Sumitra Thongprasert, MD Ongoing Lung Cancer Research in Asia Sumitra Thongprasert, MD

Objectives Provide an overview of the current state of lung cancer research in Asia Discuss current key issues and challenges Discuss potential changes and future directions

Lung Cancer Is the Most Common Cancer Globally Incidence of new cases of cancer* Account for ≈13% of all cancer diagnosed *Globocan Data, 2012; **Excluding non-melanoma skin cancer. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx#. Accessed January 25, 2015.

Lung Cancer Is the Most Common Cause of Death from Cancer Globally Total cancer mortality* Responsible for nearly 1 in 5 cancer deaths (1.59 million or 19.4% of total) *Globocan Data, 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx#. Accessed January 25, 2015.

Incidence of Lung Cancer in Asia Percentage of total new cases Asia accounts for the majority of the new cases of lung cancer diagnosed in the world http://globocan.iarc.fr/Pages/fact_sheets_population.aspx#. Accessed January 25, 2015.

Mortality of Lung Cancer in Asia Asia accounts for the majority of lung cancer mortality in the world http://globocan.iarc.fr/Pages/fact_sheets_population.aspx#. Accessed January 25, 2015.

Lung Cancer Incidence and Mortality for Select Asian Countries http://globocan.iarc.fr/Pages/fact_sheets_population.aspx#. Accessed January 25, 2015.

Driver Mutations

Key Driver Mutations in Select Asian Populations: China and Japan 1 2 1. Wu YL et al. Ann Oncol. 2011;22(suppl 9). Abstract 33. 2. Mitsudomi T. Jpn J Clin Oncol. 2010;40:101-6.

Genetic Variations and Driver Mutations: East Asian vs Western Population Genes Western/ADC n/N (%) Western/SCC n/N (%) Asian/ADC n/N (%) Asian/SCC n/N (%) TP53 164/532 (30.8) 62/113 (54.9) 325/978 (33.2) 64/179 (35.8) EGFR 940/4890 (19.2) 113/334 (3.3) 1492/3117 (47.9) 22/474 (4.6) KRAS 613/2352 (26.1) 12/187 (6.4) 236/2114 (11.2) 5/284 (1.8) LKB1 99/610 (16.2) 13/137 (9.5) 22/550 (4.0) 0/166 (0.0) EML4-ALK 55/856 (6.4) 4/89 (4.5) 71/1326 (5.4) 5/277 (1.8) PTEN 25/419 (6.0) 0/12 (0.0) 4/248 (1.6) 12/123 (9.8) BRAF 66/2028 (3.3) 1/408 (0.2) 5/321 (1.6) 0/124 (0.0) PIK3CA 6/475 (1.3) 1/71 (1.4) 4/235 (1.7) 8/124 (6.5) ErbB2 7/505 (1.4) 2/117 (1.7) 20/712 (2.8) 1/259 (0.4) ADC = adenocarcinoma; SCC = squamous cell carcinoma. Dearden S et al. Ann Oncol. 2013;24:2371-6.

Clinical Development in Lung Cancer in Asia

Asia’s Contribution to the Advancement of Treatment for NSCLC Establishment of the efficacy of EGFR-targeted TKIs in patients with EGFR mutation–positive patients1-5 Identification of EML4-ALK fusion protein as a targetable driver mutation in the treatment of NSCLC by Soda M et al in 20076 1. Maemondo M et al. N Engl J Med. 2010;362:2380-8. 2. Mitsudomi T et al. Lancet Oncol. 2010;11:121-8. 3. Mok TS et al. N Engl J Med. 2009;361:947-57. 4. Zhou C et al. Lancet Oncol. 2011;12:735-42. 5. Fukuoka M et al. J Clin Oncol. 2011;29:2866-74. 6. Soda M et al. Nature. 2007;448:561-6.

Asia in the Development of Novel Targeted Agents in the Treatment of Lung Cancer Select phase 3 first-line Asian lung cancer trials: NEJ002 (gefitinib vs carboplatin + paclitaxel, N=228) WJTOG3405 (gefitinib vs cisplatin + docetaxel, N=177) IPASS (gefitinib vs carboplatin + paclitaxel; N=1217*) OPTIMAL/CTONG-0802 (erlotinib vs gemcitabine + carboplatin, N=165) ENSURE (erlotinib vs cisplatin + gemcitabine, N=217) FASTACT-2 (erlotinib + gemcitabine + carboplatin → erlotinib maintenance vs gemcitabine + carboplatin → placebo, N=451) LUX-Lung 6 (afatinib vs cisplatin + gemcitabine, N=324**) *Non-selected patients in terms of EGFR status. **EGFR activating mutation positive patients. 1. Maemondo M et al. N Engl J Med. 2010;362:2380-8; 2. Mitsudomi T et al. Lancet Oncol. 2010;11:121-8; 3. Mok TS et al. N Engl J Med. 2009;361:947-57; 4. Zhou C et al. Lancet Oncol. 2011;12:375-42; 5. Wu YL et al. J Thoracic Oncol. 2013;8(suppl 2):S603; 6. Wu YL et al. Lancet Oncol. 2013;14:777-86; 7. Wu YL et al. Lancet Oncol. 2014;15:213-22.

Asia in the Development of Novel Targeted Agents in the Treatment of Lung Cancer Select phase 3 global lung cancer trial with study sites in Asia: First-line: LUX-Lung 3 (afatinib vs pemetrexed + cisplatin, N=345; 249 Asian) PROFILE 1014 (crizotinib vs pemetrexed + cisplatin or carboplatin, N=343; 157 Asian) Maintenance: SATURN (erlotinib vs placebo, N=889; 131 Asian) Second-line: PROFILE 007 (crizotinib vs pemetrexed or docetaxel, N=347; 157 Asian) Titan (erlotinib vs platinum doublet, N=424; 54 Asian) REVEL (ramucirumab + docetaxel vs docetaxel, N=1253; 160 Asian) LUME-Lung 1 (N=1314; 239 Asian) 1. Sequist LV et al. J Clin Oncol. 2013;31:3327-34; 2. Solomon BJ et al. N Engl J Med. 2014;371:2167-77; 3. Cappuzzo F et al. Lancet Oncol. 2010;11:521-9; 4. Shaw AT et al. N Engl J Med. 2013;368:2385-94; 5. Ciuleanu T et al. Lancet Oncol. 2012;13:300-8; 6. Garon EB et al. Lancet. 2014;384:665-73; 7. Reck M et al. Lancet Oncol. 2014;15:143-55.

Ongoing Clinical Trials in Lung Cancer in Asia

Ongoing Lung Cancer Clinical Trials in Asia Including all study phases and observational, diagnostic, and staging studies. Statistics from WHO “International clinical trials registry platform” for trials registered in 2014: http://apps.who.int/trialsearch/AdvSearch.aspx. Accessed January 26, 2015.

Ongoing NSCLC Clinical Trials in Select Asian Countries* *Some of the clinical trials are conducted in multiple Asian countries. Statistics from WHO “International clinical trials registry platform” for trials registered in 2014: http://apps.who.int/trialsearch/AdvSearch.aspx. Accessed January 26, 2015.

Ongoing Phase 3 NSCLC Clinical Trials in China, Japan, Korea, and Taiwan Total (including multinational and country-specific trials) Country-specific trials only * ** ^ # *3 out of 14 conducted only in Japan; **4 out of 14 conducted only in China; ^none conducted only in Korea; #none conducted only in Taiwan. Statistics from WHO “International clinical trials registry platform” for trials registered in 2014: http://apps.who.int/trialsearch/AdvSearch.aspx. Accessed January 26, 2015.

Ongoing NSCLC Trials in Asia China Japan Korea Taiwan Total Multicentre vs 1 country 50 93 34 24 201 Recruiting only in the country 40 77 1 118 Multicentre 10 16 33 83 Stages of development Phase I, II or I/II 26 67 19 11 123 Phase III* 14 13 55 Other** 12 23 Disease settings Metastatic 76 166 Adjuvant 8 3 Neoadjuvant Other *Including multinational and country-specific trials. **Phase IV, observational, diagnostic test, staging test. Statistics from WHO “International clinical trials registry platform” for trials registered in 2014: http://apps.who.int/trialsearch/AdvSearch.aspx. Accessed January 26, 2015.

key issues and challenges

Key Issues/Challenges Large disparity exists between highly developed and developing/underdeveloped countries in Asia Issues/challenges, particularly associated with developing/ underdeveloped countries Smoking epidemic Air pollution Lack of disease awareness, robust prevention initiatives, and early screening Inequality in access to quality care/access to clinical trials (rural vs urban) Inadequate cancer health care infrastructure Need for more and better-educated health care professionals Alternative or traditional approaches to treatment (eg, China and India)

Future Directions

Important Initiatives Needed to Improve Patient Care Education and public awareness campaigns on the importance of lifestyle modifications, screening, and early detection/intervention in disease management Increased governmental support and investment in health care infrastructure/additional resources to ensure more equitable access to care for all segments of the population Increased funding to train more health care providers to serve underprivileged populations, particularly in rural areas Increased collaboration between academic centres and the private sector, including pharmaceutical companies, to promote basic scientific research and expedite the development of effective therapies for cancers that are prevalent in Asia

Summary Lung cancer is highly prevalent in Asia, accounting for the majority of new cases diagnosed and responsible for the most cancer-related mortality in the world The Asia Pacific region has made important contributions to the advancement of the current treatment of lung cancer and continues to be a key area for research and clinical development However, a number of serious issues and challenges remain Significant governmental support and investment as well as increased collaboration with the private sector are needed to improve disease management/patient care