Neuroendocrine Tumour Theranostics

Transcription

1 Neuroendocrine Tumour Theranostics Lisa Bodei Director of Targeted Radionuclide Therapy Molecular Imaging and Therapy Service Memorial Sloan Kettering Cancer Center New York Friday, April 13, 2018

2 Disclosure A) I hold a position as an employee, consultant, assessor or scientific advisory member for a pharmaceutical, device or biotechnology company (If so, please specify your title/project/company): Advanced Accelerator Applications, Ipsen B) I work as an advisor for an industrial company NO C) I receive support from a pharmaceutical, device or biotechnology company (If so, please specify which project and whether support is in kind or monetary): NO D) I hold property rights/patents for pharmaceuticals, radiopharmaceuticals, medical devices or medical consulting firms: NO E) I have written articles for pharmaceutical, radiopharmaceutical, medical device, biotechnology or consulting companies during the last 5 years (If so, please state article, journal and co-authors): NO

3 Modlin IM et al. Lancet 2008 Efficiency of NET Diagnosis

4 Current Commonly Utilized Nuclear Techniques 111 In-pentetreotide Ga-SSA-peptides F-DOPA C-HTP P-NET P-NET SI-NET P-NET Koopmans KP et al. J Clin Oncol 2008 Koopmans KP et al. J Clin Oncol 2008

5 The Paradigm Most Utilized: THERANOSTICS Agonist induced internalization and recycling of sst 2 receptor in HEK293 cells Adapted from Waser B et al. J Nucl Med 2009 Receptor Binding and Internalization of the same Peptides for Imaging & Therapy 68 Ga-DOTATATE 177 Lu-DOTATATE

6 Normal 68 Ga-SSA PET/CT ituitary Intensity may vary with SSA intake Liver Adrenal hyroid pleen Intensity may vary with SSA intake idney Pancreatic Head/Uncinate Bladder Bodei L, Kidd M, Modlin IM, Paganelli G 2014

7 Molecular Imaging of NETs: Aims Localization of tumor and its mets Evaluation of Response to therapy Therapy selection ( cold and radiolabeled octreotide) PRRT

8 Localization: Duodenal G2 NET Symptomatic for dyspepsia. Various exams: Ex-Lap: peri-pancreatic and para-caval lymph nodes (NET, Ki67 3%). 68 Ga-DOTATOC Fused axial slice MIP image Localization of the primary in the third duodenal portion

9 Restaging: SI-NET G1 Resected SI-NET, suspect of recurrence. CT negative; elevated NETest score 68 Ga-DOTATOC Mesentery LN adjacent to anastomosis Unremarkable anastomosis with nonspecific uptake Positive for NET at surgery

10 Impact of Ga-SSA-PET/CT on patient management Syst Rev -MetaAnalysis n=1,561 patients PET/CT findings resulted in management changes in 44% of the patients Most changes being intermodality (77%; intramodality, 23%; 7 studies) Management changes suggested by Ga- SSA-PET/CT are implemented in 75% of cases by MTB (Calais J et al. JNM 2017) Barrio M et al. JNM 2017

11 Impact of 68 Ga-DOTATATE PET/CT on patient management: change of plans History of small-intestine NEN and a 6.5-cm lesion within the right proximal femur with benign appearance at MR. Unexpected soft-tissue and bone metastases were detected. The intended treatment was converted from surgery and octreotide to surgery, octreotide, plus selective radiotherapy of bone metastases. Modified from Herrmann et al. JNM 2014 in Bodei L et al. JNM 2017

12 68 Ga-SSA-PET/CT for therapy selection Selection for PRRT with 177 Lu-DOTATATE in a patient with liver mets from a G2 rectal NET 68 Ga-DOTATOC PET/CT 68 Ga-DOTATOC PET/CT c.e. T2 FSAT MRI Surgery T2FS MRI, c.e. axial image MIP image MIP image MIP image PRRT

13 SRI: correlation with PRRT response 68 Ga-SSA-PET Elevated uptake High radioactivity concentration High tumour dose Response Krenning scale: G2 G3 G4 Kwekkeboom D et al. ERC 2010

14 Interobserver agreement for 68 Ga-DOTATATE Reading of 68 Ga-DOTATATE PET/CT for (re)staging is consistent among readers with low and high levels of experience Increased erroneous recommendations for PRRT among non experienced readers Image based recommendations for or against PRRT require experience and training Fendler WP et al. JNM 2016

15 Examples

16 Low grade uptake: questionable PRRT indication Atypical bronchial NET with LN and osseous metastasis

17 No uptake, no PRRT Pancreatic MINEN, with liver mets

18 Intense uptake, selection for PRRT T, SUV 43.2 T, SUV 36.9 L, SUVav 5.1 S, SUVav 24.6

19 Intense uptake, questionable indication for PRRT ECOG 2, weight loss, compromised hematological function at baseline

20 Beyond size...opportunities for molecular imaging Integration of molecular imaging in RECIST criteria for therapy monitoring Novel Strategies for Current Somatostatin Receptor Imaging Novel Receptor Radiopeptides Integration of Molecular and Imaging Information Sundin A et al. NEN 2012 Bodei L et al. NEN 2014 Garcia-Carbonero R et al. Cancer Met Rev 2015 Future of New York, the City of the Skyscrapers, 1925

21 SSR agonists: 64 Cu-DOTATATE vs. 68 Ga-DOTATOC n=59 patients Same patient-based sensitivity Greater lesion-based sensitivity Greater tumor/background (more distinct uptake, lower liver and splenic uptake) Johnbeck CB et al. J Nucl Med 2017

22 SSR antagonist 68 Ga-DOTA-JR11: reduced internalization but greater retention Almost No BKG!!! 68 Ga-DOTA-JR In-pentetreotide Weber W et al

23 Glucagon-like Peptide 1 Receptor peptides: 68 Ga-DOTA-exendin-4 GLP1-R scan to localize occult insulinomas Pos IHC for insulin 68 Ga-DOTA-exendin-4 PET/CT facilitates the localization and curative resection of occult insulinoma 111 In-DTPA-exendin-4 Cuthbertson DJ et al. Clin Endocrinol 2016

24 CXCR4-R ligands: actionable theranostics for poorly differentiated NENs n=12 0% of G1, 50% of G2 and 80% of G3 patients had 68 Ga- Pentixafor-positive lesions CXCR4 imaging could be used to select patients for CXCR4 radiotherapy G3 Gastric NEC (Ki67: 90%) Werner RA et al. Theranostics 2017

25 Residual disease: negative imaging, positive NETest 68 Ga-DOTATATE scan A B D C simple cyst cholelithiasis At cholecystectomy no evidence of hepatic metastases. Random intra-operative hepatic needle biopsy however demonstrated NET metastases. Bodei L et al. JNM 2017

26 177 Lu-DOTATATE Closer than we think, Arthur Radebaugh, Chicago Tribune, 1960 PRRT

27 The Lessons derived from 20 yrs of Clinical Trials with Y- and Lu-PRRT in GEP and BP NETs EFFICACY Decrease in tumor size Symptom relief QoL improvement Decrease in biomarker levels Increase in survival FDG PET/CT prognostic factor for reduced PFS Kwekkeboom DJ et al. JNM 2005, 2008 Bodei L et al. Eur J Nucl Med Mol Imaging 2004, 2008, 2011 Kwekkeboom DJ et al. Endocrine Rel Cancer 2010 Brans B et al. Eur J Nucl Med 2007 Cremonesi M et al. Q J Nucl Med Mol Imaging 2011 Ezziddin S et al. EJNMMI 2014, JNM 2014 Sabet A et al. JNM 2013, EJNMMI 2014 Bodei et al. EJNMI 2015 TOLERABILITY Well tolerated Generally mild acute side effects: Amino Acid-related: nausea, vomiting PRRT-related: fatigue, mild hair loss (Lu-tate), Rarely: exacerbation of syndrome Sub-acute hematological toxicity mild: reversible in 90% Chronic kidney and BM toxicity Generally mild if precautions undertaken Currently mostly used: 177 Lu-DOTATATE

28 Long Term Toxicity after PRRT Basel, CH Milan, IT Rotterdam, NL Basel, CH Milan, IT Tot=2523 pts Rotterdam, NL Milan, IT Bonn, GE Milan, IT Renal toxicity not an issue with Lu-tate Bone marrow toxicity low and comparable with other anti neoplastic therapies Bodei L et al. Sem Nucl Med 2016

29 PRRT with Y- and Lu-peptides: Nephrotoxicity: n=807 : 34.6% : 1.5% 90 Y+ 177 Lu and 90 Y alone associated with significantly higher nephrotoxicity Severe nephrotoxicity was virtually absent after 177 Lu-peptides Only up to 34% of nephrotox were explained by risk factors Bodei L et al. EJNMMI 2015

30 Symptom Control after 177 Lu-DOTATATE NET type Schedule Pts Symptom Concomitant SSA Symptomatic Response Author All NETs GBq All NETs 31 GBq + 5FU 111 Diarrhea 62% 67% Khan S Diarrhea, flushing, pain P-NETs 28.2 GBq 68 Fatigue, pain, nausea n.a. 9/10 Kong G % Significant improvement Marinova M 2017 Significant symptomatic improvement regardless of the objective response

31 Survival: Role of Disease Control after 177 Lu-octreotate n=282 pts Disease Control after PRRT impacts on Survival Modified from Kwekkeboom DJ et al. JCO 2008

32 Disease Control: Role of FDG status mpfs=21.2 mo mpfs=68.7 mo FDG PET is the only independent prognostic factor for PFS and OS regardless of the total administered activity Sansovini M et al. EJNMMI 2017

33 NETTER -1 Study: Results First international, multicenter, randomized, controlled study Evaluate efficacy and safety of 177 Lu-Dotatate + SSAs compared to Octreotide LAR 60mg Subjects: inoperable, SSTR positive, midgut NET, progressive with Octreotide LAR 30mg 177 Lu-Dotatate was safe and more effective than Octreotide 60 mg: PFS (Not Reached vs 8.5 months, p<0.0001) ORR (13% vs 4%, p=0.0008) OS (not reached vs months, interim analysis; p=0.0043) Strosberg J et al. NEJM 2017

34 NETTER-1: Quality of Life Global Health Status 177 Lu arm Av. % of pts 60mg Oct arm Av. % of pts Comments Improvement 28% 15% Statistically significant Worsening 18% 26% improvement in 177 Lu arm Diarrhea Improvement 39% 23% Statistically significant improvement in 177 Lu arm Worsening 23% 19% Pain Improvement 41% 28% Worsening 17% 25% Trend towards improvement in 177 Lu arm not statistically significant Flushing Improvement 42% 38% Improvement in both arms with Worsening 22% 19% no clear advantage in 177 Lu arm Benefit in important domains associated with 177 Lu treatment Vs. HD octreotide. Confirmed treatment value of 177 Lu on patient QoL, in addition to the meaningful increase in PFS already reported. Strosberg J et al. JNM 2017 Abs.

35 Efficacy of 177 Lu-DOTATATE in P-NETs Non-controlled studies Schedule Pts Best response PFS TTP OS Authors 25.5 GBq (5 cycles, normal pts; 18 GBq in risk pts) 52 29% PR+CR - 36 mo - Sansovini GBq in 4 cycles 68 60% PR 34 mo - - Ezziddin GBq in 4 cycles % CR+PR 30 mo 31 mo 71 mo Brabander 2017 PRRT with 177 Lu-DOTATATE is a favorable therapeutic option in patients with pancreatic NETs with objective responses and impact on survival parameters

36 Efficacy of 177 Lu-DOTATATE in BP-NETs Non-controlled studies Schedule Pts Best response PFS TTP OS Authors 90 Y-DOTATOC (11 GBq); 177 Lu-DOTATATE (21GBq) ; 90 Y-TOC+ 177 Lu-TATE (7+13 GBq) % PR+MR 29% PR+MR 38% PR+MR 23 mo 31 mo 31 mo - 46 mo >110 mo 61 mo Mariniello GBq in 4 cycles 22 27% PR 27 mo - 42 mo Sabet GBq in 4 cycles 23 30% CR+PR 20 mo 25 mo 52 mo Brabander 2017 PRRT with 177 Lu-DOTATATE is a favorable therapeutic option in patients with broncho-pulmonary NETs with objective responses and impact on survival parameters

37 Position of PRRT in the therapeutic algorithm of SI-NETs Pavel M et al. NEN 2016

38 PRRT: indications...prrt is indicated for sst2 positive, metastatic or inoperable NETs, mainly of the gastroenteropancreatic and bronchial tracts... the ideal candidates are NETs grade 1 or 2... FDA/EMA Approval: LUTATHERA is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.

39 PRRT, phases Pre-Therapeutic Assessment Therapeutic phase Cycle 1 Cycle 2 Cycle 3 Cycle 4 Follow-up Histopathological characterization 68 Ga-DOTATATE/TOC 177 Lu-DOTATATE CT/MRI 68 Ga-DOTATATE/TOC CT/MRI Safety Labs (CBC, CMP) Recommended every 2 wks

40 The Challenge for the Next Years 1a -Systematic Review of RCT 2a -Systematic Review of cohort studies 3a -Systematic Review of case-control studies 4-Case series Registration in BP NETs New RCTs and other trials: in GEP-NETs vs other STD of care (e.g. EVE) in BP-NETs vs STD of care PPGL, NB, liver mets, etc. Lutate SI-NETs, b -RCT Validation of new strategies: Combinations with chemo or biologics Intra-arterial New theranostics (SS-ANT, GLP-1R, GIP) 2b Individual cohort studies Personalization ESMO GL 2012 Based upon: risk factors FDG status, dosimetry Personalisation of individual response and tolerability: (circulating NET transcripts) 3b Individual case-control studies Expert opinion The interim results of NETTER-1 registration trial has increased the utilization of PRRT in the NET tumor boards.

41 COMPETE study 177 Lu-Edotreotide ( 177 Lu-DOTATOC) vs. Everolimus in GEP- NETs Prospective randomized Controlled Open-label Multicentre phase III study to evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy with 177 Lu-edotreotide compared to targetedd molecular therapy with Everolimus in patients with inoperable, progressive, somatostatin receptor-positive gastroentero-pancreatic neuroendocrine tumors STARTED RECRUITING IN EUROPE TO BE STARTED SOON IN THE US

42 Combinations with Chemo or Biologics Adequately powered, prospective and rigorously analyzed studies are underway New combinations with check point inhibitors planned in high grade NENs Bodei L et al. Sem Nucl Med 2016

43 Intra-arterial PRRT This strategy produce 60% PR+CR Kratochwil C et al. ERC 2011

44 PRRT with SSR-ANTAGONISTS 177 Lu-DOTA-JR11 in NETs Baseline Follow up 68 Ga-DOTA-JR11 60 min p.i. (MIP) 68 Ga-DOTA-JR11 fused transaxial image Contrast CT, arterial phase Contrast CT, arterial phase Complete response! 20 heavily pretreated pts: 10 completed 2 cycles, 10 had 1 cycle After only 1 cycle, evaluable pts had (RECIST 1.1): PR in 7/19 (37%), SD in 9/19 (47%), PD in 3/19 (16%) Prolonged but reversible G3/4 toxicity in 4/10 pts treated with 2 full dose cycles Favorable response justifies continuation Weber W, Bodei L. et al

45 OPS101 trial 177 Lu-OPS101 ( 177 Lu-DOTA-JR11) An international multicenter, open-label study to evaluate safety, tolerability, biodistribution, dosimetry and prelimary efficacy of 177 Lu- OPS201 for the therapy of somatostatin receptor-positive neuroendocrine tumors STARTED IN EUROPE AND AUSTRALIA TO BE STARTED SOON IN THE US

46 What determines the response? Kidd M, Modlin M. 2017

47 n=158 Predictive accuracy: 95% Specific Transcript Genes + Histopathology Grading

48 Conclusions Theranostics, particularly of SSR, are the mostly utilized paradigm in NET diagnosis and therapy Ga-SSA-PET/CT is the most accurate dg tool and is used in combination with morphological imaging Novel peptides and imaging and molecular strategies are being developed PRRT has been accepted in the clinical algorithms of the major scientific societies and is now approved for GEP SI NETs: Lu demonstrated efficacy in a RCT P NETs: Lu demonstrated efficacy in non controlled trials RCTs: required in other clinical scenarios to establish the position in the treatment algorithm Molecular genomics: required to predict and define efficacy and tolerability in conjunction with imaging