Slide 1. Slide 2. Slide 3. Disclosures. Personalized Medicine for Advanced NSCLC in East Asia. No conflicts related to this presentation

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1 Slide 1 12 th International Lung Cancer Conference Personalized Medicine for Advanced NSCLC in East Asia Masahiro Tsuboi, M.D., Ph.D. Group Chair, Lung Cancer Surgical Study Group in Japan Clinical Oncology Group (JCOG) Chief, Division of Thoracic Surgery, Kanagawa Cancer Center, Yokohama Associate-Professor, Department of Thoracic Surgery & Oncology, Tokyo Medical University Slide 2 Disclosures No conflicts related to this presentation Slide 3 What is the Personalized Medicine? Principle; Knowing genomic variants may help studying effect of a drug and tailor it to a particular population. Walgren et al., J Clin Oncol 23, , 2005 Chakma J. Journal of Young Investigators 22, Issue 2. August 2011

2 Slide 4 Topics Current status of the therapeutic strategy as Personalized Medicine Success story; EGFR-mutation status - EGFR-TKIs Guideline Current issue; discrepancy in metabolic status as for toxicities Gene Polymorphism?? Slide 5 Background; Asian Landscape A US retrospective population-based study has found Asian ethnicity (vs. Caucasians) to be a favorable prognostic factor for overall survival among smoker (HR=0.847, 95%CI ) as well as neversmokers (HR=0.861, 95%CI ). The higher prevalence of EGFR-TKI sensitive mutations among Asians compared with Caucasians accounts for most of the differences in management of Asian and Caucasians patients. The number of cases with mutations insensitive to EGFR- TKI is increasing in Asia. Slide 6 Molecular classification of Japanese lung cancer patients according to the addicted oncogene, which means Mutations of the EGFR and related genes SQ Jpn J Clin Oncol (2010)40, NOS La Adeno

3 Slide 7 ASCO2011, #7519, PD Maemondo M, et al. N Engl J Med ; Slide 8 Maemondo M, N Engl J Med ; Slide 9 Maemondo M, N Engl J Med ;

4 Slide 10 Slide 11 EGFR mutation Targeted Therapy EURTAC; Erlotinib vs chemo ASCO2011 #7583 Rafael Rosell PFS Erlotinib mpfs 9.7m Slide 12 Summary of recent clinical trials for EGFR M + patients PFS(months) HR for PFS(95%CI) OS(months) Study Patient group N TKI Chemotx G Chemotx Subset analyses of patients selected by clinical background Asian, light-nonsmoker, G 261 IPASS ( ) 9 5 adenocarcinoma Korean, non-smoker, First SIGNAL 42 adenocarcinoma Phase III trial for patients selected by EGFR mutation Japanese, NEJ EGFR mutation G 8 4 G (0 31, 1 22) ( ) WJTOG3405 OPTIMAL Japanese, EGFR mutation Chinese EGFR mutation G 9 2 E ( ) 30.9 N/A ( ) N/A N/A EURTAC Caucasian EGFR mutation 173 E ( )

5 Slide 13 Summary of EGFR-TKIs EFGR mutation is a great predictive factor on the efficacy of EGFR-TKIs. General cytotoxic agent EGFR-TKIs (Gefitinib, Erlotinib) Response Rate Median PFS 30% 4-5 months 70% 10 months Slide 14 Actually, these data has influenced to East-Asia guideline and clinical practice. Unfortunately, I don t know the current status, such as this users in clinical practice. At least, this was not extended to Japan. NCCN Guidelines in Asia Slide 15

6 Slide 16 Slide 17 Slide 18

7 Slide 19 Slide 20 The therapeutic guideline for Lung Cancer produced by Japan Lung Cancer Society, ver In Japan Slide 21 Japanese special; Different situation for choosing the chemotherapy from other countries The indication of Erlotinib is the 2 nd or more setting on chemotherapy. Interstitial Lung Disease; ILD is a critical issue for using EGFR-TKI. There are four commercial testing of EGFR mutation The cost of this testing is covered by the public insurance. Cetuximab has been not approved yet. Asian subset of FLEX study; not demonstrated the efficacy of this compound yet

8 Slide 22 1 st line treatment of c-stage IV NSCLC Pleural effusion/pericardial effusion without therapeutic intervention (drainage) & Asymptomatic brain & bone metastases Clinical stage IV NSCLC Pleural effusion/pericardial effusion with therapeutic intervention (drainage) Symptomatic brain metastases Chemotherapy EGFR mutation positive EFGR mutation negative EGFR mutation unknown Symptomatic bone metatstases Solitary metastasis of Adrenal gland ct1-3n0 The possibility of Surgical indication; Special situation The therapeutic guideline for Lung Cancer produced by Japan Lung Cancer Society, ver Slide 23 1 st line treatment of c-iv NSCLC with EGFR mutation EGFR mutation positive ECOG Performance status; 0-1 ECOG Performance status; 2 ECOG Performance status; 3-4 *; There is no priority among two decisions, because the clear difference on OS has been not demonstrated in two Japanese data. ***; Only phase II data. Decision should depend on the patient s informed consent, because the risk of ILD. Gefitinib Chemotherapy with cytotoxic agents* Gefitinib Chemotherapy with cytotoxic agents** Gefitinib*** BSC Back to 1 st page The therapeutic guideline for Lung Cancer produced by Japan Lung Cancer Society, ver Slide 24 What is the difference between US and East-Asia (Japan)? East-Asia (Japan) EGFR Mutation status US 組織型 SQ vs non-sq 組織型 SQ vs non-sq EGFR Mutation status

9 Slide 25 NCCN Guideline Slide 26 One of the critical issue In Japan, most of the patients with advanced & recurrent NSCLC have been examined recently. Who should undergo the EGFR mutation testing in practice? Slide 27 Molecular classification of Japanese lung cancer patients according to the addicted oncogene EGFR Less than 10% SQ Jpn J Clin Oncol (2010)40, NOS La Adeno There was no evidence for Non-Ad (SQ) IPASS Adenocarcinoma NEJ study Non-Ad 11/114 (SQ 3) WJTOG3405 Non-Ad 3/83(SQ 1)

10 Slide 28 NEJ002 subset; non-adeno. 11 cases Sq.; 3 cases, Adenosq.; 2 cases. Large; 1 case, NOS; 5 cases Response rate; 46% Disease Control rate; 82% Median PFS; 12 months This mpfs was similar to that of Adeo. But, few cases!! Slide 29 PFS comparing non-ad NSCLC patients harboring sensitive EGFR mutations with Ad patients harboring sensitive EGFR mutations. T Shukuya, N Yamamoto et al. Cancer Sci 2011 Sensitive mutation was defined as exon 19 deletion, G719X, L858R or L861Q of EGFR. % non-adeno NSCLC patients harboring sensitive EGFR mutations adenocarcinoma patients harboring sensitive EGFR mutations Ad; MPFS; 9.8m, RR; 69% P= Non-Ad MPFS; 3.1m, RR; 35% month Slide 30 Molecular classification of Japanese lung cancer patients according to the addicted oncogene This is the 2 nd story as the personalized medicine?

11 Slide 31 EML4-ALK Targeted Therapy; ASCO2011 Crizotinib phase I/II update #2501 Ross Camidge Crizotinib mpfs 10.0m Slide 32 2 nd topic of this talk Discrepancy in metabolic status as for toxicities; Gene Polymorphism?? Slide 33 BIBW2992 (afatinib) Toxicity Global phase III (ESMO 2010) Japanese phase II (ASCO 2011 poster discussion) AE All Grades (%) Grade 3 (%) All Grades (%) Grade 3 (%) Diarrhea x 2 times Rash/acne Stomatitis Nail effect Decreased appetite Epistaxis Pruritis

12 Slide 34 ARQ 197 (cmet inhibitor) + Erlotinib in previously treated NSCLC R A N D O M I Z E Japanese Phase I Erlotinib 150 mg PO QD + ARQ mg PO BID 28-day cycles Erlotinib 150 mg PO QD + placebo 28-day cycles Erlotinib 150 mg PO QD + ARQ , 360 mg PO BID 28-day cycles Global Phase III Non-SQ Slide 35 CYP2C19 (metabolizing enzyme of ARC197) Gene Polymorphism Xenobio. Metabol. and Dispos., 16, 69 (2001), Clinician, 503, 88 (2001) Ethnic difference for gene polymorphism on CYP2C19 The incidence of PM of Asian (10-20%) is more frequent than that of Europeans and Americans ( few %) Slide 36 ARQ 197 phase I study in Japanese patients ASCO2011 poster discussion Relationship between C max / AUC 0-12 of ARQ 197 (Day 1) and Neutropenia Cmax (ng/ml) C max AUC 0-12 Extenssive polymorphisum Poor polymorphisum Under administration of ARQ mg 6000 Patients with PM have had severe AE. (Westerners; few%, Asian;10-20%) AUC0-12 (ng h/ml) 0 Until Day Dose (mg bid) Dose (mg bid) 031 (#73, EM) Colorectal, *1/*3, female, 1.54 m 2, G4 neutropenia (Day 19) 032 (#74, EM) NSCLC, *1/*1, female, 1.25 m 2, G4 neutropenia (Day 22) 045 (#82, EM) Gastric, *1/*2, male, 1.69 m 2, G4 neutropenia (Day 23, 50) After Day (#31, PM) NSCLC, *2/*3, male, 1.56 m 2, G4 neutropenia (Day 56) 043(#83, EM) Colorectal, *1/*1, male, 1.59 m 2, G4 neutropenia (Day 71)

13 Slide 37 R A N D O M I Z E ARQ 197 (cmet inhibitor) + Erlotinib in previously treated NSCLC Erlotinib 150 mg PO QD + ARQ mg PO BID 28-day cycles Erlotinib 150 mg PO QD + placebo 28-day cycles Global Phase III Non-SQ Japanese Phase I Erlotinib 150 mg PO QD + ARQ , 360 mg PO BID 28-day cycles Asian Phase III EGFR wild Slide 38 conclusions EGFR-TKI is the first personalized medicine in NSCLC (lung adenocarcinoma). EGFR-TKIs is the key drug in East-Asia. The clinical implication of the EGFR mutation testing for the patients with non-adeno. is controversy. The differences of toxic profile may be based on the polymorphism of metabolizing enzyme. Still under-discussable, especially in East-Asia. Slide 39

14 Slide 40 Save the date! October 27-31, 2013 Slide 41 Thanks for your attention. Kanagawa Cancer Center, Yokohama, Japan