Outline Changing lung cancer epidemiology and demographics - PDF document

UCSF Continuing Medical Education Disclosures Revolution Medicines Consulting AstraZeneca Research Funding Novartis Research Funding Lung Cancer in Non-Smokers Roche Research Funding Mirati Research Funding Takeda Research Funding Collin Blakely, MD, PhD Spectrum Research Funding Assistant Professor MedImmune Research Funding UCSF Thoracic Oncology October 10, 2019 1 2 Lung Cancer in the U.S. Outline Changing lung cancer epidemiology and demographics EGFR-mutant lung cancer diagnosis and treatment Lung cancer screening guidelines seer.cancer.gov 3 4 1 | [footer text here]

Lung Cancer in the U.S. seer.cancer.gov seer.cancer.gov 5 6 Non-smoking related lung cancer on the rise Relationship of lung cancer to smoking Surgeon General Report From: Proportion of Never-Smoker Non–Small Cell Lung Cancer Patients at Three Diverse Institutions J Natl Cancer Inst. 2017;109(7). doi:10.1093/jnci/djw295 7 8 2 | [footer text here]

Lung cancer is the leading cause of cancer mortality in Shifting Subtypes of Lung Cancer China for both Men and Women Male Cancer Mortality Female Cancer Mortality In 2015, a total of 733,300 new lung cancer cases and 610,200 lung cancer deaths were estimated in China. Lung Cancer, Volume 84, Issue 1, Pages 13–22 CA: A Cancer Journal for Clinicians, Volume: 66, Issue: 2, Pages: 115-132, First published: 25 January 2016, DOI: (10.3322/caac.21338) 9 10 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. EGFR-mutant lung cancer is decreasing overall, but more for men than women. Lung cancer rates in never smokers are increasing. 11 12 3 | [footer text here]

Current breakdown of oncogenic driver mutations in lung Oncogenic driver mutations identified in NSCLC adenocarcinoma in the U.S. NTRK- fusions EA Collisson et al. Nature 000 , 1-8 (2014) doi:10.1038/nature13385 Pao and Girard, Lancet 2011 13 14 Spectrum of oncogenic driver mutations in lung EGFR-mutations significantly more frequent in Asian population adenocarcinomas from Asian never smokers. EGFR 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.0028204 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028204 Zhang et al. Nature Communications volume 10 , Article number: 1772 (2019) 15 16 4 | [footer text here]

Why did I get this? Constitutively active mutant-EGFR drives a subset of lung cancers Genetic association of EGFR-mutant lung cancer in never smoking Asian women Sequist L V et al. JCO 2007;25:587-595 Nat Genet. 2012 Dec;44(12):1330-5. doi: 10.1038/ng.2456. Epub 2012 Nov 11. 17 17 18 Landmark IPASS study performed in Asia EGFR TKIs for the treatment of advanced EGFR- mutant lung cancer are effective but not curative From March 2006 through October 2007, a total of Erlotinib Afatinib 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 + Zhou et al., Lancet Oncol. 2011 Sequist L V et al. JCO 2013;31:3327-3334 paclitaxel Aug;12(8):735-42. Resistance invariably occurs Mok TS et al. N Engl J Med 2009;361:947-957. 19 20 5 | [footer text here]

Mechanisms of acquired resistance to EGFR TKI therapy Osimertinib is Active Against EGFR Sensitizing Mutations and T790M Other (AXL, STAT3, NF- k B) SCLC BRAF mut T790M PIK3CA ~ 40 % mut EGFR Osimertinib Bypass Pathways HER2 amp MET amp Osimertinib EGFR amp Other EGFR mut 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 21 22 1 st vs 3 rd Generation EGFR TKI Progression Free Survival Less benefit observed for Asian patients Soria et al., N Engl J Med 2018; 378:113-125 Soria et al., N Engl J Med 2018; 378:113-125 23 24 6 | [footer text here]

25 25 26 Summary of EGFR-mutant lung cancer 75% frequency of EGFR mutations in lung cancers from Asian never smokers Lung Cancer Screening 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 27 28 7 | [footer text here]

20% reduction in lung cancer deaths in LDCT screening group National Lung Cancer Screening Trial Cumulative Numbers of Lung Cancers and of Deaths from Deaths from Lung Cancer. Lung Cancer. 20% 55-74 years old, > or = 30 pack-years, if quit, in last 15 years • 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 Number needed to screen = 307 per death prevented The National Lung Screening Trial Research Team. N Engl J Med 2011;365:395-409. The National Lung Screening Trial Research Team. N Engl J Med 2011;365:395-409. 29 30 Asians were underrepresented in the study Deaths Lung Cancer Screening Recommendations from Lung Cancer. Role of LDCT for screening high risk never smokers is unknown and not currently recommended. 31 32 8 | [footer text here]

The leading cause of cancer mortality for women in the U.S. is? LDCT is recommended for lung cancer screening in the following patient: A. Breast Cancer A. 65 year old male non-smoker with 10 years of second hand smoke exposure. B. Lung Cancer B. 45 year old male, current 20 pack year smoking history and C. Ovarian Cancer radon exposure. D. Cervical Cancer C. 55 year old Asian female, never smoker. D. 60 year old female with 30 pack year smoking history, but quit 10 years ago. 33 34 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 Thank you! D. Chronic infection E. None of the above (anyone with lungs can get lung cancer). 35 36 9 | [footer text here]