day) mortality decreases by 25%Peto R et al. BMJ 2000; 321:323-9Godtfredsen NS. et al. JAMA 2005; 294:1505-10

NSCLCSlow 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 ReceptorEML4-ALK: Echinoderm Microtubule-associated protein-Like 4-Anaplastic Lymphoma kinase

KRASMost 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. 2015https://sangakukan.jp/journal/journal_contents/2013/01/articles/1301-02-1/1301-02-1_earticle.html

EGFRMutation 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. 2015Brambilla E. et al. Eur Respir J. 2009; 33(6): 14851497 Erlotinib

EML4-ALKEstimates 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. 2015https://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 timeNo survival benefit or reproducible results of agents like -carotene, retinoic acid, selenium, -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, 2014Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015

Clinical PresentationsIn 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 syndromesMay involve any systems, e.g. endocirne, neuromuscular or muscoskeletal, cardiovascular, GI, or renal

DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014A group of symptoms that may develop when substances released by some cancer cells disrupt the normal function of surrounding cells and tissue

Diagnosis

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 scansDiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015

PET: A positron emission tomography (PET)scanis a type of imaging test. It uses a radioactive substance called a tracer to look for disease in the body. APET scanshows how organs and tissues are working19

TNM Staging Estimate prognosis and guidance of therapy Staging system established by American Joint Committee on Cancer (AJCC)

TNMSize of the tumorExtent of Nodal Involvement Presence of metastatic sitesDiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014

Quick Reference Guide

Lababede O. et al. CHEST 1999; 115:233235

Management

Goals of Therapy Limited Stage (I & II)Complete remission

Advanced Stage (III & IV)Prolong progression free survivalImprove 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 IIIAVinorelbine/cisplatin (VC) most data on survival benefit Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015

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 conditionsNon-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015

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 cellsAmerican 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 mutationSecond 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: