Gastrointestinal Cancer (Non colorectal) Dr Özlem Er

Transcription

1 Best of ASCO 2012 İstanbul Gastrointestinal Cancer (Non colorectal) Dr Özlem Er

2 Gastrointestinal Cancer (Non colorectal) LBA 4000: A Randomised Multi-centre Trial of Epirubicin, Oxaliplatin, and Capecitabine plus Panitumumab in Advanced Oesophagogastric Cancer (REAL3) LBA 4003: Phase II-III Randomised Trial of Definitive Chemoradiotherapy with FOLFOX or Cisplatin and Fluorouracil in Esophageal Cancer. PRODIGE 5 - ACCORD 17 Trial: Final Results 4004: Optimum Time to Assess Complete Clinical Response Following Chemoradiation Using Mitomycin or Cisplatin, with or without Maintenance Cisp/5FU in Squamous Cell Carcinoma of the Anus:Results of ACT II 4008: A Randomized Controlled Phase II Study of the Prophylactic Effect of Urea-Based Cream on the Hand-Foot Skin Reaction Associated with Sorafenib in Advanced Hepatocellular Carcinoma

3 A randomised multi-centre trial of epirubicin, oxaliplatin, and capecitabine plus panitumumab in advanced oesophagogastric cancer (REAL3) Dr T Waddell MBChB, MRCP On behalf of the REAL-3 trial collaborators T. Waddell, I. Chau, Y. Barbachano, D. Gonzalez-de-Castro, A. Wotherspoon, C. Saffery, G. Middleton, J. Wadsley, D. Ferry, W. Mansoor, T. Crosby, F. Coxon, D. Smith, J. Waters, T. Iveson, S. Falk, S. Slater, A. Okines, D. Cunningham

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5 Rationale for REAL3 Trial OG cancers 2 nd commonest cause of cancer death worldwide (>1.1 million deaths/yr) 1 REAL2 trial 2 : EOC vs ECF (median OS 11.2mo vs 9.9mo, p=0.020; HR 0.80) EGFR pathway: Variable rates of over-expression in OG cancer (30-90%) Association with poor prognosis 3,4 Potential therapeutic target 1. GLOBOCAN Cunningham et al, NEJM Yonemura et al, Oncology Kim et al, BJC 2009

6 REAL3 Trial Design Untreated advanced adenocarcinoma or undifferentiated carcinoma of the oesophagus, OGJ or stomach R Arm A: EOC Arm B: meoc-p EOC (Arm A): Epirubicin 50mg/m 2 IV D1 Oxaliplatin 130mg/m 2 IV D1 Capecitabine 1250mg/m 2 /day PO in two divided doses D1-21 meoc-p (Arm B) 1: Epirubicin 50mg/m 2 IV D1 Oxaliplatin 100mg/m 2 IV D1 Capecitabine 1000mg/m 2 /day PO in two divided doses D1-21 Panitumumab 9mg/kg IV D1 1. Okines et al, JCO 2010

7 Key Eligibility Criteria Inoperable locally advanced / metastatic adenocarcinoma or undifferentiated carcinoma oesophagus, GOJ, stomach RECIST-measurable disease No prior chemotherapy / radiotherapy including previous adjuvant therapy PS 0, 1 or 2 Archival tissue available for biomarker analyses Locally advanced tumours suitable for chemo-radiotherapy excluded EGFR positivity / HER-2 status / KRAS mutation status not required for study entry

8 Endpoints Primary endpoint: overall survival Aimed for 10% improvement in 1-year survival rate (45% 55%) Hazard ratio events, 90% power, 2-sided alpha 0.05 Planned n=730 Secondary endpoints: RR, PFS, toxicity, QoL, effect of KRAS mutation status Exploratory biomarker analyses

9 Study Progress First patient recruited: June participating UK centres Peak accrual >30 pts/month : Phase I dose finding (29 pts) 1 19 pts excluded from subsequent analyses : Phase II (200 pts) 2 52% RR in meoc-p arm (49%PR + 3%CR) Futility threshold exceeded for trial continuation 2010 onwards: Phase III trial 1. Okines et al, JCO Chau et al, ASCO 2011

10 Study Progress October 2011: Annual review of unblinded data by IDMC Inferior OS outcome in meoc-p arm HR 1.53, p=0.006 Based on 169 events (EOC:68, meoc-p:101) Phase III Trial closed (n=553, 76% total) All patients crossed over to EOC Data for patients still on treatment censored at time of trial closure

11 Patient Demographics EOC: 275 n (%) meoc-p: 278 n (%) Total: 553 n (%) Median Age (range) 62 (26-83) 63 (26-83) 62 (26-83) Gender Male 226 (82.2) 232 (83.5) 458 (82.8) Female 49 (17.8) 46 (16.5) 95 (17.2) PS (42.5) 118 (42.4) 235 (42.5) (52.0) 144 (51.8) 287 (51.9) 2 15 (5.5) 16 (5.8) 31 (5.6) Site Oesophagus 111 (40.4) 106 (38.1) 217 (39.2) O-G Junction 75 (27.3) 94 (33.8) 169 (30.6) Stomach 89 (32.4) 78 (28.1) 167 (30.2) Extent Locally advanced 25 (9.1) 35 (12.6) 60 (10.8) Metastatic 250 (90.9) 243 (87.4) 493 (89.2) Histology Adenocarcinoma 272 (98.9) 273 (98.2) 545 (98.6) Undifferentiated 3 (1.1) 5 (1.8) 8 (1.4)

12 Probability of Survival (%) 100 Primary Endpoint OS EOC EOC-P Median OS (95% CI) % alive at 1 year (95% CI) 11.3m ( ) 46% (38% - 54%) 8.8m ( ) 33% (26% - 41%) HR 1.37, p = HR 1.37 (95% CI: ) 0 Number at risk Months from Randomisation EOC EOC-P Based on 251 OS events

13 Probability of Survival (%) 100 Trial Results - PFS EOC EOC-P Median PFS (95% CI) % alive and progressionfree at 1 year (95% CI) 7.4m ( ) 21% (14% - 27%) 6.0m ( ) 20% (14% - 26%) HR 1.22, p = HR 1.22 (95% CI: ) Number at risk Months from Randomisation EOC EOC-P Based on 333 PFS events

14 Trial Results - RR Best Response EOC (n=238) meoc-p (n=254) CR 5 (2%) 8 (3%) PR 95 (40%) 108 (43%) SD 51 (21%) 46 (18%) PD 19 (8%) 30 (12%) Not evaluable 68 (29%) 62 (24%) ORR 42% 46% Odds Ratio for Response 1.16 (95% CI: ) p-value Patients who had not reached 1 st response assessment at time of data censoring are excluded (n=61)

15 Trial Results Toxicity EOC (n=269) meoc-p (n=272) Toxicity Grade 3 Grade 4 Grade 3 Grade 4 p-value Vomiting 8.2% 0.0% 7.4% 0.0% - Mucositis 0.0% 0.0% 5.1% 0.0% <0.001 Diarrhoea 10.4% 0.7% 17.3% 0.0% Lethargy 11.2% 0.7% 16.9% 0.0% - Hand Foot syndrome 4.8% 0.0% 5.9% 0.0% - Peripheral Neuropathy 6.7% 0.0% 1.1% 0.0% DVT 3.0% 0.0% 3.3% 1.1% - Pulmonary Embolism* 0.0% 4.5% 0.0% 7.0% - Rash 0.7% 0.0% 9.9% 0.4% <0.001 *One G5 PE in meoc-p arm

16 Trial Results - Toxicity EOC (n=269) meoc-p (n=272) Toxicity Grade 3 Grade 4 Grade 3 Grade 4 p-value Infection* 9.7% 2.2% 8.8% 1.1% - Febrile Neutropenia** 8.9% 3.3% 5.9% 1.5% Neutropenia 18.2% 10.8% 8.1% 5.9% <0.001 Anaemia 4.8% 1.5% 3.3% 0.4% - Thrombocytopenia 2.6% 1.5% 1.1% 0.0% Hypokalaemia 5.2% 1.9% 3.3% 1.1% - Hypomagnesaemia 0.4% 0.0% 4.0% 0.7% Any G3-5 Toxicity 70.3% 75.0% *Two G5 infections in each arm **Two G5 febrile neutropenia events in EOC arm

17 Dose Intensity EOC meoc- P Median no. of cycles (n) 6 5 Dose intensity for cycles given (% of expected dose in each arm) Epirubicin 89.9% 89.1% Oxaliplatin 89.9% 89.6%* Capecitabine 91.0% 86.9%* Panitumumab % Dose reductions due to toxicity 36% 39% Treatment cessation due to toxicity 18% 18% * Not including protocol-specified baseline dose reductions

18 Probability of Survival (%) Probability of Survival (%) Biomarkers: Rash on meoc-p 100 OS 100 PFS 80 G0 Rash (n=63) G1-3 Rash (n=209) 80 G0 Rash (n=63) G1-3 Rash (n=209) 60 log-rank p-value < log-rank p-value < Median OS 10.2m 20 Median PFS 6.8m 0 Median OS 4.3m Months 0 Median PFS 3.6m Months Similar correlation between rash and response rate (p<0.001) 25

19 Probability of Survival (%) Biomarkers: Rash on meoc-p OS in patients reaching first CT at 12 weeks: G0 Rash (n=24) G1-3 Rash (n=167) log-rank p-value Median OS 10.5m Median OS 7.7m Months

20 Molecular Biomarkers Performed in first 200 patients (phase II) 1 KRAS mut. Codon 12 Codon 13 Codon 61 EOC (n=85) 3/85 (3.5%) meoc+p (n=90) 7/90 (7.8%) Total (n=175) 10/175 (5.7%) BRAF mut. 0/82 (0%) 0/85 (0%) 0/167 (0%) PIK3CA mut. Exon 20 Exon 9 0/79 (0%) 0/79 (0%) 0/79 (0%) 4/81 (4.9%) 0/81 (0%) 4/81 (4.9%) 4/160 (2.5%) PTEN null 9/80 (11.3%) 16/87 (18.4%) 25/167 (15.0%) HER-2 pos. 17/86 (19.8%) 11/88 (12.5%) 28/174 (16.1%) 1. Chau et al, ASCO 2011

21 Probability of Survival Probability of Survival Molecular Biomarkers KRAS and PIK3CA mutations appear to be prognostic in multivariate* analysis (all tested patients) KRAS wt (n=165) KRAS mt (n=10) PIK3CA wt (n=156) PIK3CA mt (n=4) HR 2.1 (95%CI ) p-value HR 3.2 (95%CI ) p-value Median OS 10.0m Median OS 6.0m Median OS 4.0m Median OS 10.0m Months Months No prognostic effect of PTEN / HER-2 Predictive effect cannot be reliably studied currently *Variables included PS and disease stage

22 Conclusions 1 Addition of panitumumab to EOC was not beneficial in an unselected OG population Poorer OS outcome possibly due to reduced chemotherapy delivery in meoc-p arm lower doses of oxaliplatin and capecitabine lower median number of cycles Analysis based on less than 50% of OS events Future analyses will be influenced by data censoring and treatment crossover

23 Conclusions 2 RR was not a good surrogate for efficacy Panitumumab-associated rash appears to have a predictive role KRAS and PIK3CA mutations represent potential negative prognostic biomarkers Ongoing analyses aim to explore role of other putative biomarkers in this trial setting

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25 PHASE II-III RANDOMISED TRIAL of DEFINITIVE CHEMORADIOTHERAPY with FOLFOX or CISPLATIN and FLUOROURACIL in ESOPHAGEAL CANCER PRODIGE 5 - ACCORD 17 trial: Final Results T. Conroy, MP. Galais, JL. Raoul, O. Bouché, S. Gourgou, JY. Douillard, PL. Etienne, V. Boige, I. Martel-Lafay, P. Michel, C. Llacer-Moscardo, J. Bérille, L. Bedenne, A. Adenis; UNICANCER-GI/PRODIGE Group Centre Alexis Vautrin, Nancy; Centre François Baclesse, Caen; Centre Eugène Marquis, Rennes and Institut Paoli-Calmettes, Marseille; Centre Hospitalier R. Debré, Reims; Centre Val d Aurelle, Montpellier; Institut de Cancérologie de l Ouest, Nantes; Clinique Armoricaine, Saint Brieuc; Institut Gustave Roussy, Villejuif; Centre Léon Bérard, Lyon; Centre Hospitalier Universitaire, Rouen; UNICANCER R&D, Paris; Centre Hospitalier Universitaire, Dijon; Centre Oscar Lambret, Lille; FRANCE

26 Background Concurrent CRT using 5FU-Cisplatin is the standard of care in unresectable localized esophageal cancer. With 5FU-cisplatin based chemoradiation (RTOG 85-01): 20% of patients experienced major toxicities Local failure rate was 45% Herskovic A et al., N Engl J Med 1992;326: In a randomized phase II study in 97 patients comparing FOLFOX to 5FU-Cisplatin, definitive CRT with FOLFOX provided a high CR rate with a favorable toxicity profile Conroy T et al., Br J Cancer 2010;103: The study has been extended into a phase III trial

27 Prodige 5 - ACCORD 17 trial design Unresectable esophageal cancer R A N D O M I Z E 50 Gy/5 weeks + Folfox, 3 cycles 50 Gy/5 weeks + 5FU/cisplatin, 2 cy. Folfox, 3 cycles 5FU/cisplatin, 2 cycles Stratification : adenocarcinoma vs squamous-cell vs adenosquamous pretreatment weight loss < 10% vs 10% performance status: 0 vs 1 vs 2 center

28 Arm A: Folfox + RT 50 Gy Cycle 1 Cycle 2 Cycle 3 d1-2 d3-5 d8-12 d15-16 d17-19 d22-26 d29-30 d31-33 CRT RT RT CRT RT RT CRT RT Wk 1 Wk 2 Wk 3 Wk 3 Wk 5 Cycle 4 d43-44 Cycle 5 d57-58 Cycle 6 d71-72 CT CT CT Wk 7 Wk 9 Wk 11 Chemotherapy in Folfox arm: six bi-monthly cycles of FOLFOX, the first 3 cycles starting on D1, D15 and D29 concomitant with 5 weeks radiotherapy. Modified Folfox: On day 1, Oxaliplatin 85mg/m², leucovorin 200mg/m², 5-FU bolus 400mg/m²/d and from day 1 to 2, 5-FU continuous infusion 800 mg/m²/day. Tumor assessment on week 15

29 Arm B: 5FU-cisplatin + RT 50 Gy Cycle 1 Cycle 2 d1-4 d5 d8-12 d15-19 d22-26 d29-32 d33 CRT RT RT RT RT CRT RT Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Cycle 3 d50-53 Cycle 4 d71-74 CT Wk 7 CT Wk 11 Chemotherapy in 5FU-Cisplatin arm: two cycles of 5-FU/Cisplatin on week 1 and 5 of radiotherapy and two cycles of chemotherapy with 5-FU/Cisplatin on weeks 8 and 11; 5FU-cisplatin regimen: On D1, Cisplatin 75 mg/m² with hydration and from day 1 to 4, 5-FU 1000 mg/m²/day. Tumor assessment on week 15 Herskovic A et al., N Engl J Med 1992;326:

30 Main Inclusion Criteria Patients unfit for surgery or locally advanced esophageal carcinoma (disease status: any T, N0 or N1, M0 or M1a) Histologically proven adenocarcinoma, squamous-cell or adenosquamous carcinoma of the esophagus No prior treatment for esophageal cancer Age 18 years and ECOG performance status 2 Adequate bone marrow reserve, normal renal and liver functions Sufficient caloric intake > 1000 Kcal/m²/day Written informed consent

31 Exclusion Criteria Metastatic disease Multiple carcinomas of the esophagus Weight loss > 20% normal body weight Peripheral neuropathy > grade 1 Symptomatic arteritis, or myocardial infarction < 6 months Invasion of the tracheo-bronchial tree or fistula

32 Endpoints Primary: progression-free survival Secondary: complete response rate toxicity (NCI-CTC version 3.0 grading) time to treatment failure overall survival quality of life (EORTC QLQ-C30 v 3.0 and QLQ-OES18)

33 Statistical Considerations Hypothesis: Study designed to have 90% power to detect an increase of 20% in 3 year-pfs PFS defined as the first occurrence of tumor progression or metastasis, esophageal second cancer or death from any cause Sample size: 266 patients required to reach 144 events for final analysis, based on the use of the log-rank test with a two-sided significance level of 5% Intent to treat analysis (ITT)

34 Trial progress Recruitment: randomized phase II (97 patients): October 2004-December 2005 extension to phase III (170 patients): March 2008-August 2011 Final accrual: 267 patients Current analysis database lock: 28 February 2012 Number of events observed: 187 (70% of the sample size) Median follow-up: 25.3 months

35 Flow Chart Folfox 5FU/cisplatin Total Total randomized Did not fulfill all eligibility criteria Untreated patients ITT population Safety population * 5** (100%) 131 (97.8%) 133 (100%) 128 (96.2%) * all with metastatic disease ** 3 patients with metastatic disease, 1 with high creatinine, 1 with myocardial ischemia

36 Patient Characteristics Characteristics Folfox N=134 5FU/cisplatin N=133 p Median age (yrs) [range] 61 [38-85] 61 [41-81] NS Male gender 110 (82.1%) 107 (80.5%) NS Baseline PS score 0 71 (53.4%) 68 (51.1%) 1 62 (46.6%) 62 (46.6%) NS (2.6%) Weight loss grade 0 59 (44.0%) 53 (39.8%) (32.1%) 31 (23.1%) 43 (32.3%) 36 (27.1%) NS 3 1 (0.8%) 1 (0.8%)

37 Tumor Characteristics Characteristics Folfox N=134 5FU/cisplatin N=133 p Tumor type Adenocarcinoma 19 (14.2%) 18 (13.5%) NS Squamous-cell carcinoma 114 (85.1%) 115 (86.5%) Adenosquamous 1 (0.7%) - TNM classification Stage I 0 (0%) 1 (0.7%) NS Stage II A 31 (21.1%) 31 (23.3%) Stage II B 10 (7.5%) 7 (5.3%) Stage III 67 (50.0%) 72 (54.1%) Stage IV A 8 (6.1%) 8 (6.1%) Stage IV B 4 (3.1%) 4 (3.1%)

38 Tumor Characteristics Characteristics Folfox N=134 5FU/cisplatin N=133 p Median tumor length (mm) [range] 58 [11-150] 59 [7-120] NS Tumor location cervical 8 (6%) 4 (3%) NS upper thoracic 35 (26.1%) 40 (30%) middle thoracic lower thoracic 54 (40.2%) 37 (27.6%) 59 (44.4%) 30 (22.6%)

39 Safety: Hematologic AEs AE, % per patient Folfox N=131 Grade 3/4 5FU/cisplatin N=128 p Grade 3/4 Neutropenia NS Febrile Neutropenia NS Infection with Neutropenia NS Anemia NS Thrombocytopenia NS AE, adverse event

40 Safety: Main Nonhematologic AEs AE, % per patient Folfox N=131 All Grade 3/4 5FU/cisplatin N=128 All Grade 3/4 p-value all grades Dysphagia NS Esophagitis NS Fatigue NS Vomiting NS Mucositis Diarrhea NS Alopecia Peripheral neuropathy Creatinine

41 Treatment Completion Folfox 5FU/cisplatin p-value No of treated pts Median radiotherapy dose Full radiotherapy dose Full chemoradiotherapy All cycles of chemotherapy 50.0 Gy 50.0 Gy NS 98.4 % 98.4 % NS 67.9 % 72.2 % NS 71 % 76.2 % NS Treatment delayed 14.8 % 16.1 % NS

42 Responses and progressive disease Folfox-RT 5FU-cisplatin-RT n % n % Patients Complete response 55 (41.0) 55 (41.3) Events 94 (70.1) 93 (69.9) First event of PD Primary tumor Lymph nodes 2 nd esophageal T Metastases Toxic death Sudden death** Death: other causes Second cancer *p= (25.5) (12.8) (2.1) (31.9) (1.1) (1.1) (17.0) (8.5) (23.7) (17.2) (1.1) (26.9) (6.4) (3.2) (14.0) (7.5) **sudden death < 15 days from chemotherapy *

43 Probability Progression-Free Survival HR=0.93: 95%CI[ ] Med PFS Folfox+RT: 9.7 mo. [ ] Med PFS 5FU/CDDP+RT: 9.4 mo. [ ] Number at risk 5FU/CDDP+RT FOLFOX+RT Months FU/CDDP+RT FOLFOX+RT

44 Overall Survival HR=0.94: 95%CI[ ] Med OS Folfox+RT: 20.2 mo. [ ] Med OS FU/CDDP+RT: 17.5 mo. [ ] Number at risk 5FU/CDDP+RT FOLFOX+RT Months FU/CDDP+RT FOLFOX+RT

45 Conclusions Definitive chemoradiotherapy with Folfox does not improve PFS in unresectable localized esophageal cancer Full completion of treatment rates, CR rate and survival are similar for both regimens Folfox shows more gr. 1-2 peripheral neurotoxicity, results in fewer toxic and sudden deaths as well as less mucositis, alopecia and decreased renal toxicity Concomitant chemoradiotherapy with Folfox is a safer new option, especially in patients with contraindication to cisplatin Bottom line, Folfox is more convenient and leads to shorter chemotherapy (12 days vs days) given in an outpatient setting

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47 The optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin C (MMC) or Cisplatin (CisP) with or without Maintenance CisP/5FU in squamous cell carcinoma of the anus: Results of ACT II Dr Rob Glynne-Jones on behalf of the NCRI ACT II Trial Management Group and Investigators ASCO, Chicago, June Abstract ID: 4004 Cancer Research UK grant number: C444/A628 ISRCTN number: Funder Sponsor

48 ACT II Objectives To evaluate in a factorial design whether chemoradiation using CisP or MMC produces a higher complete response rate maintenance therapy (5FU/CisP) will improve local control /prolong survival by preventing or delaying disease dissemination Accrual patients randomised Jun 01 Dec 08 Median follow-up - 5 years

49 ACT II Factorial Design Chemoradiation Comparison MMC 5FU CRT No maintenance MMC 5FU CRT +Maintenance versus CisP 5FU CRT No maintenance CisP 5FU CRT +Maintenance MMC N=472 CisP N=468

50 ACT II Factorial Design Maintenance Comparison MMC 5FU CRT No maintenance CisP 5FU CRT No maintenance No Maint N=446 versus MMC 5FU CRT Maintenance CisP 5FU CRT Maintenance Maint N=448

51 Chemoradiation Regimens RT week 5FU MMC mg/m 2 d1-4 & hour continuous iv infusion 12mg/m 2 d1 only iv bolus, max single dose 20 mg 6 RT week 5FU CisP mg/m 2 d1-4 & hour continuous iv infusion 60mg/m 2 d1 & 29 iv infusion 6

52 ACT II Response Assessments From start of CRT 11 weeks - ie 4 wks after end of CRT DRE +/- EUA 18 weeks - ie weeks post CRT and pre-maintenance DRE +/- EUA 26 weeks - ie post maintenance 4 wks DRE +/- EUA plus abdo-pelvic CT scan, chest X-ray

53 ACT II Radiotherapy 50.4 Gy 28 daily fractions 5 ½ weeks Two-phase technique Both phases planned simultaneously

54 Tumour Stage MMC (472) CisP (468) T stage T1 T2 49% (232) 54% (254) T3 T4 48% (225) 44% (205) TX N Stage Node negative 63% (297) 62% (290) Node positive 32% (150) 33% (155) NX 25 23

55 Response at 26 weeks Patients with response data (863) MMC (432/472) CisP (431/468) CR primary 90% 90% CR N0 83% (358) 84% (362) CR N+ 3% (15) 3% (12) CR Nx 4% (18) 3% (12) PR 3% (14) 6% (24) SD 1% (5) 1% (6) PD 5% (22) 3% (15) P=0.66

56 Missed Response Assessment at 26 weeks Reason excluded N = 77 Death 23 Progression /salvage surgery 8 Too unwell 5 Assessment inconclusive 2 Did not attend 12 Not assessed 25 Not known 2

57 CR at 26 weeks Difference (95% CI) P value MMC CisP 83% (358/432) No Maint 82% (337/409) 84% (362/431) Maint 85% (348/410) +1% (-3.8 to 6.1) p = % (-2.6 to 7.5) p = 0.34

58 Timing of CR Assessment (691 pts with data at all 3 time-points) Wk Pts with CR CR rate% MMC CisP Absolute risk difference 7.1% (-0.1, +14.5) p= % (-7.9, +4.8) p= % (-6.3, +4.5) p=0.74 HR (95% CI) (CR vs not CR) PFS OS 0.71 (0.53, 0.95) p= (0.38, 0.71) p< (0.15, 0.29) p< (0.49, 0.99) p= (0.34, 0.70) p< (0.15, 0.31) p<0.001

59 ACT II Compliance & Toxicity Radiotherapy 92% MMC vs 90% CisP - total dose 50.4Gy ~3% >7 d interruptions Chemotherapy - weeks 1 & 5 75% MMC vs 72% CisP full dose weeks 1 & 5 Acute toxicity 58% MMC vs 60% CisP Grade 3 13% MMC vs 12% CisP Grade 4 71% MMC vs 72% CisP combined Grade 3/4

60 PFS -free survival MMC vs CisP comparison 74% 73%

61 PFS-free survival CR vs Not CR week 11 80% 72%

62 PFS free-survival CR vs Not CR week 26 83% 45%

63 Overall Survival CR vs Not CR week 26 93% 61%

64 ACT II Conclusions Excellent CR rate at 6 months - 83% v 84% 60% of pts not in CR at 11 weeks achieved CR at 26 weeks. We recommend assessment at 26 weeks in future trials

65 NCCN Guidelines for follow-up version 2, Re-evaluation with DRE at 8-12 weeks after CRT Classify as CR or persistent disease or progressive disease Persistent disease - watch closely for 4 weeks to see if further regression Progressive disease - requires histologic confirmation

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67 A Randomized Controlled Phase II Study of the Prophylactic Effect of Urea-Based Cream on the Hand-Foot Skin Reaction Associated with Sorafenib in Advanced Hepatocellular Carcinoma Zhenggang Ren 1,Kangshun Zhu 2, Haiyan Kang 3, Minqiang Lu 2, Zengqiang Qu 4, Ligong Lu 5, Tianqiang Song 6, Weiping Zhou 4, Hui Wang 7, Weizhu Yang 8, Xuan Wang 9, Yongping Yang 10, Lehua Shi 4, Yuxian Bai 11, Sheng-Long Ye 1* 1 Zhongshan Hospital, Fudan University, Shanghai, China; 2 The Third Affiliated Hospital of Sun Yatsen University, Guangdong, China; Military Hospital, Beijing, China; 4 Eastern Hepatobiliary Surgery Hospital of the Second Military Medical University, Shanghai, China; 5 Guangdong Provincial People's Hospital, Guangdong, China; 6 Tianjin Cancer Hospital, Tianjin, China; 7 Jilin Provincial Tumor Hospital, Jilin, China; 8 Union Hospital of Fujian Medical University, Fujian, China; 9 The 81 Hospital of the Chinese People's Liberation Army, Nanjing, China; Military Hospital, Beijing, China; 11 Heilongjiang Provincial Cancer Hospital, Heilongjiang, China

68 Background Hand-foot skin reaction (HFSR) is one of the most common adverse events associated with Sorafenib (SOR), with the incidence ranging from 21% to 93%. 1 HFSR can significantly impact the physical, psychological, and social well-being of patients and can lead to dose reductions and discontinuations that may potentially diminish the beneficial effects of anticancer therapy. 2-3 Randomized, controlled trials (RCTs) targeting prevention/palliation of HFSR have not been reported. 4-5 We sought to investigate the prophylactic effect of urea-based creams on the incidence of HFSR associated with SOR treatment of patients with advanced HCC. 1 L. Zhang, et al. Clin and Exp Dermatology 2011, 36, Porta C, et ai. Clin Exp Med 2007; 7: Robert C, et al. Lancet Oncol 2005; 6: Anderson R, et al. The Oncologist 2009; 14: Lacouture ME, et al. The Oncologist 2008;13:

69 Study Rationale and Objective Rationale Mild hyperkeratosis is an early sign of HFSR, and sometimes the only manifestation of sorafenib-related HFSR; Urea is useful for the treatment of hyperkeratotic conditions and has been recommended for treatment of multitargeted kinase inhibitor-related HFSR 1 Objective To investigate the prophylactic effect of an urea-based cream on HFSR associated with SOR; Primary endpoint: Incidence of all grade HSFR within 12 weeks of starting SOR treatment. Secondary endpoint: Incidence of grade 2 HFSR within 12 weeks of starting SOR treatment; Time to first HFSR occurrence; Duration of HFSR Percentage of patients undergoing dose reduction/interruption Percentage of patients undergoing dose termination HFSR associated health-related quality of life using the HF-QoL questionnaire. 1 Lacouture et al., The Oncologist 2008; 13:

70 Study Design Design An investigator-initiated*, phase II, open-label, prospective, randomized study, conducted at 64 centers in China; Patient Population: patients with advanced HCC untreated for SOR Statistics: Primary endpoint compared between the treatment groups using a Fisher s exact test; the severity in HFSR analyzed by appropriate Mantel- Haenszel statistics. Time to first HFSR and duration of HFSR described between the two groups by Kaplan-Meier estimates and log-rank tests. One-sided α of and a power of 90%; 26 pre-selected/pre-coded AEs were recorded from week 0-14 and included AEs commonly associated with SOR (eg: 1. diarrhea, 2. rash, etc.) * This study was sponsored by the Chinese Anti-Cancer Association (CACA) with financial support from Bayer Healthcare.

71 Study Schema Inclusion Criteria: Patients being started on SOR for HCC Exclusion Criteria: Previous SOR Concomitant anticancer therapy SOR > 800mg/d R A N D O M I Z E N=871 Arm A: Urea-based cream plus best supportive care with concomitant SOR on Day 1 Arm B: Best supportive care (BSC) until development of HFSR with concomitant SOR on Day 1 n=439 n=432 Primary Endpoint: - Incidence all grade HFSR within 12wks Secondary Endpoint: - Incidence of grade 2 HFSR - Time to first HFSR - Duration of HFSR - % of patient with dose reduction/interruption - % of patient with dose termination - HF-QoL SOR dosage and dose modification/interruption was to follow the local label. Arm A: Urea (10%) based cream (Eucerin) TID. Arm B: BSC allowed use of moisturizing creams (non-urea-based) as needed. Once HFSR occurred, patients were able to use any cream as guided by investigator, including urea-based creams. Type of cream and frequency of use in Arm B were not recorded. Patients were followed every 2 weeks for 12 weeks with one follow up visit at week 14.

72 Best Supportive Care (BSC) Treatment type Recommendations Patient-led practical prevention 1. Reduce exposure of hands and feet to hot water 2. Avoid constrictive clothing 3. Avoid excessive rubbing 4. Avoid vigorous exercise or activities that place undue stress on hands and feet 5. Sparingly apply an alcohol-free moisturizer after bathing if the skin gets dry 6. Moisturizing cream can be applied sparingly on the hands and feet 7. Moisturizing cream can be worn at night under cotton gloves and socks 8. Wear open shoes with padded soles during treatment 9. A pedicure prior to treatment may be effective for patients with plantar hyperkeratosis Patient-led practical management 1. Soak hands in very cool water for 10 to 15 minutes three times a day if this is found to provide relief and dry well 2. Apply petroleum jelly to the hands and feet while the skin is still moist 3. Apply moisturizers sparingly 4. Use a foot bath and pumice stone to exfoliate feet (or regular pedicures) in case of hyperkeratotic lesion and apply moisturizing cream immediately afterwards 5. Use shock-absorbing soles to relieve painful pressure points

73 HF-QoL The HF-QoL is a 38 item questionnaire, containing 20 items related to hand-foot syndrome/hand-foot skin reaction (HFS/R) symptoms (HFS/R Symptom Cluster), and 18 items related to the impact of HFS/R symptoms on daily activities (HFS/R Activities Cluster). It was developed to measure HFS/R symptoms and QoL impacts from a broad spectrum of anticancer agents Response options for the HF-QoL items range from 0 Not at all to 4 always, or extremely. For items in each cluster, the scoring algorithm creates a total score value range of 0 to 100, where a higher score is indicative of worse symptom burden or greater impact of the HFS/R on daily activities The HF-QoL was developed following FDA Guidelines 1-2. It was validated in a Phase IIb randomized double-blind multinational breast cancer study 3. 1 Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims DRAFT GUIDANCE released February M. Aklilu, et al. Journal of Clinical Oncology. Vol 26, No 15S (May 20 Supplement), 2008: Data not published

74 Patient Disposition Total Enrolled (N=901) Randomized (N=871) Prophylactic Urea-based Cream + BSC Arm A (N=439) BSC Arm B (N=432) N=11 (2.5%) IC* withdrawal N=9 (2.1%) N=18 (4.1%) Death N=24 (5.6%) N=37 (8.4%) PD** N=38 (8.8%) N=25 (5.7%) Lost to F/U*** N=20 (4.6%) ArmA AcmB 91 patients censored in Arm A N=439 N= patients censored in Arm B * IC: informed consent ** PD: Progression Disease *** F/U: follow-up Final Analysis for HFSR

75 Baseline Patient Characteristics - 1 Prophylactic Urea-based Cream + BSC (Arm A) N=439, % BSC (Arm B) N=432, % Total N=871, % Median age at enrollment 51.8 yr 52.0 yr 51.9 yr Male Median Weight (kg) Median Height (cm) Etiology Hepatitis B Hepatitis C ECOG score Previous anti-cancer therapy Yes Hepatectomy

76 Baseline Patient Characteristics - 2 Disease History Prophylactic Urea-based Cream + BSC (Arm A) N=439, % (n) BSC (Arm B) N=432, % (n) Total N=871, % (n) Alcohol / drug addiction 0.7 (3) 0.9 (4) 0.8 (7) Allergy 0.9 (4) 0.5 (2) 0.7 (6) Emphysema / COPD 1.2 (5) 0.2 (1) 0.7 (6) Asthma 0.9 (4) 0.9 (4) 0.9 (8) Hypertension 5.3 (23) 4.4 (19) 4.9 (42) Diabetes 2.5 (11) 3.3 (14) 2.9 (25) Thyroid gland disease 0.2 (1) 0.2 (1) 0.2 (2) Dermatosis* 0.2 (1) 0.5 (2) 0.4 (3) * Including 1 patient of skin eruption in Arm A; 1 patient of psoriasis and 1 patient of unidentified dermatosis in Arm B

77 Incidence of Worst-grade HFSR Grade of HFSR* Prophylactic Urea-based Cream + BSC (Arm A) N=439 (%) BSC (Arm B) N=432 (%) Total N=871 (%) 0 193(44.0) 114(26.4) 307(35.3) P Value All Grade (%) 246(56.0%) 318(73.6%) 564(64.8%) < (35.3) 192(44.4) 347(39.8) 2 72(16.4) 98(22.7) 170(19.5) 3 19(4.3) 28(6.5) 47(5.4) 2/3 91 (20.7) 126(29.2) 217(24.9) Primary Endpoint: The incidence of all-grade HFSR was significantly lower in Arm A (p<0.0001) Secondary Endpoint: The incidence of grade 2 HFSR was significantly lower in Arm A (p=0.004) The incidence of HFSR by grade was lower in Arm A More patients in Arm A did not develop HFSR

78 % Prevalence of All-grade HFSR at Each Visit r2l r2l r2l Arm A Arm B r1l r1l r1l r1l Week Week Week 0 Week 2 Week 4 Week 6 Week 8 EOS* Arm A Arm B % *EOS: 2 weeks after end of study

79 Time to the first HFSR event Secondary Endpoint The median time to the first HFSR event was 2.5 fold longer in Arm A compared to Arm B (84 days vs. 34 days, p<0.0001)

80 HF-QoL* Secondary Endpoint HFSR Symptoms (20 items) HFSR Daily Activity (18 items) P value Module Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 EOS** HFSR Symptoms < HFSR Daily Activity * Based on a scoring algorithm that creates a total score value range of 0 to 100, where a higher score is indicative of worse symptom burden or greater impact of the HFS/R on daily activities. ** EOS: two weeks after end of study

81 Dose Modification (interruption, reduction, termination) Dose Modification Due to HFSR Prophylactic Urea-based Cream + BSC (Arm A) N=439 (%) Best Supportive Care (Arm B) N=432 (%) Total N=871 (%) Dose Reduction/Interruption 40 (9.1) 51 (11.8) 91 (10.5) Dose Termination 5 (1.1) 3 (0.7) 8 (0.9)

82 Efficacy Results at Week 12 Tumor Response at Week 12 Prophylactic Ureabased Cream + BSC (Arm A) N=333 (%) Best Supportive Care (Arm B) N=337 (%) Total N=670 P Value CR 0 (0) 1 (0.3) 1(0.15) PR 37 (11.1) 33 (9.8) 70(10.45) SD 292 (87.7) 297(88.1) 589(87.9) PD 4 (1.2) 6 (1.8) 10 (1.5) RR (CR+PR) 37 (11.1) 34 (10.1) 71 (10.6).6674 DCR (CR+PR+SD) 329 (98.8) 331 (98.2) 660 (98.5).5350

83 Sorafenib-related AEs* (all Grade) Adverse Event Prophylactic Urea-based Cream + BSC (Arm A) N=333 (%) Best Supportive Care (Arm B) N=337 (%) Diarrhea 46 (10.5) 44 (10.2) Fatigue 13 (3.0) 19 (4.4) Anorexia 8 (1.8) 10 (2.3) Hypertension 7 (1.6) 7 (1.6) Headache 6 (1.4) 12 (2.8) Dry skin 5 (1.1) 13 (3.0) Rash 4 (0.9) 6 (1.4) Nausea 2 (0.5) 3 (0.7) Weakness 1 (0.2) 2 (0.5) Vomiting 1 (0.2) 3 (0.7) Total 268 (61.0) 327 (75.7) * Duration of AE observation period was 14 weeks

84 Non-blinded study Limitations Observation period of 14 weeks possibly too short Extent of use of a moisturizing cream in Arm B prior to development of HFSR was not documented Lack of a true control arm (no cream)

85 Summary This is the first large prospective, randomized control trial examining the prophylactic use of an urea-based cream for treatment of HFSR associated with a multikinase inhibitor. This study met its primary endpoint of significantly reducing incidence of all grade HFSR within 12 weeks of starting Sorafenib treatment (p<0.001). Use of an urea-based cream significantly reduced the incidence of grade 2 HFSR (p=0.004). The time to the first HFSR event was 2.5 fold longer in the arm receiving prophylactic urea cream (p<0.0001) The prophylactic use of urea-base cream improved health-related quality of life as measured by the HF-QoL, reducing the HFSR symptom burden and impact of HF symptoms on daily activities.

86 Conclusions These results suggest that prophylactic use of an ureabased cream in advanced HCC patients treated with sorafenib: Reduces the incidence and severity of HFSR Delays the time to first occurrence of HFSR Improves hand-foot associated health related quality of life

87 TEŞEKKÜRLER Dr Özlem Er