Personalized Medicine for Advanced NSCLC in East Asia

Personalized Medicine for Advanced NSCLC in East Asia - Update treatment strategy for NSCLC based on Japanese clinical practice guideline - Masahiro Tsuboi, M.D., Ph.D. Associate-professor, School of Medicine, Yokohama City University Chief, Division of Thoracic Surgery, Respiratory Disease Center Chair of Comprehensive Cancer Center, Yokohama City University Medical Center

Topics Current status of the therapeutic strategy as Personalized Medicine Guideline of NCCN in Asia Guideline of Japan Lung Cancer Society Discrepancies between Japanese one and others Success story; EGFR-mutation status - EGFR-TKIs

Molecular classification of Japanese lung cancer patients according to the addicted oncogene, which means mutations of EGFR and related genes SQ Jpn J Clin Oncol (2010)40, 101 106 NOS Adeno La

Phase III Study of EGFR-TKI for EGFR mutated NSCLC Study Ref EGFR-TKI RR MPFS NEJ 002 New Eng J Med 2010 HR (PFS) CBDCA+PTX Gefitinib 74% 10.8 m 0.30 WJTOG3405 Lancet Oncol 2010 CDDP+DOC Gefitinib 62% 9.2 m 0.49 OPTIMAL Lancet Oncol 2011 CBDCA+GEM Erlotinb 83% 13.1 m 0.16 EURTAC ASCO 2011 Platinum + GEM or DOC Erlotinib 58% 9.7m 0.37

Summary of EGFR-TKIs EFGR mutation is a great predictive factor on the efficacy of EGFR-TKIs. Response Rate Median PFS General cytotoxic agent EGFR-TKIs (Gefitinib, Erlotinib) 30% 4-5 months 70% 10 months

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. And, no update data has demonstrated on website since 2009. At least, this was not extended to Japan. NCCN Guidelines in Asia

www.nccn-asia.org

As for the 1 st line treatment strategy for stage IV NSCLC Japanese guideline by Japan Lung Cancer Society

The structure of Japanese Guideline Readers type Decision Tree type (~2010) Guidelines 2012 (draft) 1 st -line chemo for NSCLC stage IV Positive for EGFR gene mutation PS 0-1 PS 2 < 75 75 EGFR-TKI alone Gefitinib alone Combination with a platinum agent ± Bev Non-platinum agent alone Combination with a platinum agent ± maintenance therapy Combination with carboplatin ± Bev Combination with a non-platinum agent EGFR-TKI alone Non-platinum agent alone Combination with a platinum agent PS 3-4 Gefitinib alone Nonsquamous cell cancer Positive for ALK gene translocatio n Negative or unknown for EGFR gene mutation and ALK gene translocatio n PS 0-1 PS 0-1 PS 2 PS 3-4 PS 0-1 < 75 75 < 75 75 < 75 75 Combination with a platinum agent ± Bev Non-platinum agent alone Combination with a platinum agent ± maintenance therapy Combination with carboplatin ± Bev PS 2 Non-platinum agent alone Combination with a platinum agent PS 3-4 Factors in decision Palliative therapy points Selection&Sequence Combination with a non-platinum agent Crizotinib alone Combination with a Combination with a platinum agent ± Combination with a non-platinum agent platinum agent ± Bev maintenance therapy Important! Non-platinum agent alone Combination with carboplatin ± Bev Non-platinum agent alone Palliative therapy Combination with a platinum agent ± maintenance therapy Non-platinum agent alone Combination with a platinum agent Combination with a non-platinum agent Combination with carboplatin Crizotinib alone Crizotinib alone Squamous cell cancer PS 2 PS 3-4 Non-platinum agent alone Palliative therapy Combination with a platinum agent

Key words on guideline Histologic type Squamous vs. Non-squamous Driver mutation status PS EGFR mutation ALK translocation 0-1, 2, and 3-4 Age Less than 75 y.o. vs. 75 y.o. or more Conditions on approval

Except T790M Patients with EGFR mutation

The distinctive feature of Japanese Lung Cancer EGFR mutation in Adenocarinoma EGFR EGFR The incidents of EGFR mutation EGFR EGFR EGFR Japan > USA / EU 50% 15% EGFR Suda K, et al. Cancer Metastasis Rev 2010

Phase III Study of EGFR-TKI for EGFR mutated NSCLC Study Ref EGFR-TKI RR MPFS NEJ 002 New Eng J Med 2010 HR (PFS) CBDCA+PTX Gefitinib 74% 10.8 m 0.30 WJTOG3405 Lancet Oncol 2010 CDDP+DOC Gefitinib 62% 9.2 m 0.49 OPTIMAL Lancet Oncol 2011 CBDCA+GEM Erlotinb 83% 13.1 m 0.16 EURTAC ASCO 2011 Platinum + GEM or DOC Erlotinib 58% 9.7m 0.37 Japanese health insurance covers only Gefitinib.

Japanese special situation; Different situation for choosing the chemotherapy from other countries The indication for Erlotinib is the 2 nd -line or more setting on chemotherapy. The 1 st line use will be approved in 2013 /2014. Interstitial Lung Disease; ILD is a critical issue for using EGFR-TKI. The mortality rate due to drug induced ILD was 0.5% in patients with EGFR active mutation. There are five commercial tests for EGFR mutation The cost of this testing is covered by the public insurance. US$250. Cetuximab has been not approved yet. Asian subset of FLEX study; not demonstrated the efficacy of this compound yet

Comparison of guideline to Stage IV NSCLC 1 st -line in each country Japanese ASCO ESMO NCCN Update 2012 (tentative) 2011 Divergence EGFR mutation Histology > mutation EGFR-TKI (PS 3,4 & Elderly : Gef) 2010 Consensus conference - - 2012 Histology > mutation Gefitinib EGFT-TKI Erlotinib ALK mutation Crizotinib - - Crizotinib Cis or Carbo Cis Carbo Cis =Carbo Cis Cis =Carbo Maintenance Non-SQ (C1) SQ (C2) Switch Switch is option Continuous (1) Switch (2A) Elderly Single > platinum Should not be selected by age alone PS 2 Single > platinum Single Fit; platinum Unfit; single Single / Platinum Single, platinum

Three commercial ALK testing including IHC, FISH and/or RT-PCR was approved. The cost of this testing is covered by the public insurance. US$500~815 Patients with ALK translocation

Comparison of guideline to Stage IV NSCLC 1 st -line in each country Japanese ASCO ESMO NCCN Update 2012 (tentative) 2011 2010 Consensus conference 2012 Divergence EGFR mutation Histology > mutation EGFR-TKI (PS 3,4 & Elderly : Gef) - - Histology > mutation Gefitinib EGFT-TKI Erlotinib ALK mutation Crizotinib - - Crizotinib Cis or Carbo Cis Carbo Cis =Carbo Cis Cis =Carbo Maintenance Non-SQ (C1) SQ (C2) Switch Switch is option Continuous (1) Switch (2A) Elderly Single > platinum Should not be selected by age alone Fit; platinum Unfit; single Single, platinum PS 2 Single > platinum Single Single / Platinum

Crizotinib; Conditions on approval <USA> 2011/8/26 Patients with locally advanced or metastatic non-small cell NSCLC that is ALK-positive as detected by an FDA-approved test. <Japan> 2012/3/30 Patients with inoperable advanced or relapsed ALK-positive NSCLC We can use Crizotinib from 1 st -line treatment

Phase I study of Crizotinib in ALK-Non Small-Cell Lung Cancer Kwak EL, et al. New Engl J Med 2010 N= 82 ORR: 57% PFS(6m): 72% Evidence of Crizotinib Only 1 clinical trial data (phase I study) Only 2 nd or more-line data (No first-line data)

Guidelines for lung cancer 2012 (draft) 1 st -line chemotherapy for NSCLC stage IV Positive for EGFR gene mutation PS 0-1 PS 2 < 75 75 EGFR-TKI alone Gefitinib alone Combination with a platinum agent ± Bev Non-platinum agent alone Combination with a platinum agent ± maintenance therapy Combination with carboplatin ± Bev Combination with a non-platinum agent EGFR-TKI alone Non-platinum agent alone Combination with a platinum agent PS 3-4 Gefitinib alone Nonsquamous cell cancer Positive for ALK gene translocation PS 0-1 PS 2 PS 3-4 < 75 75 Combination with a platinum agent ± Bev Non-platinum agent alone Non-platinum agent alone Palliative therapy Combination with a platinum agent ± maintenance therapy Combination with carboplatin ± Bev Combination with a platinum agent Combination with a non-platinum agent Crizotinib alone Crizotinib alone Crizotinib alone Negative or unknown for EGFR gene mutation and ALK gene translocation PS 0-1 PS 2 PS 3-4 PS 0-1 < 75 75 < 75 75 Combination with a platinum agent ± Bev Non-platinum agent alone Non-platinum agent alone Palliative therapy Combination with a platinum agent ± maintenance therapy Non-platinum agent alone Combination with a platinum agent ± maintenance therapy Combination with carboplatin ± Bev Combination with a platinum agent Combination with a non-platinum agent Combination with carboplatin Combination with a non-platinum agent Squamous cell cancer PS 2 PS 3-4 Non-platinum agent alone Palliative therapy Combination with a platinum agent

Age; Elderly population

The distinctive feature of Japanese Lung Cancer Center for Cancer Control and Information Services, National Cancer Center, Japan The incidence of Elderly patients is much higher. Median age 75years in clinical practice The distribution of treated patients with lung cancer in clinical practice.

Japanese domestic phase III studies for elderly patients Trial Treatment n RR(%) MST(m) 1 year (%) WJTOG9904 JCO 2006 JCOG0207 ASCO 2007 JCOG/WJOG ASCO 2011 Docetaxel 89 22.7 14.3 36.7 Vinorelbine 91 9.9 9.9 5836 W Doc 63 26.2 10.7 45.2 W Doc + Cisplatin 63 55 17 66.6 DOC 137 24.6 14.8 58.2 W Doc + Cisplatin 139 34.4 13.3 54.5

JCOG0803 /WJOG4307L Abe T, et al. ASCO 2011 Abs 7509 VS Sep, 2010 days MST 1 yr sur Docetaxel 17.3 m 65.6% CDDP+Doc 13.3 m 52.6% HR=1.577 (0.976 2.485) MST 1 yr sur Docetaxel 14.8 m 58.2% CDDP+Doc 13.3 m 54.5% HR=1.183 (0.830 1.687)

Phase III of CBDCA+Paclitaxel vs single-agent in patients age 70 to 89 (IFCT-0501) HR: 0.64 P=0.00004 Causes of deaths Single agent CBDCA +TXL MST: 6.2m MST: 10.3m Toxic deaths 1.3% 4.4% Cancer 79.6% 65.3% Quoix E, et al. Lancet 2011

Japanese domestic phase III studies for elderly and EGFR mutated patients Elderly patients Trial Treatment n RR(%) MST(m) 1 year (%) WJTOG9904 JCO 2006 JCOG0207 ASCO 2007 JCOG/WJOG ASCO 2011 Docetaxel 89 22.7 14.3 36.7 Vinorelbine 91 9.9 9.9 5836 W Doc 63 26.2 10.7 45.2 W Doc + Cisplatin 63 55 17 66.6 DOC 137 24.6 14.8 58.2 W Doc + Cisplatin 139 34.4 13.3 54.5

1 st -line therapy for elderly NSCLC (stage IV) (negative or unknown for EGFR gene mutation and ALK gene translocation) PS 0-1, 75 (1) Patients should not be excluded from chemotherapy only become of their age. (A) <Regimens> (1) Monotherapy with a third-generation anticancer agent is recommended. (A) (2) Combination therapy with carboplatin should also be considered as a treatment option. (C1)

Comparison of guideline to Stage IV NSCLC 1 st -line in each country Japanese ASCO ESMO NCCN Update 2012 (tentative) 2011 2010 Consensus conference 2012 Divergence EGFR mutation ALK mutaiton Histology > mutation EGFR-TKI (PS 3,4 & Elderly : Gef) - - Histology > mutation Gefitinib EGFT-TKI Erlotinib Crizotinib - - Crizotinib Cis or Carbo Cis Carbo Cis =Carbo Cis Cis =Carbo Maintenance Non-SQ (C1) SQ (C2) Switch Switch is option Continuous (1) Switch (2A) Elderly Single > platinum Should not be selected by age alone Fit; platinum Unfit; single Single, platinum PS 2 Single > platinum Single Single / Platinum

Future perspectives Oncogenic driver mutation on NSCLC The development of treatment for patients with less frequent driver mutation will proceed. Adeno.in Japanese 2012 As a result, the number of agents approved by low grade evidence will be increasing (Ex. Crizotinib). Critical issue; how to incorporate low grade evidence (phase II study.) into the guideline. This matter may become important when the clinical guideline is established. ROS 1% HER2 2% RET 2% NONE 29% ALK 4% KRAS 9% EGFR 53% Kohno et al., Nature med, 2012(modified)

Take home massages EGFR-TKI is the first personalized medicine in NSCLC (lung adenocarcinoma). EGFR-TKIs is the key drug in East-Asia. Basically, there are no major differences between the Japanese clinical guideline and others. Key words on decision making process are as follows; Histology, Driver mutation status, PS, Age, drug specific tolerability and so on.