Cooperative Group Update - Japan; JCOG & WJOG -

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1 Cooperative Group Update - Japan; JCOG & WJOG - 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

2 Cooperative Groups for Lung Cancer in Japan JCOG, Tokyo, Multi-disease Japan Clinical Oncology Group - no legal entity - only one fully MHLW-sponsored WJOG, Osaka, Multi-disease West Japan Oncology Group - NPO - donated from Industries/ registration fee by investigators LOGIK, Fukuoka Lung Oncology G. in Kyusyu SLCG/OLCSG, Okayama Setouchi Lung Cancer G. JMTO, Kyoto The Japan Multinational Trial Organization NEJ, Sendai North East Japan TCOG, Tokyo Tokyo Clinical Oncology G. TORG, Yokohama Thoracic Oncology Research G. CJLSG, Nagoya Central Japan Lung Study G.

3 JCOG; Japan Clinical Oncology Group

4 JCOG/Lung Cancer Surgical Study Group Study No. P.I. Trial Phase JCOG0201 T. Koike Diagnosis of Radiological Early Lung Cancer Observation cohort JCOG0707 M. Tsuboi Adjuvant Chemotherapy for Stage IA(T1b)-IB NSCLC Phase III JCOG0804/ WJOG4507L M. Tsuboi Limited Resection (Wide wedge resection) for Possible Early Lung Cancer Phase II JCOG0802/ WJOG4607L H. Asamura Lobectomy and Limited Resection for NSCLC 2cm or less in size Phase III JCOG1205/ 1206 M. Tsuboi Adjuvant chemotherapy for p-stage I-IIIA High Grade Neuroendocrine Lung Cancer (LCNEC, SCLC) Planning / phase III

5 Randomized phase III study n=480 p-stage IA (2cm<), IB Completely resected NSCLC PS: 0-1 Age: ys R A N D M I Z E Within 8weeks after surgery Stratified factors; Institute, Gender, Size, Histology, Age JCOG0707 TS-1 (80mg/m2/day, day1-14, q3weeks, 1 year) n=480 UFT (250mg/m2/day, 2 years) Primary endpoint: Overall survival, Secondary endpoints: Disease-free survival and toxicity P.I.; Tsuboi M.

6 JCOG0707(UFT vs. TS-1 for p-stage I NSCLC ) enrolment status Accrual number in month Estimated accrual number Accumurated accrual number Current enrollment: 692 cases at this June

7 JCOG0804/WJOG4507L; Phase II Trial of Limited Resection (Wide wedge resection) for Possible Early Adenocarcinomas (GGO Part-solid GGO) ; (Single-arm study) Subject ---- Non-solid GGO or part-solid GGO Solid part < 25% Why one arm? Very few event (cancer-related death) to perform comparative study Intervention Wide Wedge resection Endpoint Recurrence-free survival rate at any site Sample size patients Trial has started since June in 2009 PI; Tsuboi M (JCOG) & Yoshino I (WJOG)

8 JCOG0804/WJOG4507L (early NSCLC LR P2) Final enrollment: 334 cases in April, 2011 Accrual number in month Estimated accrual number Accumurated accrual number

9 JCOG0802/WJOG4607L; Phase III Randomized Trial between Lobectomy and Limited Resection for Part-solid GGO Solid T1a disease Non-inferiority design Peripheral carcinoma, <=2 cm Negative hilar node Stratified factors; Institute, Gender, Histology (Ad vs, Non-ad), Solid or non-solid Randomize Lobectomy Since Aug Segmentectomy Endpoints: Primary: OS Secondary: pulmonary function Sample size: 1,100 PI: Asamura H. (JCOG) & Okada M (WJOG)

10 JCOG0802/WJOG4506L (small NSCLC LB vs. SG P3) Accrual number in month Estimated accrual number Accumulated accrual number Current enrollment: 538 cases at this June

11 JCOG1205/1206; Randomized Phase III Study of Irinotecan+CDDP and ETP+CDDP for completely resected high neuroendocrine tumors (LCNEC, SCLC) p-stage I-IIIA Completely resected HGNE-LC (LCENC, SCLC) PS: 0-1 Age: ys Within 8weeks after surgery R A N D M I Z E Cis. (60mg/m2, day1) + CPT-11 (60mg/m2, day1, 8, 15) q4wks x 4 cycles n=220 Stratified factors; Institute, Gender, Stage, histology (SCLC/LCNEC, Age (70) Primary endpoint: Overall survival, Secondary endpoints: Disease-free survival and toxicity Cis. (80mg/m2, day1) + ETP (100mg/m2, day1-3) q3wks x 4 cycles P.I.; Tsuboi M.

12 JCOG/Lung Cancer Study Group for SCLC JCOG1011

13 #7028 (PD) Randomized Phase III Study Comparing Etoposide and Cisplatin (EP) with Irinotecan and Cisplatin (IP) following EP plus Concurrent Accelerated Hyperfractionated Thoracic Radiotherapy (EP/AHTRT) for the Treatment of LD-SCLC: JCOG0202. Kubota et al. R E G I S T R A T I O N Induction Chemoradiotherapy Etoposide/ Cisplatin AHTRT 45Gy N=250 1 st 2 nd R E G I S T R A T I O N R *adjusted by PS [0 vs 1], response to induction chemoradiotherapy [CR+good PR vs PR+SD], and institutions Consolidation Chemotherapy Arm A: Etoposide/ Cisplatin 3 cycles Arm B: Irinotecan/ Cisplatin 3 cycles PCI for CR or good PR

14 Propotion JCOG0202 Primary Analysis: OS after Randomization MST 3yrs 5yrs EP 3.2y 52.9% 35.8% IP 2.8y 46.6% 33.7% one sided p=0.703 # HR= %CI[ ] # Stratified log-rank test, with PS and Response to Induction Chemoradiotherapy as strata Years after randomization Four cycles of EP plus AHTRT is still the standard treatment for LD-SCLC

15 #7003 (oral) A phase III study comparing amrubicin and cisplatin (AP) with irinotecan and cisplatin (IP) for the treatment of ED-SCLC: JCOG0509. Kotani et al. ED-SCLC yrs PS 0-1 Stratification PS institution sex Sample size n= 282 (n= 141 per Arm) R A N D O M I Z E IP irinotecan 60 mg/m 2 D1,8,15 cisplatin 60 mg/m 2 D1 Q4 weeks x 4 cycles amrubicin 40 mg/m 2 D1-3 cisplatin 60 mg/m 2 D1 Q3 weeks x 4 cycles AP PCI for CR cases 2.5Gy 10 Fr a non-inferiority study Primary endpoint; Overall survival Secondary endpoints; PFS, ORR, AE and QOL Accrual : May 2007 December 2010

16 Proportion surviving(%) #7003 (oral) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% A phase III study comparing amrubicin and cisplatin (AP) with irinotecan and cisplatin (IP) for the treatment of ED-SCLC: JCOG0509. Kotani et al. Overall Survival IP AP Pts Events Median(m) [95% CI] IP [ ] AP [ ] HR* : %CI , *stratified Cox regression, with PS and sex as strata Survival time(months) Irinotecan plus cisplatin remains the standard treatment for ED-SCLC in Japan.

17 JCOG/Lung Cancer Study Group for NSCLC Study number phase Target Reference arm Experimental arm Primary endpoint Sample size 0301 III Elderly unresectable stage III RT alone (60Gy) RT (60Gy) + weekly CBDCA (30mg/m2) x 20 times Overall survival / WJOG 4307L* III Elderly stage IIIB/IV Doc.(60mg/ m2) q3wks Weekly Cis. (20mg/m2) + Doc (25mg/m2) Overall survival 380 *; This trial was terminated after the planned interim analyses, because This study failed to demonstrate any advantage of the addition of weekly CDDP to single-agent DOC in first line chemotherapy for elderly advanced NSCLC patients.; ASCO2011

18 #7017 (PD) Updated Results of A Phase III Trial Comparing Standard Thoracic Radiotherapy with or without Concurrent Daily Low-dose Carboplatin in Elderly Patients with Locally Advanced NSCLC: JCOG0301. Okamoto et al. N=200 Median age: 77 years old PS0-2 R RT arm: TRT 60Gy/30 fr CRT arm: CBDCA 30mg/m 2 20 times + TRT 60Gy/30 fr Updated OS Updated PFS CRT arm CRT arm RT arm RT arm MST (mo.) 3-yr (%) HR (95%CI) p Med PFS (mo.) p RT arm % CRT arm % ( ) (one-sided) 8.9 (one-sided) The CRT using daily carboplatin is considered to be the standard treatment for elderly pts with locally advanced NSCLC.

19 WJOG; West Japan Oncology Group

20 WJOG/Thoracic Oncology Study Group for NSCLC Study number 5108L 5208L 5610L phase Target Reference arm III since Jun III since Jul III since Sep Previous treated advanced adeno. IIIB/IV, squamous Advanced non-sq. without harboring EGFR mutation Gefitinib (250mg/day) Cis. (80mg/m2) + Doc. (60mg/m2) x 4-6 cycles CBDCA+PEM+ Bev. followed by Bev. alone Experimental arm Erlotinib (150mg/day) Nedaplatin (100mg/m2)+ Doc. (60mg/m2) x 4-6 cycles CBDCA+PEM+ Bev. followed by Bev.+PEM Primary endpoint PFS (noninferiority) Sample size 560 OS 350 OS 620

21 WJOG/Thoracic Oncology Study Group for NSCLC Study number phase Target Reference arm Experimental arm Primary endpoint Sample size 3605 (LETS study)* III IIIB/IV Carbo. + Paclitaxel Carbo. + TS-1 OS (noninferiority) L (IMPACT) III P-II-IIIA. EGFRmut without T790M Cis. + VNR Gefitinib DFS 230 *; JCO2010; 28: The translational research is ongoing.

22 IMPACT; WJOG6401L; phase III trial of gefitinib as adjuvant therapy in NSCLC with EGFR mutation Stage II IIIA EGFR mu-positive Without T790M Complete resection PS; y.o. R A N D M I Z E Primary endpoint; DFS at 5 year Secondary endpoints: OS and toxicity gefitinib 250mg/day for 2 yr. n=115 Cis. (80mg/m2, day1) +VNR (25mg/m2, day1, 8) q3wks X 4 cycles n=115 Stratified by: Institute, Stage, Gender, 19 deletion vs. L858R Since Sep Current; 42+ P.I.; Tada H.

23 #7010 (PD) The SELECT study: A multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive NSCLC. Neal et al. N=63 Asian: 89% Ex19/L858R: 61%/36% I/II/IIIA: 53%/19%/28% Toxicities; tolerable Primary endpoint; 2YS; 94%

24 Others

25 #7515 (PD) Randomized Phase III Trial of S-1 plus Cisplatin versus Docetaxel plus Cisplatin for Advanced NSCLC : TCOG0701-CATS TRIAL (Cisplatin And TS-1 TRIAL). Katakami et al. S-1 plus cisplatin is a standard first-line chemotherapeutic regimen for advanced NSCLC in Japan.

26 JIPANG; Randomized Phase III Study of PEM+CDDP and VNR+CDDP in adjuvant setting for completely resected Non-squamous LC p-stage II-IIIA Completely resected NSCLC PS: 0-1 Age: ys Within 8weeks after surgery R A N D M I Z E Stratified factors; Institute, Gender, Stage, EGFR mut. status, Age (70) n=400 Cis. (75mg/m2, day1) + PEM (500mg/m2, day1) q3wks x 4 cycles n=400 Primary endpoint: Overall survival, Secondary endpoints: Disease-free survival and toxicity Since Feb Current; 20+ Cis. (80mg/m2, day1) + VNR (25mg/m2, day1, 8) q3wks x 4 cycles P.I.; Tsuboi M.

27 NEJ009; Phase III study comparing gefitinib with gefitinib combined with carboplatin/pemetrexed for advanced non-small cell lung cancer with EGFR mutation NSCLC with sensitive EGFR mutations detected by PNA-LNA PCR clamp method Without T790M Stage IIIB/ IV Chemo-naïve ECOG PS years old Stratified factors; Institute, Gender, Stage Primary endpoint: Overall survival, Secondary endpoints: PFS, ORR and toxicity R A N D M I Z E n=170 Carbo. (AUC=5, day1) + PEM (500mg/m2, day1) q3wks x 4 cycles + Gefitinib n=170 Since Oct Current; 50 cases + Gefitinib (250mg/day) P.I.; Inoue A.

28 Summary JCOG/LCSSG-WJOG/SSG have several trials regarding surgical issues, especially the focus to sublobar resection for T1a disease. JCOG has trials regarding several SCLC and elderly NSCLC. WJOG have a lot of studies for NSCLC. Several phase III studies are performed by other groups