Jacob Sands, MD Dana-Farber Cancer Institute October 25, 2017 Lung Cancer Updates Jacob Sands, MD Dana-Farber Cancer Institute October 25, 2017

Advances in Lung Cancer Epidemiology Targeted Therapy Immunotherapy Lung Screening

Advances in Lung Cancer Epidemiology Targeted Therapy Immunotherapy Lung Screening

Advances in Lung Cancer Epidemiology Targeted Therapy Immunotherapy Lung Screening

Epidemiology Trends in Death Rates Among Males for Selected Cancers, United States, 1930 to 2008. Rates are age adjusted to the 2000 US standard population. Due to changes in International Classification of Diseases (ICD) coding, numerator information has changed over time. Rates for cancers of the lung and bronchus, colorectum, and liver are affected by these changes. (Reprinted with permission from John Wiley and Sons [Siegel R, Naishadham D, Jemal A. Cancer Statistics, 2012.CA Cancer J Clin 2012; 62:10–29]; copyright 2012 American Cancer Society, Inc.)

Overall Survival NSCLC Clinical Stage Pathologic Stage MST= Median Survival Time Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007; 2:706.

Advances in Lung Cancer Epidemiology Targeted Therapy Immunotherapy Lung Screening

EGFR Mutations (the beginning)

EGFR mutation First line treatment with EGFR-TKI was established including gefitinib and erlotinib. Erlotinib – US Gefitinib – Asia and Europe

EGFR mutation First line treatment with EGFR-TKI was established including gefitinib and erlotinib. Erlotinib – US Gefitinib – Asia and Europe Then Afatinib (Lux Lung 3 published 2013 but first line 2016) Osimertinib (T790M, published 2/16/2017) Dacomitinib (presented June, 2017 but not FDA approved therapy)

Newest EGFR FLAURA Median PFS (HR 0.46, p<0.001) Osimertinib 18.2 mos Gefinitib/Erlotinib 10.2 mos Overall Survival not yet mature but trending promising Improved outcomes in brain mets Progression in the brain: 6% osimertinib 15% gefitinib/erlotinib

Newest EGFR FLAURA 54% improvement in PFS with osimertinib Duration of response significantly higher Improved outcomes in brain Grade 3/4 events about 12% lower in the osimertinib arm

ALK Crizotinib has been standard of care 1st line (published 2013) Ceritinib Lorlatinib Brigatinib Alectinib

ALK Alectinib

ALK Alectinib

BRAF V600E

BRAF V600E (dabrafenib plus trametinib)

Small Cell Lung Cancer No established targeted therapy

Small Cell Lung Cancer DLL-3 is a potential target AbbVie paid $5.8 billion upfront with $4 billion reserved for milestones to purchase Rova-T from Stemcentrx

Small Cell Lung Cancer, rovalpituzumab

Advances in Lung Cancer Epidemiology Targeted Therapy Immunotherapy Lung Screening

Immunotherapy Nivolumab Pembrolizumab Atezolizumab Durvalumab

Immunotherapy Nivolumab Pembrolizumab Atezolizumab Durvalumab

Immunotherapy Nivolumab Pembrolizumab Atezolizumab Durvalumab

Immunotherapy Nivolumab Pembrolizumab Atezolizumab Durvalumab

Non-Small Cell Lung Cancer Squamous Non-Squamous

Pacific (durvalumab after chemo/rads for stage 3)

Advances in Lung Cancer Epidemiology Targeted Therapy Immunotherapy Lung Screening

Trends in Death Rates Among Males for Selected Cancers, United States, 1930 to 2008. Rates are age adjusted to the 2000 US standard population. Due to changes in International Classification of Diseases (ICD) coding, numerator information has changed over time. Rates for cancers of the lung and bronchus, colorectum, and liver are affected by these changes. (Reprinted with permission from John Wiley and Sons [Siegel R, Naishadham D, Jemal A. Cancer Statistics, 2012.CA Cancer J Clin 2012; 62:10–29]; copyright 2012 American Cancer Society, Inc.)

Overall Survival NSCLC Clinical Stage Pathologic Stage MST= Median Survival Time Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007; 2:706.

Non-Small Cell Lung Cancer Many patients become symptomatic with clinical stage IV disease

Non-Small Cell Lung Cancer Many patients become symptomatic with clinical stage IV disease 5 year survival = 2%

Non-Small Cell Lung Cancer Clinical stage IA 5 year overall survival = 50% Pathologic stage IA 5 year overall survival = 73% Early stage lung cancer screening 5 year overall survival about 90%

Non-Small Cell Lung Cancer About 63-70% of patients diagnosed in screened population have stage I lung cancer Early stage lung cancer screening 5 year overall survival about 90%

Lung Cancer Screening

National Lung Screening Trial Multi-center randomized controlled trial Low dose non-contrast CT scan Single view posteroanterior chest radiography Total of 53,454 persons were enrolled Study cost: $250 million

NLST: Lung Cancer Diagnoses

NLST: Death from Lung Cancer

NLST The 892 lung cancers in participants with no screening test included 35 in participants who were never screened, 802 that were diagnosed during the post-screening period, and 55 in participants who were due for a screening test.

NLST The 892 lung cancers in participants with no screening test included 35 in participants who were never screened, 802 that were diagnosed during the post-screening period, and 55 in participants who were due for a screening test.

National Concerns/Criticisms Increased radiation exposure “False positives” We are invasively treating indolent cancers Cost to the system

Average age of patients in screening trials is 62 Radiation Exposure LDCT 1 mSv Years of annual lung screening Mammogram .7 mSv Lumbar Spine Films 2 mSv 2 Diagnostic Chest CT 10 mSv 10 Triphasic CT AB/P 25 mSv 25 Background Exposure Colorado 3 mSv/year 11.8 mSv/year 3 11.8 Occupational Exposure 50 mSv/year 50 Transatlantic Flight .1 mSv 10 flights = 1 LDCT Here is a chart for comparison purposes. LDCT exposure is similar to a mammogram. A Lumbar spine film series is 2mSv or the equivalent of 2 years of annual LDCT scanning. Triphasic CT abd/pel is 25mSv. Background exposure is 3 mSv at sea level and 11.8mSv in Denver Colorado. Occupational exposure for a radiation worker is 50mSv, which is the equivalent of 50 LDCT studies. A transatlantic flight is .1mSv such that 7 transatlantic flights equals 1 LDCT. Also an important consideration regarding radiation risk is the 10-30 year latency period to develop secondary malignancies as a result of RT exposure. The average age of patients in screening programs is 62. So…. we are not talking about screening healthy children, teenagers, or even young adults. With a 10-30 year latency period the risk is acceptable at these exposures, when weighed against the knowledge that one in one hundred of these patients has lung cancer. 10 -30 year latency period to develop secondary malignancies from RT exposure Average age of patients in screening trials is 62

Average age of patients in screening trials is 62 Radiation Exposure LDCT 1 mSv Years of annual lung screening Mammogram .7 mSv Lumbar Spine Films 2 mSv 2 Diagnostic Chest CT 10 mSv 10 Triphasic CT AB/P 25 mSv 25 Background Exposure Colorado 3 mSv/year 11.8 mSv/year 3 11.8 Occupational Exposure 50 mSv/year 50 Transatlantic Flight .1 mSv 10 flights = 1 LDCT Here is a chart for comparison purposes. LDCT exposure is similar to a mammogram. A Lumbar spine film series is 2mSv or the equivalent of 2 years of annual LDCT scanning. Triphasic CT abd/pel is 25mSv. Background exposure is 3 mSv at sea level and 4.5mSv in Denver Colorado. Occupational exposure for a radiation worker such as myself is 50mSv, I am allowed each year to be exposed to the equivalent of 50 LDCT studies. A transatlantic flight is .1mSv such that 7 transatlantic flights equals 1 LDCT. Also an important consideration regarding radiation risk is the 10-30 year latency period to develop secondary malignancies as a result of RT exposure. The average age of patients in screening programs is 62. So…. we are not talking about screening healthy children, teenagers, or even young adults. With a 10-30 year latency period the risk is acceptable at these exposures, when weighed against the knowledge that one in one hundred of these patients has lung cancer. 10 -30 year latency period to develop secondary malignancies from RT exposure Average age of patients in screening trials is 62

National Concerns/Criticisms Increased radiation exposure “False positives” We are invasively treating indolent cancers Cost to the system

ACR Adopted 6mm as minimum nodule size. Ground glass opacity cutoff 2cm Duration of nodule stability 3 months (decreased from 2 yrs)

National Concerns/Criticisms Increased radiation exposure “False positives” We are invasively treating indolent cancers Cost to the system

National Concerns/Criticisms Increased radiation exposure “False positives” We are invasively treating indolent cancers Cost to the system

Limitations of Analysis 1) Excluded 150 NLST participants from analysis (48 had lung cancer) due to not having adequate info to project survival More in CT group (probably bias against CT) 2) Assumed CT screening program did not affect smoking status 3) This analysis performed with NSLT (not ACR)

Lung Cancer Updates MANY advances in therapies with exciting things on horizon Targeted therapy Immunotherapy Lung screening is one of the biggest advances (not yet happening)