non-small cell lung cancer - ce.mayo.edu · pdf file©2017 mfmer | slide-1 non-small cell...

©2017 MFMER | slide-1

Non-Small Cell Lung Cancer:Where We Are Today

Sila Shalhoub, PharmDPGY2 Oncology Pharmacy [email protected]

Pharmacy Grand Rounds September 26, 2017


Objectives• Identify the impact of known risk factors on patients

with specific subtypes of NSCLC

• Classify different treatment options based on staging and tumor characteristics

• Discuss the updated 2017 ASCO guidelines for stage IV NSCLC

• Outline a therapy strategy based on patient considerations and pathologic profile


Lung Cancer • Second most common cancer

• #1 leading cause of cancer death

• Deaths from lung cancer > colon + breast + prostate combined

• 2017 estimates: • 222,500 new cases• 155,870 deaths

• Types• Non-small cell lung cancer (NSCLC) -85% • Small cell lung cancer (SCLC) -15%

Chalela R, et al. J Thorac Dis. 2017 Jul;9(7):2142-2158American Cancer Society. Key Statistics for Lung Cancer. 2017


Risk Factors

Molina JR, et al. MayoClinProc. 2008 May;83(5):584-594National Cancer Institute. Lung Cancer. 2017

American Cancer Society. What Is Non-Small Cell Lung Cancer. 2017

Genetic/family history

Diet

Air pollution

Chemical exposure

Radiation

SMOKING


NSCLC Subtypes • Adenocarcinoma

• Most common (40%) • Originate in mucus secreting cells, outer part of the lung• Common in young, non-smokers, females

• Squamous cell carcinoma• Second most common (25%-30%)• Originate in the cells that line the inside of the airways

• Large cell carcinoma• Account for 10%-15% • Can appear in any part of the lung • Grow and spread quickly

• NSCLC not otherwise specified (NOS) American Cancer Society. What Is Non-Small Cell Lung Cancer. 2017

Chalela R, et al. J Thorac Dis. 2017 July;9(7):2142-2158


Presentation & Diagnosis

• Cough• Dyspnea• Hemoptysis• Infection

Sign & Symptoms

• CT• MRI vs. PET • Tissue biopsy

Diagnostic

• Pain • Weight loss • Malaise • Loss of appetite

CT: computed tomography MRI: magnetic resonance imaging PET: positron-emission tomography

American Cancer Society. What Is Non-Small Cell Lung Cancer. 2017


Staging and Prognosis • AJCC 7th edition TNM system

• T: Tumor N: Node M: Metastasis

• 8th edition published in Jan 2017 • Divided stage IA to IA1-3

• Addition of stage IIIC

• Divided stage IV to IVA and IVB

AJCC: American Joint Committee on Cancer Goldstraw P, et al. J Thorac Oncol 2016; 11:39

NCCN. Non-Small Cell Lung Cancer. 2017American Cancer Society. Non-Small Cell Lung Cancer Survival Rates. 2016

Stage 5-year survival rate

IA 49%

IB 45%

IIA 30%

IIB 31%

IIIA 14%

IIIB 5%

IV 1%


Treatment

• Surgical resection Stage I

• Surgical resection +/- ChemotherapyStage II

• Surgical resection • Chemo-radiotherapy Stage III

• Surgical resection • Chemo-radiotherapy• Targeted therapy • Immunotherapy

Stage IV

American Cancer Society. What Is Non-Small Cell Lung Cancer. 2017NCCN. Non-Small Cell Lung Cancer. 2017


40yo F non-smoker with newly diagnosed stage III NSCLC. Which of the following subtypes is she most likely to have?

A. Adenocarcinoma

B. Squamous cell carcinoma

C. Large cell carcinoma

D. NSCLC not otherwise specified (NOS)


Treatment of Stage IV NSCLC


Treatment of Stage IV NSCLC • Historically

• Two-drug platinum-based combination• Carboplatin + paclitaxel

• Median survival time• Untreated: ~ 4 – 6 months• Treated: ~ 8 – 11 months

• Currently • Focusing on biomarkers

Abbasi S, et al. Lung Cancer International. 2011


Biomarkers

PD-L1 status

EGFR mutation

ALK gene

rearrangementBRAF

mutation

ROS1 gene

rearrangement

PD-L1: Programmed Death-Ligand 1 EGFR: Epidermal Growth Factor ReceptorALK: Anaplastic lymphoma kinase

BRAF: human gene that encodes a protein called B-RafROS1: proto-oncogene receptor tyrosine kinase

©2017 MFMER | slide-13Janku F, et al. Nature Reviews Clinical Oncology. 2010;7:401-141

Signaling Pathway


Mutation Prevalence

15%

5%

3%

2%

0% 5% 10% 15% 20%

EGFR mutation

ALK gene rearrangement

BRAF mutation

ROS1 gene rearrangment

Pikor LA, et al. Lung Cancer. 2013 Nov;82(2):179-89


Treatment Algorithm for Stage IV NSCLC

NSCLC

Squamous cell NSCLC PD-L1 status

Non-Squamous-cell

NSCLC

EGFR mutation

BRAF mutation


ROS gene rearrangement

PD-L1 status

Reck M, et al. N Engl J Med. 2017;377:849-61


ALK Gene Rearrangement • Fusion oncogene arises from EML4- ALK

translocation: results from an inversion in the short arm of chromosome 2

• Occur in 3-5% in NSCLC

• Associated with light/never smokers, younger age, and adenocarcinoma subtype

• ALK inhibitors include:• 1st generation: crizotinib• 2nd generation: alectinib, ceritinib, brigatinib

Camidge DR, et al. Clin Cancer Res. 2010 Nov;16(22):5581-90Pikor LA, et al. Lung Cancer. 2013 Nov;82(2):179-89

ALK: Anaplastic lymphoma kinaseEML4: Echinoderm Microtubule-Associated Protein-Like 4


Mechanism of Action

Burns MW, et al. Lung Cancer: Targets and Therapy. 2015:6;35-42


Evolution From Chemotherapy to Targeted Therapy (ALK+, NSCLC)• Traditionally – platinum doublet

• Crizotinib• FDA approved in 2013• Progression-free survival:

• 7.7 months in crizotinib group vs. 3 months in chemotherapy group

• Response rate: • 65% with crizotinib vs. 20% with chemotherapy

• CNS disease and resistance

Shaw AT, et al. N Engl J Med. 2013;368:2385-94


Alectinib vs. Crizotinib – ALEX trial

Peters S, et al. N Engl J Med. 2017 Aug;377(9):829-838

Study design:

International, randomized, open-label, phase 3 trial

Participants:

Previously untreated, advanced ALK-positive NSCLC including asymptomatic CNS disease

Interventions:

Patients were assigned in 1:1 ratio to either:Alectinib 600mg twice daily OR Crizotinib 250mg twice daily

End points:

Primary: Investigators-assessed progression-free survival

Secondary: Independent review committee-assessed progression free survival, time to CNS progression, objective response rate, overall survival


Results


Outcomes Alectinib n=152 (%)

Crizotinibn=151 (%) p value

Number of disease progressions or death 62 (41%) 102 (68%) ---

12-month progression-free survival 68.4% 48.7% <0.001

Independent review committee-assessed

progression free survival25.7 months 10.4 months <0.001

Rate of events of CNS progression 18 (12%) 68 (45%) <0.001


Adverse Events


Adverse events Alectinib (%) Crizotinib (%)

Any adverse event / Grade 3-5 97% / 50% 97% / 41%

Anemia 20% 5%

Myalgia 16% 2%

Increased bilirubin 15% 1%

Weight gain 10% 0%

Musculoskeletal pain 7% 2%

Photosensitivity reaction 5% 0%

Nausea / Vomiting / Diarrhea 14% / 7% / 12% 48% / 38% / 45%

Increased ALT / AST 15% / 14% 30% / 25%


Conclusion• Longer progression-free survival - HR 0.47

• Investigator’s assessed • Independent review committee-assessed

• Active against brain metastases and CNS disease• Time to CNS progression

• Overall survival?

• Safety • Less GI symptoms • More anemia, myalgia, increase bilirubin


2017 ASCO Guidelines – 1st line Non-Squamous-Cell

Carcinoma

EGFR mutation


ROS1 gene rearrangement Wild Type

AfatinibOr

ErlotinibOr

Geftinib

Crizotinib Crizotinib PD-L1 ≥50% PD-L1 <50%

Pembrolizumab

Combination of platinum based chemotherapy

+/- bevacizumabHanna N, et al. J Clin Oncol. 2017


Adverse Effects, Dosing, and Pricing Adverse events Dosing Pricing

Alectinib(Alecensa®)

Fatigue, constipation, edema, myalgia

600mg PO BID with food

$15,532 for 30-day supply

Crizotinib(Xalkori®)

Vision disorder, nausea, diarrhea/constipation, vomiting,

edema, fatigue, URTI, dizziness, neuropathy, elevated LFT’s

250mg PO BIDwith/without food


Ceritinib(Zykadia®)

Nausea, vomiting, diarrhea, fatigue, abdominal pain,

decreased appetite, weight loss

750mg PO daily on an empty

stomach


Brigatinib(Alunbrig®)

Nausea, diarrhea, fatigue, cough, headache

90mg PO daily x 7days

180mg PO dailywith/without food


Alecensa® [package insert]. Genentech USA, Inc., South San Francisco, CA. 2016Xalkori® [package insert]. Pfizer, Inc., New York, NY. 2017

Zykadia® [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ. 2017Alunbrig®. [package insert]. Ariad Pharmaceuticals, Inc., Cambridge, MA. 2017

URTI: Upper Respiratory Tract Infection LFT: Liver Function Tests


What percentage of NSCLC patients express the ALK gene mutation?

A. Less than 10%

B. 10-20%

C. 40-50%

D. 70-80%


Treatment Algorithm for Stage IV NSCLC

NSCLC

Squamous cell NSCLC PD-L1 status

Non-Squamous-cell

NSCLC

EGFR mutation

BRAF mutation


ROS gene rearrangement

PD-L1 status



Immune Checkpoint Inhibitors

Atezolizumab

NivolumabPembrolizumab


Mechanism of Action

https://s3.amazonaws.com/gotopercom/_media/_upload_image/_upload_image/AJHO_may14_schilder_figure_3.jpg

PD-1: programmed cell death protein -1 PD-L: programmed cell death ligand

Nivolumab, Pembrolizumab

Atezolizumab


• Traditionally – platinum doublet as 1st line

• Targetable genomic alteration targeted therapy

• No targetable genomic alteration • Risk of chemotherapy toxicity vs. benefit

• Median overall survival ~ 8 – 10 months

• One-year survival rate ~30 – 40%

Dang TO, et al. Expert Rev Anticancer Ther. 2016; 16(1): 13–20

Evolution From Chemotherapy to Targeted Therapy (PD-L≥50%, NSCLC)


Pembrolizumab vs. Chemo – KEYNOTE-024 Study design:

International, randomized, open-label, phase 3 trial

Participants:

Stage IV advanced NSCLC with PD-L1 expression ≥ 50% and no previous treatment

Interventions:

Patients were assigned in 1:1 ratio to either:Pembrolizumab IV 200mg q3weeks x35 cycles OR Investigator’s choice of a platinum based chemotherapy

End points:

Primary: progression-free survival

Secondary: overall survival, objective response rate, safety



Results


Outcomes Pembrolizumabn=154 (%)

Chemotherapyn=151 (%) p value

Medianprogression-free

survival 10.3 months 6 months <0.001

Estimated rate of overall survival at 6 months 80.2% 72.4% 0.005

Response rate 44.8% 27.8% ---

*66 patients (43.7%) in the chemotherapy group crossed over to received pembrolizumab after disease progression


Adverse Events Adverse events Pembrolizumab (%) Chemotherapy (%)

Any adverse event / Grade 3-5 73.4% / 26.6% 90% / 53.3%

Immune-mediated 29.2% 4.7%

Pyrexia 10.4% 5.3%

Nausea / vomiting / diarrhea 9.7% / 2.6% / 14.3% 43.3% / 20% / 13.3%

Anemia 5.2% 44%

Neutropenia 0.6% 22.7%

Thrombocytopenia 0% 11.3%

Fatigue 10.4% 28.7%



Conclusion• Pembrolizumab

• Progression-free survival vs. chemotherapy• 10.3 months vs. 6 months - HR 0.5

• Overall survival at 6 months vs. chemotherapy• 80.2% vs. 72.4% - HR 0.6

• 1st line agent in stage IV and PD-L1 tumor expression of ≥ 50%


2017 ASCO Guidelines – 1st line

Hanna N, et al. J Clin Oncol. 2017

Squamous-Cell Carcinoma

PD-L1 ≥50% PD-L1 <50%

PembrolizumabCombination of platinum based chemotherapy


Adverse Events, Dosing, and Pricing Adverse events Dosing Pricing/

6-weeks

Pembrolizumab(Keytruda®)

fatigue, diarrhea/constipation, nausea, rash, pruritus, pyrexia,

decreased appetite, cough, dyspnea, musculoskeletal pain

200mg IV q3weeks

$18,052 for 1-dose

Nivolumab(Opdivo®)

fatigue, diarrhea/constipation, nausea, rash, pruritus, pyrexia,

decreased appetite, cough, dyspnea, URTI, asthenia, arthralgia,

back pain, musculoskeletal pain

240mg IV q2weeks

$18,324 for 1-dose

Atezolizumab(Tecentriq®)

Fatigue, constipation, nausea decreased appetite, cough,

dyspnea, musculoskeletal pain

1200mg IV q3weeks

$17,240 for 1-dose

Keytruda® [package insert]. Merck & CO., Inc,. Whitehouse Station, NJ. 2016Opdivo® [package insert]. Bristol-Myers Squibb Company, Princeton, NJ. 2017

Tecentriq® [package insert]. Genentech USA, Inc., South San Francisco, CA. 2017URTI: Upper Respiratory Tract Infection


Immune Related Adverse Effects

Michot JM, et al. European Journal of Cancer. 2016;54:139-148Keytruda® [package insert]. Merck & CO., Inc,. Whitehouse Station, NJ. 2016

Opdivo® [package insert]. Bristol-Myers Squibb Company, Princeton, NJ. 2017Tecentriq® [package insert]. Genentech USA, Inc., South San Francisco, CA. 2017

Adverse Effect IncidenceColitis 10-20%

Pneumonitis 1-3%

Endocrine disorder Thyroid dysfunction HypophysitisType-1 diabetes mellitus

5 – 10%

Hepatitis 5%

Dermatitis 5-20%


Guideline Directed Treatment Options


2017 ASCO Guidelines – 1st line

NSCLC

EGFR mutation


ROS1 gene rearrangement Wild Type

AfatinibOr

ErlotinibOr

Geftinib

Crizotinib Crizotinib PD-L1 ≥50% PD-L1 <50%

Pembrolizumab


+/- bevacizumabHanna N, et al. J Clin Oncol. 2017


2017 ASCO Guidelines – 2nd line No Known mutation


PD-L1 ≥1%& No prior

immune therapy

PembrolizumabOr

NivolumabOr

Atezolizumab

NivolumabOr

AtezolizumabOr

Combination of chemotherapy

Unknown or negative

PD-L1 <1%

Prior immune therapy


No prior immune therapy


2017 ASCO Guidelines – 2nd line

EGFR mutation

BRAF mutation

ROS1 gene rearrangement

Osimertinib

Crizotinib

Or Platinum based

therapy +/- bevacizumab

(If no previously received)

Platinum doublet

T790M mutation

No T790M

mutation

PembrolizumabOr

NivolumabOr

Atezolizumab

Dabrafinib

No prior immune therapy

& PD-L1 ≥1%

Previous immune therapy



What Did ASCO Not Cover?

• 1st line therapy in BRAF mutation • Dabrafenib + trametinib• Doublet chemotherapy • PD-L1 ≥ 50% pembrolizumab

• 2nd line therapy in ALK gene rearrangement • Alectinib, crizotinib, ceritinib, brigatinib

Non-Small Cell Lung Cancer. NCCN. Version 8.2017


65yo F with newly diagnosed, large cell, stage IV NSCLC, no known mutation, PD-L1 expression is unknown. What would you recommend as a 1st line option?

A. Pembrolizumab

B. Carboplatin + paclitaxel

C. Gemcitabine + paclitaxel

D. Alectinib


50yo M , non-smoker, with newly diagnosed, ALK +, PD-L1 ≥50%, stage IV NSCLC with brain metastases. What would you recommend as a 1st line option?

A. Pembrolizumab

B. Alectinib

C. Crizotinib

D. Erlotinib


Summary• NSCLC

• Very common disease• Leading cause of cancer death

• Choice of therapy presence/absence of biomarkers

• Individualized approach • Patients’ goals and co-morbidities • Distinct improvement in outcomes for select subtype


Questions & Discussion

Sila Shalhoub, PharmDPGY2 Oncology Pharmacy Resident

[email protected]

Non-Small Cell Lung Cancer:Where We Are Today

non-small cell lung cancer - ce.mayo.edu · pdf file©2017 mfmer | slide-1 non-small cell...

Documents