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October 10, 2019

Collin Blakely, MD, PhDAssistant ProfessorUCSF Thoracic Oncology

UCSF Continuing Medical Education

Lung Cancer in Non-Smokers

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Disclosures

Revolution Medicines ConsultingAstraZeneca Research FundingNovartis Research FundingRoche Research FundingMirati Research FundingTakeda Research FundingSpectrum Research FundingMedImmune Research Funding

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Outline

Changing lung cancer epidemiology and demographics

EGFR-mutant lung cancer diagnosis and treatment

Lung cancer screening guidelines

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Lung Cancer in the U.S.

seer.cancer.gov

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seer.cancer.gov

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Lung Cancer in the U.S.

seer.cancer.gov

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Surgeon GeneralReport

Relationship of lung cancer to smoking

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From: Proportion of Never-Smoker Non–Small Cell Lung Cancer Patients at Three Diverse InstitutionsJ Natl Cancer Inst. 2017;109(7). doi:10.1093/jnci/djw295

Non-smoking related lung cancer on the rise

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Shifting Subtypes of Lung Cancer

Lung Cancer, Volume 84, Issue 1, Pages 13–22

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CA: A Cancer Journal for Clinicians, Volume: 66, Issue: 2, Pages: 115-132, First published: 25 January 2016, DOI: (10.3322/caac.21338)

Male Cancer Mortality Female Cancer Mortality

Lung cancer is the leading cause of cancer mortality in China for both Men and Women

In 2015, a total of 733,300 new lung cancer cases and 610,200 lung cancer deaths were estimated in China.

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Summary of lung cancer demographics

Lung cancer is the leading cause of cancer deaths in the U.S. and China for both men and women.

Lung cancer incidence and mortality in the U.S. is decreasing overall, but more for men than women.

Lung cancer rates in never smokers are increasing.

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EGFR-mutant lung cancer

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Pao and Girard, Lancet 2011

Oncogenic driver mutations identified in NSCLC

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EA Collisson et al. Nature 000, 1-8 (2014) doi:10.1038/nature13385

Current breakdown of oncogenic driver mutations in lung adenocarcinoma in the U.S.

NTRK-fusions

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Zhang et al. Nature Communications volume 10, Article number: 1772 (2019)

EGFR-mutations significantly more frequent in Asian population

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Spectrum of oncogenic driver mutations in lung adenocarcinomas from Asian never smokers.

Li C, Fang R, Sun Y, Han X, Li F, et al. (2011) Spectrum of Oncogenic Driver Mutations in Lung Adenocarcinomas from East Asian Never Smokers. PLOS ONE 6(11): e28204. https://doi.org/10.1371/journal.pone.0028204https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028204

EGFR

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Nat Genet. 2012 Dec;44(12):1330-5. doi: 10.1038/ng.2456. Epub 2012 Nov 11.17

Why did I get this?

Genetic association of EGFR-mutant lung cancer in never smoking Asian women

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Constitutively active mutant-EGFR drives a subset of lung cancers

Sequist L V et al. JCO 2007;25:587-595

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M ok TS et al. N Engl J M ed 2009;361:947-957.

From March 2006 through October 2007, a total of 1217 patients from 87 centers in Hong Kong, elsewhere in China, Indonesia, Japan, Malaysia, the Philippines, Singapore, Taiwan, and Thailand were randomly assigned to receive gefitinib or carboplatin + paclitaxel

Landmark IPASS study performed in Asia

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Zhou et al., Lancet Oncol. 2011 Aug;12(8):735-42.

EGFR TKIs for the treatment of advanced EGFR-mutant lung cancer are effective but not curative

Erlotinib Afatinib

Sequist L V et al. JCO 2013;31:3327-3334

Resistance invariably occurs

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Alexios Matikas , Dimitrios Mistriotis , Vassilis Georgoulias , Athanasios Kotsakis

Current and Future Approaches in the Management of Non–Small-Cell Lung Cancer Patients With Resistance to EGFR TKIs Clinical Lung Cancer, 2015

T790M

Other EGFR mutEGFR amp

MET amp

HER2 amp

PIK3CA mut

BRAF mutSCLC

Other (AXL, STAT3, NF-kB)

~ 40 %EGFRBypass Pathways

Mechanisms of acquired resistance to EGFR TKI therapy

Osimertinib

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Osimertinib

Osimertinib is Active Against EGFR Sensitizing Mutations and T790M

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1st vs 3rd Generation EGFR TKI Progression Free Survival

Soria et al., N Engl J Med 2018; 378:113-125

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Soria et al., N Engl J Med 2018; 378:113-125

Less benefit observed for Asian patients

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Summary of EGFR-mutant lung cancer

75% frequency of EGFR mutations in lung cancers from Asian never smokers

Likely a genetic component to EGFR-mutant lung cancer, but poorly understood

Targeted therapy with tyrosine kinase inhibitors are very effective, but non-curative treatments for EGFR-mutant lung cancer

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Lung Cancer Screening

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The National Lung Screening Trial Research Team. N Engl J M ed 2011;365:395-409.

Cumulative Numbers of Lung Cancers and of Deaths from Lung Cancer.

National Lung Cancer Screening Trial

55-74 years old, > or = 30 pack-years, if quit, in last 15 years

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The National Lung Screening Trial Research Team. N Engl J M ed 2011;365:395-409.

20% reduction in lung cancer deaths in LDCT screening groupDeaths from Lung Cancer.

• 1060 lung cancers in LDCT group

• 941 lung cancers in CXR group

• 443 deaths from lung cancer in CXR group

• 356 deaths from lung cancer in LDCT group

20%

Number needed to screen = 307 per death prevented

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Asians were underrepresented in the studyDeathsfrom Lung Cancer.

Role of LDCT for screening high risk never smokers is unknown and not currently recommended.

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Lung Cancer Screening Recommendations

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The leading cause of cancer mortality for women in the U.S. is?

A. Breast Cancer

B. Lung Cancer

C. Ovarian Cancer

D. Cervical Cancer

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LDCT is recommended for lung cancer screening in the following patient:

A. 65 year old male non-smoker with 10 years of second hand smoke exposure.

B. 45 year old male, current 20 pack year smoking history and radon exposure.

C. 55 year old Asian female, never smoker.

D. 60 year old female with 30 pack year smoking history, but quit 10 years ago.

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Which diagnosis should NOT be considered in a never smoker with a chronic cough?

A. Lung cancer, never smokers cannot get lung cancer.

B. Asthma

C. ILD

D. Chronic infection

E. None of the above (anyone with lungs can get lung cancer).

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Thank you!

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