YAFI Online Programming // Disease State Management and Drug Therapy

Cancer in Non-Smokers

Who, What, Why and How to Treat

Educational Objectives

After participating in this activity pharmacists will be able to:

  • DESCRIBE NSCLC’s pathogenesis in nonsmokers
  • LIST the abnormalities in growth stimulatory signaling pathways in NSCLC
  • DESCRIBE the components of individualized treatment plans for EGFR mutation positive NSCLC
  • REVIEW new and emerging treatment options in EGFR T790M mutation positive patients
  • MAXIMIZE the pharmacist’s contribution in improving treatment adherence and ongoing monitoring to attain therapeutic treatment goals

After participating in this activity pharmacy technicians will be able to:

  • LIST the basic characteristics of NSCLC in nonsmokers
  • RECALL oral TKIs used in EGFR mutation positive NSCLC
  • IDENTIFY when to refer patients to the pharmacists for recommendations or referrals

Lung Cancer

Session Offered

Release Date: June 15, 2020

Expiration Date: June 15, 2022

Course Fee

Free

Session Codes

20YC45-XFY43 Pharmacist

20YC45-TKJ86 Pharmacy Technician

Accreditation Hours

2.0 hours of CE

Abstract

Lung cancer includes many different diseases in the pulmonary space. Increasing, oncologists are diagnosing lung cancer in non- or never-smokers. Those lung cancers are often associated with a specific set of mutations. The tyrosine kinase inhibitors (TKIs) target mutations that are more likely to occur in lung cancer in non-smokers. Available in three generations, the reversible TKIs are often used as first line treatments. If patients develop resistance, TKIs from the second and third generations can be used. These drugs have unique adverse effect profiles. Pharmacy teams need to be aware of management strategies for the most common adverse effects, including cutaneous reactions and diarrhea.

In addition, all TKIs have drug-drug interactions, and pharmacy teams need to screen carefully to ensure that patients avoid some medications, or have dose modifications if they need to take others. Informed pharmacists and pharmacy technicians can help patients manage adverse effects, understand their therapies, and avoid medical misadventure.

Accreditation Statements

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and pharmacy technicians are eligible to participate in this application-based activity and will receive up to 0.2 CEU (2 contact hours) for completing the activity, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor on- line system and your participation will be recorded with CPE Monitor within 72 hours of submission

ACPE UAN:
0009-0000-20-045-H01-P
0009-0000-20-045-H01-T

Grant funding: AstraZeneca Pharmaceuticals

Cost: Free

Initial Release Date: June 15, 2020
Expiration Date: June 15, 2022

To obtain CPE credit, visit the UConn Online CE Center

Use your NABP E-profile ID and the session code 20YC45-XFY43 for pharmacists or 20YC45-TKJ86 for pharmacy technicians to access the online quiz and evaluation.

First- time users must pre-register in the Online CE Center. Test results will be displayed immediately and your participation will be recorded with CPE Mon- itor within 72 hours of completing the requirements.

For questions concerning the online CPE activities, email joanne.nault@uconn.edu

Faculty

Bisni Narayanan, Pharm D, MS, Clinical Specialty Pharmacist, Yale New Haven Health Systems, Outpatient pharmacy services, Hamden, CT

Faculty Disclosure

Dr. Narayanan has no actual or potential conflicts of interest associated with this article.

Disclosure of Discussions of Off-label and Investigational Drug Use

This activity may contain discussion of off label/unapproved use of drugs. The content and views presented in this educational program are those of the faculty and do not necessarily represent those of the University of Connecticut School of Pharmacy. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Content

Introduction

Often, when people hear that a friend or relative has lung cancer, their first question is, “Does he smoke?” Increasingly, the answer is, “No.” This answer often surprises and confuses healthcare providers and lay people. Yet lung cancer includes many different diseases in the pulmonary space. Medical researchers consider patients who have smoked fewer than 100 cigarettes during their lifetime “never-smokers,” while people who have smoked more than 100 as “eversmokers.”1 Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers.2 Patients are often diagnosed at advanced stages, and median survival time is less than a year when oncologists use conventional chemotherapy. NSCLC occurs in two common subtypes: pulmonary adenocarcinoma and pulmonary squamous cell carcinoma.3 Committed smoking cessation efforts have led to decreased lung cancer incidence in the US over the last several decades.4 But the proportion of never-smokers with lung cancer (LUNS) has grown at an alarming rate. Experts estimate roughly 25% of all lung cancers are unrelated to tobacco use, accounting for more than 300,000 deaths each year.5 LUNS ranges from 10% of lung cancers in men in Western countries to up to 40% of lung cancers in Asian women.1,2 LUNS is a distinct entity with a different tumorigenic pattern, pathology, and natural history than smoking-related lung cancer. Adenocarcinoma is the most common histology observed in never-smokers.3 Smoking is strongly associated with squamous cell carcinoma and small cell lung cancer.

LUNS is more common in women and in East Asian countries.3 Never-smokers exposed to secondhand smoke, pollution, occupational carcinogens, and those who have inherited genetic susceptibility are at increased risk. Molecular profiling has shown a higher frequency of epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule associated protein-like 4 (EML4) with anaplastic lymphoma kinase (ALK) translocations in this patient population. These unique mutations are biomarkers to classify the lung cancer and choose the most appropriate therapy. Pharmacy teams can actively help patients manage adverse effects, prevent drug interactions, and improve treatment adherence. To understand how treatment targets LUNS, one has to drill down to the molecular level and the lengthy sidebar to the right explains the science. Although the science may seem heavy, reading slowly and making note of the abbreviations can help.

References

Full List of References

1. Pallis AG, Syrigos KN. Lung cancer in never smokers: disease characteristics and risk factors. Crit Rev Oncol Hematol. 2013;88(3):494-503. doi:10.1016/j.critrevonc.2013.06.011

2. Brambilla E, Gazdar A. Pathogenesis of lung cancer signalling pathways: roadmap for therapies. Eur Respir J. 2009;33(6):1485-1497. doi:10.1183/09031936.00014009

3. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446-454. doi:10.1038/nature25183

4. Mao Y, Yang D, He J, et al. Epidemiology of lung cancer. Surg Oncol Clin N Am. 2016;25(3):439-445. doi:10.1016/j.soc.2016.02.001

5. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers--a different disease. Nat Rev Cancer. 2007;7(10):778-790. doi:10.1038/nrc2190

6. Chung C. Tyrosine kinase inhibitors for epidermal growth factor receptor gene mutation-positive non-small cell lung cancers: an update for recent advances in therapeutics. J Oncol Pharm Pract. 2016;22(3):461-476. doi:10.1177/1078155215577810

7. Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. J Thorac Oncol. 2006;1(1):7-9.

8. Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64. doi:10.3389/fonc.2014.00064

9. Gridelli C, Peters S, Sgambato A, et al. ALK inhibitors in the treatment of advanced NSCLC. Cancer Treat Rev. 2014;40(2):300-306.
doi:10.1016/j.ctrv.2013.07.002

10. Morris TA, Khoo C, Solomon BJ. Targeting ROS1 rearrangements in non-small cell lung cancer: Crizotinib and Newer Generation Tyrosine Kinase Inhibitors. Drugs. 2019;79(12):1277-1286. doi:10.1007/s40265-019-01164-3

11. Chapman AM, Sun KY, Ruestow P, et al. Lung cancer mutation profile of EGFR, ALK, and KRAS: Meta-analysis and comparison of never and ever smokers. Lung Cancer. 2016;102:122-134. doi:10.1016/j.lungcan.2016.10.010

12. Dias M, Linhas R, Campainha S, et al. Lung cancer in never-smokers - what are the differences?. Acta Oncol. 2017;56(7):931-935. doi:10.1080/0284186X.2017.1287944

13. Recondo G, Facchinetti F, Olaussen KA, et al. Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or
next-generation TKI? Nat Rev Clin Oncol. 2018;15(11):694-708. doi:10.1038/s41571-018-0081-4

14. Solassol I, Pinguet F, Quantin X. FDA- and EMA-approved tyrosine kinase inhibitors in advanced EGFR-mutated non-small cell lung
cancer: safety, tolerability, plasma concentration monitoring, and management. Biomolecules. 2019;9(11):668. Published 2019 Oct
30. doi:10.3390/biom9110668

15. Tarceva (erlotinib) [package insert]. Northbrook, IL: OSI Pharmaceuticals, LLC, an affiliate of Astellas Pharma US, Inc.; 2016. Available at
https://www.gene.com/download/pdf/tarceva_prescribing.pdf. Accessed on June 8, 2020.

16. Iressa (gefitinib) [package insert]. Wilmington, DE: AstraZeneca, Inc, 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206995s003lbl.pdf. Accessed on June 8, 2020.

17. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutationpositive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742.

18. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246.

19. Sim EH, Yang IA, Wood-Baker R, et al. Gefitinib for advanced nonsmall cell lung cancer. Cochrane Database Syst Rev. 2018;1(1):CD006847. doi:10.1002/14651858.CD006847.pub2

20. Sohn HS, Kwon JW, Shin S, et al. Effect of smoking status on progression-free and overall survival in non-small cell lung cancer patients receiving erlotinib or gefitinib: a meta-analysis. J Clin Pharm Ther. 2015;40(6):661-671. doi:10.1111/jcpt.12332

21. Zhang Y, Kang S, Fang W, et al. Impact of smoking status on EGFRTKI efficacy for advanced non-small-cell lung cancer in EGFR mutants: a meta analysis. Clin Lung Cancer. 2015;16(2):144-151. doi:10.1016/j.cllc.2014.09.008

22. Hasegawa Y, Ando M, Maemondo M, et al. The role of smoking status on the progression-free survival of non-small cell lung cancer patients harboring activating epidermal growth factor receptor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor versus platinum doublet chemotherapy: a meta-analysis of prospective randomized trials. Oncologist. 2015;20(3):307-315. doi:10.1634/theoncologist.2014-0285

23. Cortot AB, Jänne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respir Rev. 2014;23(133):356-366. doi:10.1183/09059180.00004614

24. Gilotrif (afatinib) [package insert]. Ridgefield, Connecticut. Boehringer Ingelheim Pharmaceuticals, Inc. 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf. Accessed on June 8, 2020.

25. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334. doi:10.1200/JCO.2012.44.2806

26. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced nonsmall-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213-222. doi:10.1016/S1470-2045(13)70604-1

27. Masood A, Kancha RK, Subramanian J. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer harboring uncommon EGFR mutations: Focus on afatinib. Semin Oncol. 2019;46(3):271-283. doi:10.1053/j.seminoncol.2019.08.004

28. Lau SCM, Batra U, Mok TSK, et al. Dacomitinib in the Management of Advanced Non-Small-Cell Lung Cancer. Drugs. 2019;79(8):823-831. doi:10.1007/s40265-019-01115-y

29. Gelatti ACZ, Drilon A, Santini FC. Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Lung Cancer. 2019;137:113-122. doi:10.1016/j.lungcan.2019.09.017

30. Lamb YN ,Scott LJ. Osimertinib: A Review in T790M-Positive Advanced Non-Small Cell Lung Cancer. Target Oncol. 2017;12(4):555-562. doi:10.1007/s11523-017-0519-0

31. Sgambato A, Casaluce F, Maione P, et al. Targeted therapies in non-small cell lung cancer: a focus on ALK/ROS1 tyrosine kinase inhibitors. Expert Rev Anticancer Ther. 2018;18(1):71-80. doi:10.1080/14737140.2018.1412260

32. Lazarus DR, Ost DE. How and when to use genetic markers for nonsmall cell lung cancer. Curr Opin Pulm Med. 2013;19(4):331-339. doi:10.1097/MCP.0b013e328362075c

33. Kalemkerian GP, Narula N, Kennedy EB, et al. Molecular Testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. J Clin Oncol. 2018;36(9):911-919. doi:10.1200/JCO.2017.76.7293

34. Brevet M, Arcila M, Ladanyi M. Assessment of EGFR mutation status in lung adenocarcinoma by immunohistochemistry using antibodies specific to the two major forms of mutant EGFR. J Mol Diagn. 2010;12(2):169-176. doi:10.2353/jmoldx.2010.090140

35. Nagano T, Tachihara M, Nishimura Y. Mechanism of resistance to epidermal growth factor receptor-tyrosine knase inhibitors and a potential treatment strategy. Cells. 2018;7(11):212. doi:10.3390/cells7110212

36. Wu SG, Shih JY. Management of acquired resistance to EGFR TKItargeted therapy in advanced non-small cell lung cancer. Mol Cancer. 2018;17(1):38. Published 2018 Feb 19. doi:10.1186/s12943-018-0777-1

37. United States, Department of Health and Human Services, National Institutes of Health, National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events (CTCAE).Ver.5. Bethesda, MD: NCI; 2017. [Available online at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf; cited June 8, 2020]

38. Guggina, LM., Choi, AW, Choi, JN. EGFR Inhibitors and Cutaneous Complications: A Practical Approach to Management. Oncol Ther. 2017;5:135-148. doi.org/10.1007/s40487-017-0050-6

39. Melosky B, Leighl N, Rothenstein J, et al. (2015). Management of EGFR TKI–induced dermatologic adverse events. Current Oncology.
2015;22(2):123-132. doi.org/10.3747/co.22.2430

40. Burotto M, Ali SA, O'Sullivan Coyne G. Class act: safety comparison of approved tyrosine kinase inhibitors for non-small-cell lung carcinoma. Expert Opin Drug Saf. 2015;14(1):97-110. doi:10.1517/14740338.2014.973400

41. Aw DC, Tan EH, Chin TM, et al. Management of epidermal growt factor receptor tyrosine kinase inhibitor-related cutaneous and
gastrointestinal toxicities. Asia Pac J Clin Oncol. 2018;14(1):23-31. doi:10.1111/ajco.12687

42. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674

43. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med.
2018;378(2):113-125. doi:10.1056/NEJMoa1713137

44. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662

45. Leonetti A, Sharma S, Minari R, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121(9):725-737. doi:10.1038/s41416-019-0573-8

46. Reungwetwattana T, Nakagawa K, Cho BC, et al. CNS Response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer [published online ahead of
print, 2018 Aug 28]. J Clin Oncol. 2018;JCO2018783118. doi:10.1200/JCO.2018.78.3118

47. Tagrisso (osimertinib) [package insert] Wilmington, DE. AstraZeneca, 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf. Accessed on June 8, 2020.

48. Morihito O, Kentaro T, Hajime A, et al. Safety analysis of an open label, randomized phase 2 study of osimertinib alone versus osimertinib plus carboplatin-pemetrexed for patients with non–small cell lung cancer (NSCLC) that progressed during prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy and which harbors a T790M mutation of EGFR. J Clin Oncol. 2018;36(15_suppl):

49. Ahn MJ, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study. Lancet Oncol. 2020;21(3):373-386. doi:10.1016/S1470-2045(19)30785-5

50. Geynisman DM, Wickersham KE. Adherence to targeted oral anticancer medications. Discov Med. 2013;15(83):231-241.

51. Paolella GA, Boyd AD, Wirth SM, et al. Adherence to oral aAnticancer medications: Evolving interprofessional roles and pharmacist workforce considerations. Pharmacy (Basel). 2018;6(1):23. doi:10.3390/pharmacy6010023

52. Timmers L, Boons CC, Moes-Ten Hove J, et al. Adherence, exposure and patients' experiences with the use of erlotinib in nonsmall cell lung cancer. J Cancer Res Clin Oncol. 2015;141(8):1481-1491. doi:10.1007/s00432-015-1935-0

53. Mario E L, Yevgeniy B. Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors. In: Maja M, ed. UpToDate. Waltham, MA.: UpToDate; 2020. www.uptodate.com. Accessed June 8, 2020.

54. Hirsh, V, Blais, N, Burkes, R, et al. Management of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors. Current Oncology. 2014;21(6), 329-336. doi.org/10.3747/co.21.2241

55. Vogel WH, Jennifer P. Management strategies for adverse events associated with EGFR TKIs in non-small cell lung cancer. J Adv Pract Oncol. 2016;7(7):723-735.

56. Davis ME. Ocular Toxicity of Tyrosine kinase inhibitors. Oncol Nurs Forum. 2016;43(2):235-243. doi:10.1188/16.ONF.235-243

57. Kucharczuk CR, Ganetsky A, Vozniak JM. Drug-drug interactions, safety, and pharmacokinetics of EGFR tyrosine kinase inhibitors for the treatment of non-small cell lung cancer. J Adv Pract Oncol. 2018;9(2):189-200.