Neuroendocrine Tumour Theranostics

Friday, April 13, 2018 Lisa Bodei Director of Targeted Radionuclide Therapy Molecular Imaging and Therapy Service Memorial Sloan Kettering Cancer Center New York 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 Efficiency of NET Diagnosis

Modlin IM et al. Lancet 2008 Current Commonly Utilized Nuclear Techniques

111In-pentetreotide 68Ga-SSA-peptides 18F-DOPA 11C-HTP P-NET P-NET SI-NET P-NET Koopmans Koopmans KP KP et KP KP al. al. et J al. al. Clin J Oncol Clin Oncol 2008 2008 The Paradigm Most Utilized: THERANOSTICS

Agonist induced internalization and recycling of sst2 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 68Ga-DOTATATE  177Lu-DOTATATE Normal 68Ga-SSA PET/CT

ituitary

Intensity may vary hyroid with SSA intake Intensity may vary with SSA intake Liver pleen Adrenal

idney

Pancreatic Head/Uncinate Bladder

Bodei L, Kidd M, Modlin IM, Paganelli G 2014 Molecular Imaging of NETs: Aims • Localization of tumor and its mets

• Evaluation of Response to therapy

• Therapy selection (“cold” and radiolabeled ) PRRT Localization: Duodenal G2 NET Symptomatic for dyspepsia. Various exams: Ex-Lap: peri-pancreatic and para-caval lymph nodes (NET, Ki67 3%).

68Ga-DOTATOC Fused axial slice

Localization of the primary in the third duodenal portion MIP image Restaging: SI-NET G1 Resected SI-NET, suspect of recurrence. CT negative; elevated NETest score

68Ga-DOTATOC

Mesentery LN adjacent to anastomosis

Unremarkable anastomosis with nonspecific uptake Positive for NET at surgery 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 Impact of 68Ga-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 68Ga-SSA-PET/CT for therapy selection

Selection for PRRT with 177Lu-DOTATATE in a patient with liver mets from a G2 rectal NET

68Ga-DOTATOC PET/CT 68Ga-DOTATOC PET/CT

c.e. T2 FSAT MRI

Surgery

T2FS MRI, c.e. axial image

MIP image MIP image MIP image PRRT SRI: correlation with PRRT response High radioactivity 68 concentration Ga-SSA-PET Elevated uptake

High tumour dose

Response

Krenning scale: G2 G3 G4

Kwekkeboom D et al. ERC 2010 Interobserver agreement for 68Ga-DOTATATE

• Reading of 68Ga-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 Examples Low grade uptake: questionable PRRT indication

Atypical bronchial NET with LN and osseous metastasis No uptake, no PRRT

Pancreatic MINEN, with liver mets Intense uptake, selection for PRRT

T, SUV 36.9 L, SUVav 5.1 T, SUV 43.2 S, SUVav 24.6 Intense uptake, questionable indication for PRRT

ECOG 2, weight loss, compromised hematological function at baseline Beyond size...opportunities for molecular imaging

• Integration of molecular imaging in RECIST criteria for therapy monitoring

• Novel Strategies for Current 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 SSR agonists: 64Cu-DOTATATE vs. 68Ga-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 SSR antagonist 68Ga-DOTA-JR11: reduced internalization but greater retention

Almost No BKG!!!

68Ga-DOTA-JR11 111In-pentetreotide

Weber W et al. 2015-2017 Glucagon-like Peptide 1 Receptor peptides: 68Ga-DOTA-exendin-4

GLP1-R scan to localize occult insulinomas

Pos IHC for insulin

68Ga-DOTA-exendin-4 PET/CT facilitates the localization and curative resection of occult insulinoma 111In-DTPA-exendin-4

Cuthbertson DJ et al. Clin Endocrinol 2016 CXCR4-R ligands: actionable theranostics for poorly differentiated NENs

n=12 0% of G1, 50% of G2 and 80% of G3 patients had 68Ga- 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 Residual disease: negative imaging, positive NETest

68Ga-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 177Lu-DOTATATE

Closer than we think, Arthur Radebaugh, Chicago Tribune, 1960

PRRT The Lessons derived from 20 yrs of Clinical Trials with Y- and Lu-PRRT in GEP and BP NETs

EFFICACY TOLERABILITY  Decrease in tumor size  Well tolerated  Symptom relief  Generally mild acute side effects:  QoL improvement • Amino Acid-related: nausea,  Decrease in biomarker vomiting levels • PRRT-related: fatigue, mild hair loss  Increase in survival (Lu-tate),  FDG PET/CT prognostic • Rarely: exacerbation of syndrome factor for reduced PFS  Sub-acute hematological toxicity mild: reversible in ≥90%  Chronic kidney and BM toxicity • Generally mild if precautions undertaken

Kwekkeboom DJ et al. JNM 2005, 2008 Bodei L et al. Eur J Nucl Med Mol Imaging 2004, 2008, 2011 Currently mostly used: Kwekkeboom DJ et al. Endocrine Rel Cancer 2010 177 Brans B et al. Eur J Nucl Med 2007 Lu-DOTATATE 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 Long Term Toxicity after PRRT

Basel, CH Milan, IT Rotterdam, NL Basel, CH Milan, IT

Rotterdam, NL Milan, IT Bonn, GE Tot=2523 pts 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 PRRT with Y- and Lu-peptides: Nephrotoxicity: n=807

: 34.6% : 1.5%

• 90Y+177Lu and 90Y alone associated with significantly higher nephrotoxicity • Severe nephrotoxicity was virtually absent after 177Lu-peptides • Only up to 34% of nephrotox were explained by risk factors

Bodei L et al. EJNMMI 2015 Symptom Control after 177Lu-DOTATATE

NET Schedule Pts Symptom Concomitant Symptomatic Author type SSA Response

All NETs 22.2-29.6 111 Diarrhea 62% 67% Khan S GBq 2011 All NETs 31 GBq + 10 Diarrhea, n.a. 9/10 Kong G 5FU flushing, pain 2014 P-NETs 28.2 GBq 68 Fatigue, pain, 36% Significant Marinova nausea improvement M 2017

Significant symptomatic improvement regardless of the objective response Survival: Role of Disease Control after 177Lu-octreotate

n=282 pts

Disease Control after PRRT impacts on Survival

Modified from Kwekkeboom DJ et al. JCO 2008 Disease Control: Role of FDG status

mPFS=68.7 mo mPFS=21.2 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 NETTER -1 Study: Results

 First international, multicenter, randomized, controlled study 177  Evaluate efficacy and safety of Lu-Dotatate + SSAs compared to Octreotide LAR 60mg

 Subjects: inoperable, SSTR positive, midgut NET, progressive with Octreotide LAR 30mg

177Lu-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. 27.4 months, interim analysis; p=0.0043)

Strosberg J et al. NEJM 2017 NETTER-1: Quality of Life

177Lu arm 60mg Oct arm Comments Av. % of pts Av. % of pts Global Improvement 28% 15% Statistically significant Health improvement in 177Lu arm Worsening Status 18% 26% Diarrhea Improvement 39% 23% Statistically significant improvement in 177Lu arm Worsening 23% 19% Pain Improvement 41% 28% Trend towards improvement Worsening 177 17% 25% in Lu arm not statistically significant Flushing Improvement 42% 38% Improvement in both arms with no clear advantage in 177Lu arm Worsening 22% 19%

• Benefit in important domains associated with 177Lu treatment Vs. HD octreotide. • Confirmed treatment value of 177Lu on patient QoL, in addition to the meaningful increase in PFS already reported.

Strosberg J et al. JNM 2017 Abs. Efficacy of 177Lu-DOTATATE in P-NETs Non-controlled studies

Schedule Pts Best response PFS TTP OS Authors 25.5 GBq (5 cycles, 52 29% PR+CR - 36 mo - Sansovini 2013 normal pts; 18 GBq in risk pts) 32 GBq in 4 cycles 68 60% PR 34 mo - - Ezziddin 2014 22.2-29.6 GBq in 4 133 55% CR+PR 30 mo 31 mo 71 mo Brabander 2017 cycles

PRRT with 177Lu-DOTATATE is a favorable therapeutic option in patients with pancreatic NETs with objective responses and impact on survival parameters Efficacy of 177Lu-DOTATATE in BP-NETs Non-controlled studies

Schedule Pts Best response PFS TTP OS Authors 90Y-DOTATOC (11 GBq); 114 18% PR+MR 23 mo - 46 mo Mariniello 2015 177Lu-DOTATATE (21GBq) ; 29% PR+MR 31 mo >110 mo 90Y-TOC+177Lu-TATE (7+13 GBq) 38% PR+MR 31 mo 61 mo 27 GBq in 4 cycles 22 27% PR 27 mo - 42 mo Sabet 2017 22.2-29.6 GBq in 4 cycles 23 30% CR+PR 20 mo 25 mo 52 mo Brabander 2017

PRRT with 177Lu-DOTATATE is a favorable therapeutic option in patients with broncho-pulmonary NETs with objective responses and impact on survival parameters Position of PRRT in the therapeutic algorithm of SI-NETs

Pavel M et al. NEN 2016 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 -positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. PRRT, phases

Therapeutic phase Pre-Therapeutic Assessment Cycle 1 Cycle 2 Cycle 3 Cycle 4 Follow-up

Histopathological characterization 68Ga-DOTATATE/TOC CT/MRI 177Lu-DOTATATE 68Ga-DOTATATE/TOC

Safety Labs (CBC, CMP) CT/MRI Recommended every 2 wks The Challenge for the Next Years

• Registration in BP NETs 1a -Systematic Review of• RCTNew RCTs and other trials: • in GEP-NETs vs other STD of care (e.g. EVE) • in BP-NETs vs STD of care 2018-20 • PPGL,Lutate NB, SIliver-NETsmets, 1b, etc. -RCT Validation of new2015 strategies: 2a -Systematic•Review of cohort studies• Combinations with chemo or biologics • Intra-arterial 2b –Individual • New theranostics (SS-ANT,cohort GLP-studies1R, GIP) 3a -Systematic Review• PersonalizationESMO GL 2012 of case-control studies • Based upon: risk factors FDG status, dosimetry • Personalisation of individual response3b –Individual and tolerability: (circulating NET transcriptscase-control) studies

4-Case series

1994-96 5-Expert opinion

The interim results of NETTER-1 registration trial has increased the utilization of PRRT in the NET tumor boards. COMPETE study

177Lu- (177Lu-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 177Lu-edotreotide compared to targetedd molecular therapy with Everolimus in patients with inoperable, progressive, somatostatin receptor-positive gastro- entero-pancreatic neuroendocrine tumors

STARTED RECRUITING IN EUROPE TO BE STARTED SOON IN THE US 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 Intra-arterial PRRT

This strategy produce 60% PR+CR

Kratochwil C et al. ERC 2011 PRRT with SSR-ANTAGONISTS 177Lu-DOTA-JR11 in NETs

Baseline Follow up

68Ga-DOTA-JR11 Contrast CT, arterial Contrast CT, arterial phase fused transaxial image 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): 68Ga-DOTA-JR11 • PR in 7/19 (37%), SD in 9/19 (47%), PD in 3/19 (16%) 60 min p.i. (MIP) • 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. 2015-17 OPS101 trial

177Lu-OPS101 (177Lu-DOTA-JR11) An international multicenter, open-label study to evaluate safety, tolerability, biodistribution, dosimetry and prelimary efficacy of 177Lu- OPS201 for the therapy of somatostatin receptor-positive neuroendocrine tumors

STARTED IN EUROPE AND AUSTRALIA TO BE STARTED SOON IN THE US What determines the response?

Kidd M, Modlin M. 2017 Predictive accuracy: 95% n=158

Specific Transcript Genes + Histopathology Grading 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