SIR-Spheres: Des essais cliniques à la pratique courante

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1 SIR-Spheres: Des essais cliniques à la pratique courante Un focus sur le traitement du mcrc en échappement thérapeutique Dr. Michaël Vouche, MD. PhD. Université Libre de Bruxelles Institut Jules Bordet Symposium Sirtex JFICV /06/2017

2 Disclosures Consultance fee Sirtex JFICV 2017

3 Introduction: Chemorefractory mcrc If untreated, the median survival of patients with mcrc is 6 8 months (1). The control of hepatic metastases is a key point in mcrc management. ~ % of patients with mcrc are refractory to first line chemotherapy. Hepatotoxic chemotherapies (2): 1. Poston Surg Oncol Adapted from Chun Lancet Oncol 2009

4 Introduction: Chemorefractory mcrc 2 nd line treatments: -Progressive selection of an aggressive tumor profile -Cumulative treatment-related toxicity (surgery, loco-regional, systemic treatments) - Definition of oligo-progression/resistance vs. early onset of multisite progression 2 nd line locoregional treatments such as SIRT mainly apply to: - Liver dominant disease - Sufficient perception of the tumor biology - Relatively preserved liver function

5 Locoregional Therapies: Palliative Intent Consolidation (Resistance) Salvage (oligoprogression)

6 Locoregional Therapies: Palliative Intent Pre-SIRT 2 months post-sirt 6 months post-sirt

7 Introduction to SIRT FDG PET 99 TcMAA- SPECT 90Y PET [Gy] Resin microspheres: Dose Volume Histogram Activity = (BSA - 0.2) + Tumor Involvement / (Tumor Volume + Normal Liver Volume). Glass microspheres: Dose (Gy) = Activity (GBq) X 50/Mass of treated liver (kg)

8 Limits of the technique Uncorrectable gastro-intestinal shunt (Lung shunt > 20% or 12 Gy)* Liver function: - Steatosis/Cirrhosis/CASH - Cumulative doses (max 40 Gy on 40% of total liver)* - Previous surgery / liver-directed therapies * J. Bordet Institute Cut-offs

9 Place of SIRT in the treatment of mcrc recommendation 16: For patients with liver-limited disease failing the available chemotherapeutic options Radioembolisation with yttrium-90 microspheres should be considered [II, B]. Chemoembolisation may be also considered as a treatment option [IV, B]. Radioembolisation (and chemoembolisation) of CLM in earlier treatment lines may be interesting as consolidation treatment but should be limited to clinical trials. ESMO guidelines. Annals of Oncology 2016

10 SIRT for Chemorefractory mcrc : Overall Survival Authors Jakobs Eur Radiol 2017 Damm BMC Cancer 2016 Maleux Acta Oncologica 2015 Saxena Ann Surg Oncol 2015 Sofocleous Clin Colorectal Cancer 2015 Lewandowski EJNMMI 2014 Type of Microspheres Number of patients Overall Survival Median (95% CI) Resin ( ) Resin (*Range ) Resin ( ) Resin (95% CI not reported) Resin ( ) Glass 214 (> 98 % chemorefractory) 10.6 ( )

11 To date, the only Phase III RCT reaching its primary endpoint on SIRT and CRCm. Multicentric randomized controlled trial comparing 5FU alone vs. 5FU+SIRT in chemorefractory CRCm. Cross-vover to SIRT was permitted after progression in the 5 FU alone group. Patients stratified by institution and interval to progression on prior chemotherapy 2-tailed superiority study (Intention to Treat) Primary Endpoint: Time to Liver Progression (TTLP) Secundary endpoints: - Time to Progression (TTP) - Overall Survival (OS) - Tumor Response (RECIST criteria) - Safety Hendlisz JCO 2010

12 Study Design Eligible Patients Liver-only mcrc, PS 0 2, refractory to chemotherapy Stratify Institution Interval to progression on chemotherapy Random Assignment Arm A: Arm B: 5FU protracted IV infusion (300 mg/m 2 D1 14 q3w) SIR-Spheres microspheres on Day 1 (D1) Cycle 1 (C1) + 5FU protracted IV infusion (225 mg/m 2 D1 14 C1 and 300 mg/m 2 D1 14 q3w thereafter) Eligible Patients Liver-dominant mcrc, PS 0 2 until progression SIR-Spheres microspheres until progression Hendlisz JCO 2010

13 Patient Characteristics Parameter 5FU alone 5FU + SIR-Spheres microspheres n = 23 n = 21 Male patients, n (%) 18 (78%) 10 (48%) Median age (range), years 62 (45 80) 62 (46 91) ECOG PS, n (%) 0 17 (74%) 15 (71%) 1 5 (22%) 5 (24%) 2 1 (4%) 1 (5%) Adenocarcinoma, n (%) 22 (96%) 21 (100%) Adenocarcinoma mucinous, n (%) 1 (4%) 0 Time since diagnosis of CRC, median (range), months 22 (12 44) 22 (7 52) Median sum of metast., mm (51 416) (31 324) Number of liver 1 1 (4%) 2 (10%) metastases, n (%) (44%) 10 (48%) 5 10 (44%) 8 (38%) Not measurable * 2 (9%) 1 (5%) 1 pt missing; 2 pts missing; * mainly due to extensive & confluent lesions Hendlisz JCO 2010

14 Prior/Study Treatment Parameter 5FU alone 5FU + SIR-Spheres microspheres n = 23 n = 21 Time since last chemotherapy median (range), weeks 14 (2 60) 8 (2 57) SIRT/radioembolisation dose (GBq), median activity, (range) not applicable 1.79 ( ) 5FU median dose per patient (mg), range ( ) ( ) Hendlisz JCO 2010

15 Time to Progression and Survival 5FU alone 5FU + SIR-Spheres Hazard Ratio microspheres (95% CI) n = 23 n = 21 P value Median Time to 0.38 ( ) Liver Progression: 2.1 months 5.5 months P=0.003 Median Time to 0.51 ( ) Progression: 2.1 months 4.5 months P=0.03 Median Overall 0.92 ( ) Survival: 7.3 months * 10.0 months P= months * 10 patients in the 5FU arm received SIR-Spheres microspheres as salvage therapy at progression Hendlisz JCO 2010

16 Time to Progression Hendlisz JCO 2010

17 Best Overall Hepatic Response (RECIST) 5FU alone 5FU + SIR-Spheres microspheres n = 23 n = 21 P-value Partial Response, n (%): 0 2 (10%) P=0.22 Stable Disease, n (%): 8 (35%) 16 (76%) Disease Control Rate, n (%): 8 (35%) 18 (85%) P=0.001 Progressive Disease, n (%): 14 (61%) 2 (10%) Not Evaluable, n (%): 1 (4%) 1 (5%) Surgical Resection, n (%): 0 1 (5%) One patient in Arm B was sufficiently down-sized to enable an R0 resection to be performed successfully Hendlisz JCO 2010

18 Toxicity Assessments Parameter 5FU alone 5FU + SIR-Spheres n = 23 n = 21 Grades 1 2 Grades 3 4 Grades 1 2 Grade 3 4 Gastrointestinal Stomatitis Diarrhoea Nausea Vomiting Constipation Anorexia Gastrointestinal Pain Abdominal pain Myalgia Pain other Hendlisz JCO 2010

19 Toxicity Assessments Parameter 5FU alone 5FU + SIR-Spheres n = 23 n = 21 Grades 1 2 Grades 3 4 Grades 1 2 Grade 3 4 Constitutional Fatigue Fever Dermatological/Skin Skin Hand-foot syndrome Pulmonary Dyspnea Pulmonary Neurological Neurosensorial Cognitive disturbance Cardiac arrhythmia Allergy Other Toxicity ascites; 1 with thrombocytopenia, 1 with stomach ulcer, ascites Hendlisz JCO 2010

20 Matched pair comparison between patients prospectively receiving SIR-Spheres microspheres + BSC matched retrospectively with a parallel cohort receiving BSC All patients had chemorefractory liver-dominant mcrc with intrahepatic progression. Groups were matched for 2 criteria: tumour load synchronous/metachronous metastases ALP increase CEA >200 U/mL Primary Endpoint: Overall Survival Seidensticker CVIR 2012

21 Baseline Characteristics of Patients & Disease Parameter Best Supportive Care SIR-Spheres n = 29 n = 29 Male patients, n (%) 23 (79%) 22 (76%) Median age (+SD), years 61.3 (+8.71) 61.9 (+7.37) Time since diagnosis of CRC, median (range), months 31.9 (8.4 81) 33.0 (9 86) Time since diagnosis of mcrc, median (range), months 23.5 (6.5 81) 28.0 (7 57) Karnofsky index, median (range) 80 (60 100) 80 (60 100) Extrahepatic disease, n (%) 14 (48.3%) 14 (48.3%) Prior liver-directed therapy, n (%) resection 10 (34.5%) 7 (24.1%) RFA 2 (6.9%) 1 (3.4%) brachytherapy 1 (3.4%) 4 (13.8%) TACE 0 (0%) 1 (3.4%) ns Seidensticker CVIR 2012

22 Prior Chemotherapy Lines Parameter Best Supportive Care SIR-Spheres n = 29 n = 29 Prior chemotherapy, n (%) adjuvant (for primary CRC) 5 (17.2%) 3 (10.3%) 2 lines 7 (24.1%) 8 (27.6%) 3 lines 11 (37.9%) 9 (31.0%) 4 lines 7 (24.1%) 10 (34.5%) 5 lines 3 (10.3%) 1 (3.4%) 6 lines 1 (3.4%) 1 (3.4%) ns median (range) 3 (2 6) 3 (2 6) Seidensticker CVIR 2012

23 Matching Criteria Parameter Best Supportive Care SIR-Spheres n = 29 n = 29 Liver burden, median (range) 25% (10 75) 30% (20 50) 10% 4 (13.8%) 0 (0%) 15% 1 (3.4%) 0 (0%) 20% 4 (13.8%) 3 (10.3%) 25% 8 (27.6%) 10 (34.5%) 30% 6 (20.7%) 8 (27.6%) 35% 0 (0%) 2 (6.9%) 40% 3 (10.3%) 5 (17.2%) ns 50% 2 (6.9%) 1 (3.4%) 75% 1 (3.4%) 0 (0%) Synchronous metastases, n (%) 17 (58.6%) 18 (85.7%) Alkaline phos. increase, n (%) 18 (85.7%) 27 (93.1%) Missing 8 (27.6%) 0 (0%) CEA >200 U/mL, n (%) 17 (58.6%) 17 (58.6%) Seidensticker CVIR 2012

24 Efficacy Best Supportive SIR-Spheres Hazard Ratio Care (95% CI) n = 29 n = 29 p value RECIST Response Partial Response: na 12 (41.4%) nr Stable Disease: na 5 (17.2%) Median PFS: 2.1 months 5.5 months nr Overall Survival,: 3.5 months 8.3 months 0.26 median (95% CI) ( ) ( ) ( ) p< month survival 59% 97% 12-month survival 0% 24% SIR-Spheres microspheres; na: not applicable; nr: not reported Seidensticker CVIR 2012

25 Overall Survival Overall Survival (%) n Median Survival, months SIR-Spheres microspheres mo ( ) P<0.001 Best Supportive Care mo ( ) Hazard Ratio 0.26 (95% CI ) Time (months) Seidensticker CVIR 2012

26 Patient selection and workup (our experience)

27 Is the Patient a Candidate for LRT? Performance status / Life expectancy Tumor extent (site and tumor load of the extrahepatic disease) Tumor Biology (definition of oligo-metastatic disease) Functional liver reserve Other options?

28 Tumor Vascularity 12/2014: Sigmoid cancer with synchronous liver metastases 01/2015: Sigmoid resection B-RAF, K-RAS et N-RAS : non mutated 04/2015: capecitabine + avastin + oxaliplatine 09/2015: Folfiri 12/2015: vectibix 06/2016: cetuximab + irinotecan 08/2016: CT-scan: PD (liver metastases)

29 Tumor Vascularity Enhancement Curve ALP PVP HPI : %

30 Angiography Planning Arterial phase < perfusion acquisition Angio CT VRT

31 Liver Function FDG-PET-CT 99Tc Mebrofenin SPECT-CT Liver Clearance = 7.7%/min/m² Inferior Limit: 2.7 (Cieslak et al.)

32 Conclusions

33 SIRT for Chemorefractory mcrc: SIRT is a well tolerated locoregional therapy. SIRT + 5FU prolonges the TTLP compared to 5FU monotherapy. Improved OS compared to BSC was demonstrated in a matched pair analysis. SIRT is recognized by ESMO guidelines as a valid therapy for chemorefractory mcrc. Patient selection, tumor biology and adequate timing of treatment are determinant for the success of SIRT.

34 Thank you for your attention! 35