Session 6 NEW TECHNIQUES IN RADIATION TREATMENT. Chairman : Françoise MORNEX

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2 Session 6 NEW TECHNIQUES IN RADIATION TREATMENT Chairman : Françoise MORNEX

3 INTERNAL IRRADIATION FOR ENDOCRINE TUMORS Emmanuel DESHAYES

4 INTERNAL IRRADIATION FOR ENDOCRINE TUMORS Dr Emmanuel DESHAYES Nuclear MedicineDepartment, ICM Val d Aurelle INSERM U1194 Team «Radiobiology and Targeted Radiotherapy» New Frontiers in GI Oncology 12 October 2018

5 Neuroendocrine tumors Arise in the diffuse neuroendocrine system Increased incidence and prevalence inthe last30years Functioning (secretion of peptides and amines) or non functioning Overexpression of Somatostatin Receptors (SSTR) Surgery is the only curative treatment for localized NETs 75-80% are GEP-NET 40% of patients present with metastases at diagnosis

6 Neuroendocrine tumors WHO 2017 Classification of NET, based on : Proliferation (Ki67, Mitosis) Differentiation

7 Neuroendocrine tumors RENATEN, TENPATH, etc Oronsky, 2017

8 Theranostic Target SSR (1-5)

9 Theranostic Target Peptide SSR (1-5) Octreotide/Octreotate

10 Theranostic Target Peptide Linker Chelator SSR (1-5) Octreotide/Octreotate DOTA

11 Theranostic Linker Target Peptide Chelator Diagnostic Radioisotopes Beta+ (PET) : Ga68, F18, Zr89, Cu64 Gamma(SPECT): Tc99m, In111 SSR (1-5) Octreotide/Octreotate DOTA

12 SSR Imaging: SPECT ( 111 In) vs PET ( 68 Ga) PET/CT ( 68 Ga-labeled peptides) have better diagnostic performance over 111 Inpentetreotide SPECT/CT Higher sensitivity and specificity Octreoscan ( 111 In-pentetreotide) 68 Ga-DOTATOC Deppen, 2016

13 Gallium-68 «on site» availability Germanium-68/Gallium-68 generators Beta + emitter > PET/CT imaging 68 Ge/ 68 Ga Relatively short half-life, 68 min, adapted to small molecules (peptides, fragments )

14 Theranostic Linker Target Peptide Chelator Diagnostic Radioisotopes Beta+ (PET) : Ga68, F18, Zr89, Cu64 Gamma(SPECT): Tc99m, In111 SSR (1-5) Octreotide/Octreotate DOTA

15 Theranostic Target Peptide Linker Chelator Diagnostic Radioisotopes Beta+ (PET) : Ga68, F18, Zr89, Cu64 Gamma(SPECT): Tc99m, In111 Therapeutic Radioisotopes Beta- : Lu177, Y90 Auger: In111 Alpha: Bi213 SSR (1-5) Octreotide/Octreotate DOTA In111, Ga68, Y90, Lu177, Bi213

16 PRRT: Peptide Receptor Radionuclide Therapy 177 Lu-DOTATATE is currently the most widely used radiopeptide for PRRT Antunes 2007, Cives, 2017, Bodei 2015 Internalization

17 Theranostic «We treat what we see, we see what we treat» 177 Lu: Gamma Particles : post-therapeutic SPECT imaging

18 History of PRRT for NET First PRRT: 1995 in Rotterdam: Indium-111 Pentetreotide (Auger emitter) Then 90 Y-DOTATOC and 177 Lu-DOTATOC or 177Lu-DOTATATE (LUTATHERA ) Thousands of patients treated worldwide, showing an efficacy, impact on quality of life and a favorable toxicity profile But only one Phase III prospective and randomized trial: NETTER-1 Strosberg, 2017, New England Journal of Medicine

19 NETTER-1 : Design Aim Design Evaluate the efficacy and safety of 177 Lu-DOTATATE (Lutathera ) + SSAs (symptoms control) compared to Octreotide LAR 60mg (off-label use) 1 in patients with inoperable, somatostatin receptor positive, midgut NET, progressive under Octreotide LAR 30mg (label use) International, multicenter, randomized, comparator-controlled, parallel-group Treatment and Assessments Tumour burden assessment (RECIST criteria) every 12 weeks Dose 1Dose 2 Dose 3 Dose 4 Baseline and Randomizatio n n = 115 n = administrations of 7.4 GBq of Lutathera every 8 weeks + SSAs (symptoms control label use) Octreotide LAR (high dose - 60mg every 4 weeks 1 ) 5 Years follow up 1. FDA and EMA recommendation 19

20 NETTER-1 : Study Endpoints Primary objective Compare Progression Free Survival (PFS) after treatment with 177 Lu- Dotatate plus 30 mg octreotide LAR (symptoms control) vs treatment with high dose (60 mg) octreotide LAR Secondary objectives Compare the Objective Response Rate between study arms Compare the Overall Survival between study arms Compare the Time to Progression between study arms Evaluate the safety and tolerability of 177 Lu-Dotatate Evaluate the health related quality of life (QoL) as measured by the EORTC QLQ-G.I.NET21 questionnaire 20

21 NETTER-1 : Main Inclusion Criteria Patients 18 years of age Metastatic or locally advanced, inoperable, histologically proven, midgut NET Ki67 index 20% (Grade 1-2) Progressive disease (RECIST Criteria 1.1 centrally confirmed) on uninterrupted fixed dose of octreotide LAR (20-30 mg every 3-4 weeks) Somatostatin receptor positive disease Karnofsky Performance Score 60 Including functioning and non-functioning 21

22 NETTER-1 : Progression Free Survival N = 229 (ITT) Number of events: Lu-Dotatate: 23 Oct 60 mg LAR: Lu-Dotatate Median PFS: Not reached Hazard ratio : 0.21 [ ] p < Probability 79% reduction in the risk of disease progression/death Estimated Median PFS in the 177 Lu-Dotatate arm 40 months Octreotide LAR 60 mg Median PFS: 8.4 months All progressions centrally confirmed and independently reviewed for eligibility (SAP) 22

23 NETTER-1 : Overall-Survival Update HR:0.536 (0.333, 0.864) P = mos Oct LAR 60 mg : 27.4 months 177 Lu-DOTATATE : NR Cut off 30 June 2016 Updated analysis suggests survival benefit, to be confirmed at the protocol-specified OS analysis data cut-off (5 years after last patient was randomized, or after 185 deaths) J. Strosberg Pr Strosberg courtesy, Update analysis presented at the 2018 ENETS meeting

24 NETTER-1 : Safety (Nb of patients (%), Safety Set; n=221) 177-Lu-Dotatate (n=111) Octreotide LAR 60mg (n=110) Any adverse event 106 (96%) 95 (86%) treatment Related to 95 (86%) 34 (31%) Serious adverse events 29 (26%) 26 (24%) Related to treatment 10 (9%) 1 (1%) Withdrawals due to adverse events 7 (6%) 10 (9%) treatment Related to 5 (5%) 0 (0%) 24

25 NETTER-1 : Impact on Quality of Life 177 Lu-DOTATATE significantly delays time to deterioration in HRQoL in key domains related to overall quality of life (global health, physical functioning, role functioning), as well as symptom domains relevant to midgut NETs (diarrhea, pain, fatigue). Global health Status Diarrhea Pain Fatigue 25

26 After NETTER-1 LUTATHERA ( 177 LU-DOTATATE) FDA/EMA MA approval (2017/2018) ENETS recommandations updated

27 Intestinal NEN Pavel, 2016

28 Pancreatic NEN Pavel, 2016

29 Patient Selection for PRRT SSTR expression: increased response rates with higher degree of tracer uptake on SSTR imaging ( Krenning Scale or SUV with 68 Ga PET/CT) Kwekkeboom, 2010, Endocrine Related Cancer

30 Patient Selection for PRRT SSTR expression: increased response rates with higher degree of tracer uptake on SSTR imaging ( Krenning Scale or SUV with 68 Ga PET/CT) Normal renal function (Glomerular Filtration Rate > 50mL/min) Relatively normal bone marrow function Decision of treatment : multidisciplinary board (RENATEN) Kwekkeboom, 2010, Endocrine Related Cancer

31 Treatment Procedure In nuclear medicine dprtmt (trained staff) 24-48h hospitalisation (radioshielded room?) Kidney protection: positively charged amino acids, such as lysine and/or arginine, co-infused to competitively inhibit the proximal tubular reabsorption of the radiopeptide (1-2L) Fixed activity: 7.4 GBq Radiopeptide IV injection for 30 min Usually 4 cycles, every 8 weeks Small exposure : <5µSv/h at 1 meter of patient when released

32 Acute: nausea, vomiting, abdominal pain Subacute: Bone marrow suppression G3/G4 (3-3% cycle) Transient andreversible Risk factors: > 70 years of age, prior chemotherapy, GFR <60mL/min, bone metatases (Kwekkeboom, JCO, 2008) Mild hair loss Fatigue Long term Renal failure: PRRT in NET : Side Effects More pronounced with Yttrium-90 than Lutecium-177 No evidence in a large retrospective report (1200 patients treated with 177LU-DOTATATE) (Brabander, Can. Res. 2017) Myelodysplastic syndrome (2%) and acute leukemia (1%): particularly in patients previously treated with alkylating chemotherapeutic agents

33 Treatment availability? et en France? Reimbursement in France for Intestinal NET progressive or metastatic, inoperable G1- G2 with SSTR+ Pancreas (and bronchial) NETs excluded «The French Corner»

34 Clinical Trials

35 NCT Clinical Trials: COMPETE International Multicentric randomized Phase III Trial 177 Lu-Edotreotide (= 177 Lu-DOTATOC) vs Everolimus (10 mg/jour) Randomization 2:1 ( 177 Lu-Edotreotide : Everolimus) 4 cycles of 7.5 GBq of 177 Lu-Edotreotide every 3 months GEP-NET (G1-G2): with SSTR + imaging, progressive or inoperable under SSA. 300 patients Primary objective: mpfs 30 sites worldwide, 4 French centers (Montpellier) Industrial promotion (ITM/ITG)

36 NCT Clinical Trials: OCLURANDOM National (French) multicentric phase II trial PRRT LUTATHERA (4 cycles / 8 weeks) vs Sunitinib (37,5 mg/j) Pancreatic NET,well differentiated, inoperable and progressive RECIST progression for 12 months, after first line of treatment (SSA, Chemo or Everolimus) Primary endpoint: PFSat 12 months IGR (EBaudin). 80 pts Open inmontpellier

37 NCT Clinical Trials: TERAVECT Phase II randomized trial, national multicentric (French) 111 In-pentetreotide in adjuvant setting after complete resection of liver metastases from GEP-NET. Target: small residual disease: Indium-111: short range, high LET Primary endpoint : PFS Secondary endpoints : OS, QO 126 pts Beaujon (PI: R.Lebtahi) Open Jan.2016, but suspended at the moment

38 FUTURE PERSPECTIVES

39 Combination of radiopeptides? Yttium-90 is considered to be more suitable for larger tumors due to higher energy and penetrating capacity of particles The «cross fire» effect 90 Y-DOTATOC Lu-DOTATOC/TATE Pouget, 2011 Duo-PRRT (same day) or Tandem-PRRT Combination of radiopeptides ( 90 Y-DOTATOC Lu-DOTATOC/TATE) shows improvement in OS versus 90 Y-DOTATOC alone with the same toxicity profile (Kunikowska 2011 (n=50), Villard JCO, 2012 (n=486)

40 Combination of PRRT with other treatments? PRRT+ Chemotherapy (as a radiosensitivzer)? Capecitabine or 5FU: not significantly increased toxicity (Van Essen 2008, Claringbold , Kong 2014) PRRT + Everolimus? NETTLE trial (Phase I, n=16, dose escalation): Everolimus Lu- DOTATATE : MTA everolimus = 7,5mg/day PRRT + PARPi? (Purohit 2018) Target of radiation DNA (PRRT > DNA double strand breaks). : combination with PARPi which inhibits DNA repair may enhancec its efficacy

41 Salvage PRRT? ENETS 2018: WA Van der Zwan et al: Efficacy & safety after salvage PRRT with 177 LU-DOTATATE in patients withbronchial or GEP-NET The Rotterdam Cohort Patients included if they benefited from Initial-PRRT & showed renewed progression I-PRRT = 4 cycles with 7.4GBq n= 181 R-PRRT = + 2 cycles with 7.4 GBq n= 181 RR-PRRT = + 2 cycles with 7.4 GBq n = 14 For midgut NET: median PFS: -I-PRRT: 35,5 mo -R-PRRT: 40.8 mo (p=0.41 vs I-PRRT) Toxicity profile: no more hematological of renal toxicity after R-PRRT & RR-PRRT than after I-PRRT.

42 Better selection of patients? Lisa Bodei et al. Jan 2018, EJNMMI NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ)

43 Better selection of patients? Lisa Bodei et al. Jan 2018, EJNMMI Conclusion: The PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%.

44 Alpha particle emitters?

45 Alpha particle emitters?

46 Other Perspectives? PRRT in neoadjuvant setting? Agonist ( 177 Lu-DOTATATE) vs antognist ( 177 Lu-JR11) of SSR? (Wild 2014) Treatment of G3 NEN? Which cutoff? (Ki67%><55%? (Thang et al. 2018) Selection of patients: SSTR expression? FDG SUV? Dosimetry based treatments?

47 Internal Irradiation for NET «Liver-directed» Therapies 177 Lu-DOTATATE 90 Y-Spheres 177 Lu-DOTATATE Systemic PRRT Intra Arterial PRRT SIRT Devcic, 2014

48 Take Home Messages 177 Lu PRRT : promising treatment for patients with SSTR+ NETs, especially those with G1- G2 who are inoperable and have failed treatment with SSAs Impact on PFS, OS as well as significant improvement in clinical symptoms Theranostic approach: towards a wide diffusion of Galium-68 SSTR imaging with PET/CT Remaining questions: Optimal line of treatment? Better selection of patients? Liver-directed therapies?

49 INTERNAL IRRADIATION FOR ENDOCRINE TUMORS Thank you for your attention Dr Emmanuel DESHAYES Nuclear MedicineDepartment, ICM Val d Aurelle INSERM U1194 Team «Radiobiology and Targeted Radiotherapy» New Frontiers in GI Oncology 12 October 2018

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