Evaluation of SIRFLOX Study Results. Prof. V. Heinemann CCC LMU, Klinikum Grosshadern Ludwig-Maximilian-University of Munich, Germany

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1 Evaluation of SIRLX Study Results Prof. V. Heinemann CCC LMU, Klinikum Grosshadern Ludwig-Maximilian-University of Munich, Germany

2 ESM Guideline: Response is a Goal of Treatment Performance Status of the Patient it Unfit (treatment possible?) lder Patient Therapeutic Goal it CT + Antibody Unfit Capecitabine + Bev Doublet with Reduced P-Dose R0 resection Patients with clearly resectable metastases Surgery RAS wt Doublet + anti-egr Cytoreduction (Tumor shrinkage) Molecular Profile RAS mt Combination + Bevacizumab BRA mt Triplet + Bevacizumab Disease Control (Control of Progression) RAS wt CT + Antibody Molecular Profile RAS mt CT + Bevacizumab Prolongation of S * P=luoropyrimidin ** CT=Chemotherapie *** NED=No evidence of disease

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4 SIRLX Study Design Prospective open-label RCT Primary endpoint: Progression-ree Survival (PS) in the ITT population by independent central imaging Eligible patients Non-resectable liver-only or liverdominant mcrc* No prior chemo for advanced disease WH performance status 0 1 Stratified by Presence of extrahepatic metastases Degree of liver involvement Intended use of bevacizumab Institution Secondary endpoints: PS in the liver Tumour response rate in the liver Tumour response rate at any site (RECIST 1.0) Hepatic resection rate Toxicity & safety (NCI CTCAEv3.0) Health-related quality of life verall survival, in a pre-planned combined analysis Randomised 1:1 n = 530 n = 263 enrolled m6 (+ bevacizumab) (1) n = 267 enrolled m6 (+ bevacizumab) (1) Y-90 resin microspheres 1. Bevacizumab allowed at investigator s discretion, per institutional practice Peter Gibbs et al. ASC 2015 Guy van Hazel WCGIC 2015

5 SIRLX: Extrahepatic metastasis Inclusion criteria: limited extrahepatic metastasis allowed lung: < 5 nodules 1 cm diameter or a single nodule 1.7 cm diameter and/or lymph node involvement single anatomical area <2 cm diameter

6 Treatment Schedule: SIRT day 3 or 4 of first cycle Control arm: m6 (+ bevacizumab) (1) Cycle 1 Cycle 2 Cycle 3 Cycle 4 L X X = 85 mg/m 2 L X X = 85 mg/m 2 L X X = 85 mg/m 2 L X X = 85 mg/m 2 Bev Bev Bev Bev Treatment arm: m6 (+ bevacizumab) (1) (2) Preparation Cycle 1 Cycle 2 Cycle 3 Cycle 4 Work up for SIRT n day -14 to -3 L X SIRT on day 3 or 4 L X X = 60 mg/m 2 X = 60 mg/m 2 X = 60 mg/m 2 L X L X X = 85 mg/m 2 1. Bevacizumab allowed at investigator s discretion, per institutional practice. 2. Work-up procedure at Day (D) -14 to D-3 prior to SIRT; SIR-Spheres Y-90 resin microspheres administered on either D3 or D4, of either Cycle 1 or Cycle 2. Bev

7 Statistical Plan Sample size calculation Increase median PS from 9.4 months in the control arm to 12.5 months Corresponding to a 25% relative risk reduction (Hazard Ratio: 0.75) 80% power and a two-sided alpha of 0.05 Enrollment was restricted to 40% of patients with extra-hepatic metastases PS in the liver, defined as cumulative incidence of liver progression, analyzed by Competing Risk Analysis (1,2) to account for the competing risks of 1. irst progression occurring outside the liver as this may alter the course of the disease including the impact of subsequent therapy on liver metastases 2. Death 1. ine JP, Gray RJ. J Am Stat Assoc 1999;94: Gray RJ. Ann Stat 1988;16:

8 Patient Characteristics in the ITT Population Characteristic (+ bev) (n = 263) (+ bev) (n = 267) Age, years, median (range) 63 (23 89) 63 (28 81) Sex emale Male 88 (34%) 174 (66%) 85 (32%) 182 (68%) WH performance 0 status (67%) 87 (33%) 176 (66%) 90 (34%) Extra-hepatic metastases 104 (40%) 108 (40%) Primary tumour not removed 121 (46%) 119 (45%) Synchronous metastases 233 (89%) 241 (90%)

9 Application of SIRT Characteristic SIRT application (+ bev) (n = 267) median of 20 days after randomisation range 8-76 days Both liver lobes treated 227/246 (92.3%) Single lobe treated 19/246 (7.7%)

10 Proportion Not Progressing Progression-ree Survival at Any Site n Events Median (+ bev) months (+ bev) months HR: 0.93 (95% CI: ), p= Time from Randomization (months) Number at risk (+ bev) (+ bev) Statistical calculation: 2 Increase median PS from 9.4 months in the control arm to 12.5 months in the SIRT arm

11 Probability of Hepatic Progression PS in the Liver: Cumulative Incidence of Liver Progression n Median (+ bev) months (+ bev) months HR: 0.69 (95% CI: ), p= month improvement in median PS in the liver 31% reduction in risk of disease progression in the liver Time from Randomization (months) Number at risk (+ bev) (+ bev) Competing risk analysis: accounts for progression outside of the liver and death

12 Probability of Hepatic Progression Probability of Hepatic Progression PS in the Liver: Cumulative Incidence of Liver Progression Stratified by ITT for Bevacizumab vs No Bevacizumab Patients with ITT for bevacizumab Patients with ITT for no bevacizumab N Median p-value N Median p-value + bev + bev months months p= months months p=0.028 HR: 0.69 (95% CI: ) HR: 0.69 (95% CI: ) Time from Randomization (months) n at risk + bev bev Time from Randomization (months)

13 Tumour Response Rate bjective Response Rate (RR) by RECIST v1.0 RR at Any Site RR in the Liver CR + PR: 68.1% 76.4% p= % 78.7% p= % Δ = 10% 70% 60% 50% 40% PR: PR: PR: PR: 66,5% 71,9% 66,9% 72,7% 30% 20% 10% 0% CR: CR: CR: CR: p= ,5% 4,5% 1,9% 6,0% (n = 263) (n = 267) (n = 263) (n = 267) p=0.020 Δ = 4% CR: Complete Response; PR: Partial Response.

14 Response analysis in SIRLX Characteristic (+ bev) (n = 263) (+ bev) + SIRT (n = 267) P RR any site CR in the liver RR in the liver CR in the liver Resection rate

15 Selected All-Cause Grade 3 Adverse Events Events (all-causality) (+ bev) (n = 270) Grade 3 (%) (+ bev) (n = 246) Grade 3 (%) All patients Grade 5 events Chemotherapy-associated events Neutropenia * ebrile neutropenia * Thrombocytopenia * Diarrhoea Nausea and/or vomiting SIRT-associated events Gastric or duodenal ulcer 0 3.7* Ascites 0 2.8* Hepatic failure Radiation hepatitis * Denotes statistically significant difference in incidence of the adverse event.

16 Conclusion SIRLX evaluated the combination of SIRT plus in comparison to chemotherapy with (+/- bevacizumab) in patients with liver-dominant metastasis A significant prolongation of PS (primary endpoint) was not shown However, addition of SIRT to chemotherapy induced a significant and clinically relevant prolongation of PS in the liver (7.9 months, HR 0.69, p=0.002) The objective response rate (RR) in the liver was significantly improved (RR: 79% vs 69%; CR: 6% vs 2%).

17 2016 Evaluation of depth of response within a volumetric model in patients with metastatic colorectal cancer: Results of the SIRLX study Volker Heinemann*, Guy A. van Hazel, Navesh K. Sharma, Michael P. N. indlay, Jens Ricke, Marc Peeters, Val Gebski, Mark Van Buskirk, Peter Gibbs, on behalf of the SIRLX Study Group * Department of Medical ncology, Medizinische Klinik und Poliklinik III Comprehensive Cancer Center Munich, Ludwig-Maximilian-University of Munich, Germany

18 Relation between Response and S Hypothesis: Depth of response relates to S Lethal tumour load S TTG Tumour load at baseline DpR ETS DpR Tumour nadir PS + molecular markers e.g. CEA, CA19-9 Time since start of treatment

19 Tumour size, % The Concept of DpR versus RECIST Δ S Lethal tumour load Tumour load at baseline 100% 70% Depth of response PR correlates with postprogression-survival (PPS) Therapy PR Depth of Response (DpR) RECIST is not sufficient to show this relationship

20 Depth of Response (DpR) in SIRLX Aims To evaluate the DpR concept by applying a volumetric model to the independent blinded reader RECIST v1.0 data from SIRLX 2 To relate depth of response to baseline tumour burden 1. Heinemann V et al. Eur J Cancer 2015;51: van Hazel GA et al. Journal of Clinical ncology 2016; 34:

21 Relationship between RECIST and Volume A B d M r V = 4/3. r 3. π Shrinkage RECIST WH Volume Longest diameter Surface of circle Volume 5.0 cm baseline 100% 100% 100% 4.5 cm 90% 81% 73% 4.0 cm 80% 65% 52% 3.5 cm 70% 50% 34 % 60% 85% 94% 2.0 cm 40% 15% 6% Laubender RP et al. Eur Radiol 2014;24:

22 Hepatic Tumour Burden Analysis Tumour burden (%) = 100 x tumour volume liver volume

23 Depth of Response Analysis Analyses were performed for the Intention-to-Treat (ITT) population for patients with baseline and 1 radiological independent central imaging assessment available using RECIST v1.0 The DpR model used a volume calculation based on the diameter of the lesions chosen as target lesions for RECIST evaluation It was assumed: that the target lesions were spherical that the volume of the target lesions was representative of the total tumour volume in the liver

24 Approach to Categorize Tumor Burden inite Mixture Modelling supported by RC (Receiver perating Characteristic) analysis identified an optimal cut-point of 12% tumour burden at baseline Definition of Baseline Tumor Load >12 % tumor load in the liver (245 pts) 12% tumor load in the liver (239 pts)

25 Baseline Patient Characteristics Characteristic n (%) unless stated (+ bev) (n = 251) (+ bev) (n = 235) P value Age, years Mean (SD) Median (IQR) 62.0 (10.4) 63.0 (14.0) 62.5 (11.1) 63.0 (12.0) Sex emale Male 82 (32.7) 169 (67.3) 78 (33.2) 157 (66.8)) WH performance 0 status (65.7) 85 (33.9) 156 (66.4) 79 (33.6) Extrahepatic disease 101 (40.2) 91 (38.7) Primary tumour in situ 111 (44.2) 106 (45.1) Liver involvement, % Mean (SD) Median (IQR) 18.4 (16.9) 12.7 (23.9) 17.8 (15.3) 12.6 (23.2) DpR sub-population from ITT: 486/530 (92%)

26 Mean Volume Change from Baseline (%; SE) Mean Volume Change from Baseline (%; SE) Depth of Response and Time to Nadir: Stratified by Hepatic Tumour Burden 12% Tumour Burden (ITT), n = 239 >12% Tumour Burden (ITT), n = 245 Baseline Lesion Depth of Time to Volume Response Nadir, Days Median (IQR) Mean (SD) Median (IQR) (+ bev) 68.4 cm 3 (87.6) -80.6% (34.0) 220 (193) (+ bev) 61.3 cm 3 (98.2) -72.5% (82.3) (211) Difference: 8.1% 23.5 Days p=0.912 p=0.763 p=0.152 Baseline Lesion Depth of Time to Volume Response Nadir, Days Median (IQR) Mean (SD) Median (IQR) (+ bev) cm 3 (590.1) -57.2% (109.2) 196 (176) (+ bev) cm 3 (713.7) -77.5% (29.2) 298 (246) Difference: -20.3% 102 Days p=0.188 p=0.003 p< Δ DpR = Ø 20 0 Δ DpR = 20.3% (+ bev) (+ bev) Time from Randomization (months) (+ bev) (+ bev) Time from Randomization (months)

27 Probability of Hepatic Progression Probability of Hepatic Progression 113-EUA-0715 PS in the Liver: Stratified by Tumour Burden 12% Tumour Burden (ITT), n = 239 >12% Tumour Burden (ITT), n = 245 N Median p-value (± bev) months p=0.112 (± bev) months HR: (95% CI: ) N Median p-value (± bev) months p=0.003 (± bev) months HR: (95% CI: ) Δ = 2.9 months Δ = 14.1 months Time from Randomization (months) Time from Randomization (months)

28 Response Rate (%) Hepatic Response Rates, Stratified by Tumour Burden 12% Tumour Burden (ITT) > 12% Tumour Burden (ITT) 100% RR (CR + PR) p=0.8 CR p=0.003 RR (CR + PR) p=0.022 CR p= % 83.5% 84.7% 80.2% 60% 67.2% 40% 20% 0 (+ bev) (n = 115) (+ bev) (n = 124) 1.7% (+ bev) (n = 115) 11.3% (+ bev) (n = 124) (+ bev) (n = 119) (+ bev) (n = 126) 0.8% (+ bev) (n = 119) 0 (+ bev) (n = 126)

29 Summary Liver Tumor Burden 12% P Liver Tumor Burden > 12% P RR (%) DpR (%) PS (mo) Liver

30 Summary Liver Tumor Burden 12% P Liver Tumor Burden > 12% P RR (%) CR (%) DpR (%) PS (mo) Liver

31 Conclusions SIRT using Y-90 resin microspheres (SIR-Spheres; Sirtex) significantly increased hepatic Depth of Response by 20% compared to chemotherapy The impact of SIRT on PS in the liver was greatest in patients with a baseline tumour burden >12% (27 vs 13 months) In these patients also RR was significantly improved by 13% (67% vs 80%) Conversely, the impact on the CR rate was greater (11% vs 2%) where tumour burden was 12% These findings provide additional evidence to support the benefit of SIRT in patients with mcrc