Non-Small Cell Lung Cancer - CAPhO...Non-Small Cell Lung Cancer Learning Objectives: 1. Name the...

Canadian Association of Pharmacy in Oncology Oncology Fundamentals Day 2019

Non-Small Cell Lung Cancer

Time: September 28th, 2019 at 12:10 -13:00 EDT

Speaker: Carrie Kung, BSc Pharm, PharmD, BCPS

Oncology Drug Information Specialist

Provincial Pharmacy, BC Cancer

Email: [email protected]

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mailto:[email protected]


Disclosure

I have no actual or potential conflict of interest in relation to this presentation on Non-Small Cell Lung Cancer (NSCLC).

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Learning Objectives:

1. Name the major pathological types of NSCLC

2. Describe the treatment approach to early stage NSCLC

3. Describe the treatment approach to advanced stage NSCLC

4. Recommend immunotherapies for advanced stage NSCLC in the first line setting and be able to recognize as well as manage common adverse drug reactions

5. Recommend targeted therapies for advanced stage NSCLC in the first line setting and be able to recognize as well as manage common adverse drug reactions

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Audience Question

Which of the following is a correct statement?

A. The annual projected incidence for lung cancer among Canadians is 28,000 cases

B. NSCLC accounts for 15% of lung cancer cases

C. 70% of NSCLC cases are diagnosed at early stages

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Audience Question

Which of the following is a correct statement?

A. The annual projected incidence for lung cancer among Canadians is 28,000 cases

B. NSCLC accounts for 15% of lung cancer cases

C. 70% of NSCLC cases are diagnosed at early stages

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Canadian Cancer Statistics Advisory Committee. Canadian Cancer Statistics 2018. Toronto, ON: Canadian Cancer Society; 2018. Available at: cancer.ca/Canadian-Cancer-Statistics-2018-EN (accessed on Sept 1, 2019)








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Lung Cancer Classification

Lung Cancer

Non-Small Cell

85%

Adenocarcinoma

40%

Squamous Cell Carcinoma

25-30%

Large Cell Carcinoma

10-15%

Small Cell

15%

Lung Carcinoid Tumour

5%

https://www.cancer.org/cancer/non-small-cell-lung-cancer.html7

https://www.cancer.org/cancer/non-small-cell-lung-cancer.html

Adenocarcinoma

• Arise from cells in the glands

• Slower growth

• Usually develop in bronchioles, close to periphery of the lungs

• More common in non-smokers, females, younger patients

8https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/lung-adenocarcinoma

https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/lung-adenocarcinoma

Squamous Cell Carcinoma

• Arise from thin, flat squamous cells of airway lining

• Faster growth, early metastases

• Usually develop in bronchi, close to the center of the lungs

• More common in smokers

9https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/squamous-cell-lung-cancer

https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/squamous-cell-lung-cancer

Large Cell Carcinoma

• Distinctively different from adenocarcinoma, squamous cell carcinoma, and larger than small cell carcinoma

• Faster growth, early metastases

• Usually develop close to the periphery of the lungs

• More common in males

10https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/large-cell-lung-cancer

https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/large-cell-lung-cancer








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Early Stage NSCLC

Stage I Stage II

At initial diagnosis 30% of NSCLC cases

Cancer location Ipsilateral Ipsilateral

5 year survival 68 – 92% 53 – 60%

Treatment modality SurgeryChemotherapyRadiation Therapy

SurgeryChemotherapyRadiation Therapy

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Advanced Stage NSCLC

Stage III Stage IV

At initial diagnosis 70% of NSCLC cases

Cancer location Ipsilateral, Contralateral Contralateral, Metastatic

5 year survival 13 – 36% <1 – 10%

Treatment modality SurgeryChemotherapyRadiation Therapy

ChemotherapyRadiation TherapyImmunotherapyTargeted Therapy

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Advanced Stage NSCLC: First Line Treatment Algorithm

Advanced NSCLC

Programmed Death-Ligand 1 (PD-L1)

Expression Positive

PembrolizumabAtezolizumab

Epidermal Growth Factor Receptor (EGFR) Mutation

Positive

GefitinibErlotinibAfatinib

OsimertinibNecitumumabDacomitinib

Anaplastic Lymphoma Kinase

(ALK) Mutation Positive

CrizotinibCeritinibAlectinib

ROS1 Mutation Positive

Crizotinib

BRAF V600E Mutation Positive

Dabrafenib + Trametinib

16

Hellmann M and West H. Management of advanced non-small cell lung cancer lacking a driver mutation: immunotherapy. Lilenbaum RC, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)

http://www.uptodate.com/

Immunotherapies for NSCLC

Immunotherapy Health Canada Approved First Line Indication Dose

Pembrolizumab (2015) • Monotherapy for metastatic NSCLC with high PD-L1 (≥ 50%) expression

• In combination with carboplatin and either paclitaxel or nab-paclitaxel for metastatic, squamous NSCLC

• In combination with pemetrexed and platinum for metastatic, non-squamous NSCLC

200 mg IV q 3 weeks

Atezolizumab (2017) • In combination with bevacizumab, paclitaxel, and carboplatin for metastatic, non-squamous NSCLC

1200 mg IV q 3 weeks

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https://pdf.hres.ca/dpd_pm/00052759.PDF, https://pdf.hres.ca/dpd_pm/00052588.PDF

https://pdf.hres.ca/dpd_pm/00052759.PDF


Audience Question

• PD is a 55 yo F with advanced NSCLC. She has just received her 3rd cycle of pembrolizumab 7 days ago. Today she presents to your pharmacy complaining of extreme fatigue, feeling cold constantly, generalized muscle aches, and newly developed constipation. She’d like to get a vitamin supplement to boost her energy and an OTC medication to relieve her constipation.

What would you recommend?

A. Assure PD that these are self-limiting symptoms – no medications are needed

B. Recommend multivitamin 1 tablet PO daily and docusate 200 mg PO daily

C. Advise PD to report these symptoms to her doctor immediately for further workup

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Audience Question





C. Advise PD to report these symptoms to her doctor immediately for further workup

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Immune-Mediated Adverse Reactions and Clinical Management

❑ Supportive care for symptom management❑ Immunotherapy treatment interruption ❑ Corticosteroid: initial dose of 0.5 to 2

mg/kg/day prednisone or equivalent followed by a taper

❑ Tumour necrosis factor-alpha antagonist e.g. infliximab 5 mg/kg x 1, repeat in 2 weeks PRN

❑ Permanent immunotherapy treatment discontinuation

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https://www.researchgate.net/figure/Select-immune-related-adverse-events_fig2_281515954Postow M and Wolchok J. Patient selection criteria and toxicities associated with checkpoint inhibitor immunotherapy. Atkins M, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)

https://www.researchgate.net/figure/Select-immune-related-adverse-events_fig2_281515954


Audience Question





C. Advise PD to report these symptoms to her oncology team immediately for further workup

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Advanced NSCLC


Expression Positive



Positive







Crizotinib



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Lilenbaum RC. Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor. West, HJ, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)


Targeted Therapies for NSCLC with EGFR Mutation

EGFR Targeted Therapy Health Canada Approved First Line Indication Dose

Gefitinib (2003) • Monotherapy for locally advanced or metastatic NSCLC with EGFR mutations

250 mg PO daily

Erlotinib (2007) • Monotherapy for locally advanced or metastatic NSCLC with EGFR mutations

150 mg PO daily

Afatinib (2014) • Monotherapy for metastatic adenocarcinoma NSCLC with EGFR mutations

40 mg PO daily

Osimertinib (2016) • Monotherapy for locally advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations

80 mg PO daily

Necitumumab (2017) • In combination with gemcitabine and cisplatin for locally advanced or metastatic, squamous NSCLC with EGFR mutations

800 mg IV on days 1 and 8 of 3-week cycle

Dacomitinib (2019) • Monotherapy for locally advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations

45 mg PO daily

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https://pdf.hres.ca/dpd_pm/00041427.PDF, https://pdf.hres.ca/dpd_pm/00047154.PDF, https://pdf.hres.ca/dpd_pm/00051644.PDF, https://pdf.hres.ca/dpd_pm/00052586.PDF, https://pdf.hres.ca/dpd_pm/00038502.PDF, https://pdf.hres.ca/dpd_pm/00050253.PDF







Audience Question

• EG is a 70 yo F with EGFR-positive NSCLC. She was prescribed afatinib 40 mg PO daily 1 week ago. Today she presents to your pharmacy with minor pruritic rash on her face.


A. Assure EG that the rash will improve on its own - no medications are needed

B. Advise EG to apply moisturizer frequently and she may try OTC topical corticosteroid cream

C. Advise EG to stop afatinib immediately as she is developing an allergic reaction to this drug

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Audience Question

• EG is a 70 yo F with EGFR-positive NSCLC. She was prescribed afatinib 40 mg PO daily 1 week ago. Today she presents to your pharmacy with minor pruritic rash on her face.


A. Assure EG that the rash will improve on its own - no medications are needed

B. Advise EG to apply moisturizer frequently and she may try OTC topical corticosteroid cream

C. Advise EG to stop afatinib immediately as she is developing an allergic reaction to this drug

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Targeted Therapies: Dermatological ADRs

• Onset of symptoms:

• Pruritis, acneiform rash: 1-2 weeks

• Dry Skin: 2-3 weeks

• Nail Changes: 1-2 months

• Incidence of skin rash and clinical management:

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https://pdf.hres.ca/dpd_pm/00041427.PDF, https://pdf.hres.ca/dpd_pm/00047154.PDF, https://pdf.hres.ca/dpd_pm/00051644.PDF, https://pdf.hres.ca/dpd_pm/00052586.PDF, https://pdf.hres.ca/dpd_pm/00038502.PDF, https://pdf.hres.ca/dpd_pm/00050253.PDFMelosky B. Management of EGFR TKI-induced dermatologic adverse events. Curr Oncol 2015;22(2):123-32.

EGFR Targeted Therapy

All Incidence (%) ≥ Grade 3 Incidence (%)

Clinical Management

Gefitinib 66-71 3-5 □ Topical moisturizer□ Topical corticosteroids□ Treatment interruption or discontinuation□ Sun protection

Erlotinib 73-99 2-19

Afatinib 81-100 15-16

Osimertinib 58 1

Necitumumab 78 6

Dacomitinib 78 21







Audience Question

• A month later, EG returns to your pharmacy with a 5% benzoyl peroxide gel in her hand. Her facial pruritic rash has turned into severe pustules and her doctor is putting her on a short break from afatinib until her rash resolves. Meanwhile, EG’s grand-daughter has recommended this benzoyl peroxide product for her. EG couldn’t wait to try this product when her doctor restarts her on afatinib.


A. Assure EG that her skin rash likely will not recur, so there is no need for benzoyl peroxide gel

B. Agree that EG may give benzoyl peroxide gel a try and remind her about sun protection

C. Suggest EG to contact her doctor for a minocycline prescription before she restarts afatinib

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Audience Question

• A month later, EG returns to your pharmacy with a 5% benzoyl peroxide gel in her hand. Her facial pruritic rash has turned into severe pustules and her doctor is putting her on a short break from afatinib until her rash resolves. Meanwhile, EG’s grand-daughter has recommended this benzoyl peroxide product for her. EG couldn’t wait to try this product when her doctor restarts her on afatinib.


A. Assure EG that her skin rash likely will not recur, so there is no need for benzoyl peroxide gel

B. Agree that EG may give benzoyl peroxide gel a try and remind her about sun protection

C. Suggest EG to contact her doctor for a minocycline prescription before she restarts afatinib

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Advanced NSCLC


Expression Positive



Positive







Crizotinib



30

Shaw AT and Solomon B. Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer. Lilenbaum RC, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)


Targeted Therapies for NSCLC with ALK Mutation

ALK Targeted Therapy Health Canada Approved First Line Indication Dose

Crizotinib (2012) • Monotherapy for locally advanced or metastatic NSCLC with ALK mutation

250 mg PO bid

Ceritinib (2015) • Monotherapy for locally advanced or metastatic NSCLC with ALK mutation

450 mg PO daily

Alectinib (2016) • Monotherapy for locally advanced or metastatic NSCLC with ALK mutation

600 mg PO bid

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https://pdf.hres.ca/dpd_pm/00050506.PDF, https://pdf.hres.ca/dpd_pm/00048635.PDF, https://pdf.hres.ca/dpd_pm/00047525.PDF




Audience Question

• AL is a 52 yo M with ALK-positive NSCLC. He has been taking ceritinib 450 mg PO daily for 5 days. Today he presents to your pharmacy complaining of minor diarrhea.


A. Advise AL to continue ceritinib as his symptom is likely caused by gastroenteritis and will resolve on its own in the next few days

B. Advise AL to continue ceritinib even though his symptom is likely caused by ceritinib; recommend oral fluid hydration, bland foods, and he may try OTC antidiarrheal medication

C. Advise AL to stop ceritinib and contact his doctor immediately as he is intolerant to this medication

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Audience Question

• AL is a 52 yo M with ALK-positive NSCLC. He has been taking ceritinib 450 mg PO daily for 5 days. Today he presents to your pharmacy complaining of minor diarrhea.


A. Advise AL to continue ceritinib as his symptom is likely caused by gastroenteritis and will resolve on its own in the next few days

B. Advise AL to continue ceritinib even though his symptom is likely caused by ceritinib; recommend oral fluid hydration, bland foods, and he may try OTC antidiarrheal medication

C. Advise AL to stop ceritinib and contact his doctor immediately as he is intolerant to this medication

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Targeted Therapies: Gastrointestinal ADRs

• Onset of Symptoms:

• Nausea, vomiting, diarrhea: 2-5 days

• Incidence of diarrhea and clinical management:

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https://pdf.hres.ca/dpd_pm/00050506.PDF, https://pdf.hres.ca/dpd_pm/00048635.PDF, https://pdf.hres.ca/dpd_pm/00047525.PDFRothenstein JM. Managing treatment-related adverse events associated with ALK inhibitors. Curr Oncol 2014;21(1):19-26.

ALK Targeted Therapy All Incidence (%) ≥ Grade 3 Incidence (%) Clinical Management

Crizotinib 54 2 □ non-pharmacological measures□ antidiarrheal medications□ treatment interruption or discontinuation likely not needed

Ceritinib 82 5

Alectinib 18 1




Audience Question

• A week later, AL returns to your pharmacy asking you to recommend a multivitamin for his eyes. He notices that he is not seeing as clearly as before which he attributes to aging.


A. Recommend a lutein-containing multivitamin for AL

B. Advise AL to continue ceritinib even though his symptom is likely caused by ceritinib

C. Advise AL to stop ceritinib and contact his doctor immediately for further workup

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Audience Question

• A week later, AL returns to your pharmacy asking you to recommend a multivitamin for his eyes. He notices that he is not seeing as clearly as before which he attributes to aging.


A. Recommend a lutein-containing multivitamin for AL

B. Advise AL to continue ceritinib even though his symptom is likely caused by ceritinib

C. Advise AL to stop ceritinib and contact his doctor immediately for further workup

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Targeted Therapies: Ophthalmological ADRs

• Onset of Symptoms:

• Reduced visual acuity, flashing lights, vitreous floaters, photopsia: 7 days

• Incidence of visual disturbance and clinical management:

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https://pdf.hres.ca/dpd_pm/00050506.PDF, https://pdf.hres.ca/dpd_pm/00048635.PDF, https://pdf.hres.ca/dpd_pm/00047525.PDFShaw AT and Solomon B. Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer. Lilenbaum RC, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)

ALK Targeted Therapy All Incidence (%) ≥ Grade 3 Incidence (%) Clinical Management

Crizotinib 63 0.3 □ patient counselling□ treatment interruption or discontinuation likely not needed

Ceritinib 13 0

Alectinib 12 0






Advanced NSCLC


Expression Positive



Positive







Crizotinib



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https://pdf.hres.ca/dpd_pm/00050506.PDFSequist LV and Neal JW. Personalized, genotype-directed therapy for advanced non-small cell lung cancer. Lilenbaum RC, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)Lin JJ and Shaw AT. Recent advances in targeting ROS1 in lung cancer. J Thorac Oncol 2017;12(11):1611-25.




Advanced NSCLC


Expression Positive



Positive







Crizotinib



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https://pdf.hres.ca/dpd_pm/00050662.PDF, https://pdf.hres.ca/dpd_pm/00050553.PDFSequist LV and Neal JW. Personalized, genotype-directed therapy for advanced non-small cell lung cancer. Lilenbaum RC, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)Khunger A et al. Dabrafenib in combination with trametinib in the treatment of patients with BRAF V600-positive advanced or metastatic non-small cell lung cancer: clinical evidence and experience. Ther Adv Respir Dis 2018; 12: 1753466618767611.




Targeted Therapies for NSCLC with BRAF V600E Mutation

Targeted Therapy Health Canada Approved First Line Indication Dose

Dabrafenib (2013) • In combination with trametinib for metastatic NSCLC with BRAF V600E mutation

150 mg PO bid

Trametinib (2013) • In combination with dabrafenib for metastatic NSCLC with BRAF V600E mutation

2 mg PO daily

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https://pdf.hres.ca/dpd_pm/00050506.PDF, https://pdf.hres.ca/dpd_pm/00048635.PDF, https://pdf.hres.ca/dpd_pm/00047525.PDF





Questions?

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References• AstraZeneca Canada. IRESSA® product Monograph. Mississauga, Ontario; 25 September 2017.

• AstraZeneca Canada Inc. TAGRISSO® product monograph. Mississauga, Ontario; 6 August 2019.

• Boehringer Ingelheim (Canada) Ltd. GIOTRIF® product monograph. Burlington, Ontario; 6 June 2019.

• Canadian Cancer Statistics Advisory Committee. Canadian Cancer Statistics 2018. Toronto, ON: Canadian Cancer Society; 2018. Available at: cancer.ca/Canadian-Cancer-Statistics-2018-EN (accessed on Sept 1, 2019)

• Eli Lilly Canada Inc. PORTRAZZA® product monograph. Toronto, Ontario; 16 March 2017.

• GlaxoSmithKline Inc. TAFINLAR® product monograph. Mississauga, Ontario; 12 April 2019.

• Hellmann M and West H. Management of advanced non-small cell lung cancer lacking a driver mutation: immunotherapy. Lilenbaum RC, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)

• Hoffmann-La Roche Limited. ALECENSARO® product monograph. Mississauga, Ontario; 25 September 2018.

• Hoffmann-La Roche Limited. TARCEVA® product monograph. Mississauga, Ontario; 4 September 2018.

• Hoffman-La Roche Limited. TECENTRIQ® product monograph. Mississauga, Ontario; 8 August 2019.

• https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/large-cell-lung-cancer

• https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/lung-adenocarcinoma

• https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/squamous-cell-lung-cancer

• https://www.cancer.org/cancer/non-small-cell-lung-cancer.html

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https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/large-cell-lung-cancer

https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/lung-adenocarcinoma

https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer/squamous-cell-lung-cancer


References• Khunger A et al. Dabrafenib in combination with trametinib in the treatment of patients with BRAF V600-positive advanced or metastatic non-small

cell lung cancer: clinical evidence and experience. Ther Adv Respir Dis 2018; 12: 1753466618767611.

• Lilenbaum RC. Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor. West, HJ, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)

• Lin JJ and Shaw AT. Recent advances in targeting ROS1 in lung cancer. J Thorac Oncol 2017;12(11):1611-25.

• Melosky B. Management of EGFR TKI-induced dermatologic adverse events. Curr Oncol 2015;22(2):123-32

• Merck Canada Inc. KEYTRUDA® product monograph. Kirkland, Quebec; 4 July 2019.

• Novartis Pharmaceuticals Canada Inc. MEKINIST® product monograph. Dorval, Quebec; 5 April 2019.

• Novartis Pharmaceuticals Canada Inc. ZYKADIA® product monograph. Dorval, Quebec; 5 December 2018.

• Pfizer Canada Ulc. VIZIMPRO® product monograph. Kirkland, Quebec; 22 February 2019.

• Pfizer Canada Inc. XALKORI® product monograph. Kirkland, Quebec; 27 March 2019.

• Postow M and Wolchok J. Patient selection criteria and toxicities associated with checkpoint inhibitor immunotherapy. Atkins M, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)

• Rothenstein JM. Managing treatment-related adverse events associated with ALK inhibitors. Curr Oncol 2014;21(1):19-26.

• Sequist LV and Neal JW. Personalized, genotype-directed therapy for advanced non-small cell lung cancer. Lilenbaum RC, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)

• Shaw AT and Solomon B. Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer. Lilenbaum RC, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on September 1, 2019.)

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