THERANOSTICS: MOLECULAR IMAGING DRIVING TARGETED THERAPY

Size: px

Start display at page:

Download "THERANOSTICS: MOLECULAR IMAGING DRIVING TARGETED THERAPY"

Sandra Boyd
5 years ago
Views:

1 THERANOSTICS: MOLECULAR IMAGING DRIVING TARGETED THERAPY Dr Nat Lenzo BSc BMedSci(Hons) MBBS MMed EMBA FRACP FAANMS Clin. Assoc. Prof. in Medicine - Dept. of Medicine, University of WA Fellow in Medicine - Macquarie University, Sydney NSW General Physician & Nuclear Physician nat.lenzo@theranostics.com.au

2 Disclosures Founding Director: Theranostics Australia PI Ipsen sponsored Lu-177 OPS201 trial Lutetium-177 satareotide in metastatic neuroendocrine tumours (carcinoid, paraganglioma, phaeochromacytoma)

3 Outline What is Theranostics? Gallium-68/Lutetium-177 Theranostic Pair Paradigm Gallium-68 PSMA Imaging in Prostate Cancer Lutetium-177 PSMA Treatment in Prostate Cancer Future

4 FREMANTLE HOSPITAL

5 OUTPATIENT RADIOPEPTIDE AND RADIOIMMUNOTHERAPY CENTRE Prof Harvey Turner Fremantle Hospital 2014

6 Theranostics (Theragnostics)

7 Theranostics First used by PharmaNetics president and CEO John Funkhouser developing diagnostic tests directly linked to the application of a specific therapies. PharmaNetics - point of care coagulation tests supporting coagulation therapies September 25, key day FDA granted simultaneous approval for Genentech s Herceptin for the treatment of Stage IV breast cancer and Dako s HercepTest for diagnosis of Her2 overexpression

8 Theranostics in Nuclear Medicine Not a new paradigm Dr S Seidlin ( ) Montefiore Hospital New York City 1943 Radioactive iodine (I-131) for metastatic thyroid cancer Tracer dose followed by therapeutic dose Low dose I-131 or I-123 still used

9 Thyroid Cancer Ablative Dose Image 1 year later

10 Thyroid Cancer I-131 F18-FDG

11 131 I post-therapy scan. Tuttle RT et al. (2007) Radioactive iodine therapy in poorly differentiated thyroid cancer Nat Clin Pract Oncol 4: doi: /ncponc0979

12 131 I post-therapy transaxial single-photon-emission CT. Tuttle RT et al. (2007) Radioactive iodine therapy in poorly differentiated thyroid cancer Nat Clin Pract Oncol 4: doi: /ncponc0979

13 Positron Emission Tomography Biochemical/Molecular Changes Physiological Changes Anatomical Changes PET MR Spectroscopy Nuclear Medicine Functional MRI/CT MRI/multislice CT

14 Perth Cyclotron Installation DECEMBER 2002 SIR CHARLES GAIRDNER HOSPITAL PERTH

15 JUNE 2003 SIR CHARLES GAIRDNER HOSPITAL PERTH

16 Gallium PET Radiotracers Germanium - Gallium 68 Generators

18 Gallium-68 Products Gallium Citrate Gallium MAA Gallium DTPA Gallium Octreotate Gallium PSMA Gallium Pentixafor Gallium Herceptin Gallium Exendin Gallium Satareotide Etc.

19 PERSONALISED MEDICINE, THERANOSTICS & RADIOPEPTIDE THERAPY (RPT) Therapy Diagnostics Ga 68 Theranostics Lu 177 Targeted therapy Molecular receptor

20 Ga-68/Lu-177 octreotate

21 Radionuclide Therapy Ga-68 octreotate PET-CT Primary NET lesion Secondary liver mets

22 Radionuclide Therapy 13 JAN FEB Ga OCTREOTATE 177 Lu OCTREOTATE Courtesy: Prof Harvey Turner

23 MULTIMODALITY RADIOPEPTIDE 177 Lu-OCTREOTATE THERAPY NET 7.8 GBq 4 8 WEEKS + CAPECITABINE 750 mg/m 2 bd DAY - 5 to DAY 10 +/- TEMOZOLOMIDE 200 mg /m 2 per DAY DAY 5 to DAY 10

24 Metastatic Insulinoma Treated with Lu-177 octreotate A.Initial B. 4 months C. 9 months after treatment (Ong, Henley, Hurley, Turner et al. Eur J Endocrinol May 1, )

25 ORR PRRT PANCREATIC G 1/2 NETS Lu-OCTREOTATE + CAPECITABINE + TEMOZOLOMIDE (n = 38) Courtesy: Prof Harvey Turner

26 PRRT PANCREATIC G 1/2 NETS Lu-OCTREOTATE + CAPECITABINE + TEMOZOLOMIDE median PFS 4 years, OS not reached Courtesy: Prof Harvey Turner

27 DURABLE COMPLETE RESPONSE OBJECTIVE: CT (RECIST 1:1) METABOLIC: 177 Lu-OCTREOTATE SYMPTOMATIC: COMPLETE REMISSION 7 th Nov th Nov 2014

28 AAA Netter I Study Lu-177 octreotate vs sandostatin

30 September 29, 2017 Advanced Accelerator Applications Announces European Approval of Lutetium (177Lu) Oxodotreotide (Lutathera ) for Gastroenteropancreatic Neuroendocrine (GEP-NET) Tumors Completes First Thera(g)nostic Radiopharmaceutical Pairing in Oncology October 30, 2017 Advanced Accelerator Applications Announces $3.9 Billion All Cash Proposed Tender Offer by Novartis January 26, 2018 Advanced Accelerator Applications/Novartis Announces US FDA Approval for Lutathera for US Market (Already approved in Europe/UK/NZ)

31 Radionuclide Therapy Benefits Higher radiation dose deposited directly to target tissue (10-100x greater than external beam) Decreased toxicity to adjacent tissue short pathway Selective targeting possible e.g. anti-cd20, somatostatin receptor (SSTR), PSMA receptor Dosimetry possible Can combine with chemotherapy, external beam radiotherapy and potentially other radionuclides Various isotopes, energy and method of administration

33 Radionuclide Therapy

34 Ga-68 PSMA PET Imaging 2009/2010 first publications of Ga-68 PSMA targeting PSMA receptor for Prostate Cancer imaging (Germany) July 2014: Wesley Hospital Brisbane performed first clinical Ga-68 PSMA PET CT for prostate cancer in Australia (16 th July 2014) Peter MacCallum Victoria performed their first clinical Ga-68 PSMA PET CT in July 2014 May 2015: Oceanic Molecular Hollywood performed 1 st Ga PSMA PET scan (3 rd site in Australia) Feb 2018: 5 sites in Perth & approx. 40 sites in Australia providing Ga PSMA PET mostly private radiology practices 34 Fastest growing imaging test in Australia; no Medicare funding Some sites doing 20+ scans per week; $650-$1250 AUD per scan (average $900 AUD) Public hospitals in Perth and some Eastern States public hospitals do not charge NZ - $2300 NZD; Singapore - $2500 SGD; USA $3500 USD

35 Why the explosion? Prostate cancer Approx cases diagnosed annually in Australia Most common cancer diagnosis in Australia (more than breast, lung and melanoma) 1/3 will show biochemical relapse (PSA) within 10 years More men die per year from prostate cancer (>3000) in Australia than women die from breast cancer No major advance in therapeutic options in last 15 yrs Surgery/brachytherapy/radiotherapy ADT/pelvic irradiation 2 nd line ADT/Docetaxel/2 nd line chemo (cabazitaxel) Radium (palliation) Overall survival benefit of 2 nd line therapies modest at best 35

36 Status of PCa treatments EJNM 2015

37 Prostate cancer imaging with PSMA-ligands PSMA: prostate-specific membrane antigen cell surface protein with overexpression in prostate cancer transmembraneous localization including large extracellular part promising target for prostate cancer specific imaging and therapy recently: development of various PSMAligands for PET imaging e.g. 68 Ga-PSMA: Glu-NH-CO-NH-Lys- (Ahx)-[ 68 Ga(HBED-CC)] (only for 68 Ga) and PSMA I&T (TUM/Scintomics), suitable for M 3+ labeling ( 68,67 Ga, 177 Lu, 90 Y, 111 In )

38 [ 68 Ga]PSMA-Ligand PET in recurrent prostate cancer Detection rate with [ 68 Ga]PSMA-Ligand: 73 patients PSA: median 3.04 ng/ml (range ng /ml) mixed PET/CT and PET/MR imaging 100% Courtesy: Eiber M (NuklMed) and T.Maurer (Urology) at Technische Universität München 5.26% 75% 36.36% 50% 16.67% 94.74% 25% 41.67% 54.55% 0% PSA < 1ng/ml PSA 1-2 PSA 2 high confidence low confidence Courtesy: Eiber M 2013; Dept. Nucl Med, TU Munich;

39 [ 68 Ga]PSMA-Ligand PET in recurrent prostate cancer Asokendaran, Henderson, Meyrick, Wester, Lenzo. ANZSNM 2016 Detection rate with [ 68 Ga]PSMA-Ligand (all pts with negative CT +/- bone scan): 102 pts; Age range years. PSA range ng/ml, 67/102 positive scans 15/67 (22%) recurrence confined to prostatic bed; lowest positive scan 0.17 ng/ml Detection Rates According to PSA Levels (%) Gallium PSMA PET Diagnostic CT P= P< P= < >1.5 PSA Level (ug/l)

41 Ga-68 PSMA PET CT Rising PSA following definitive therapy for prostate cancer and negative CT +/- bone scan: Data similar to European counterparts with Very high sensitivity if PSA >1.5 (~90%) Decreased sensitivity if PSA <0.5 (~25%) and minimal value if PSA <0.2 1/5 th had recurrence in prostate bed; mostly pelvic or abdominal nodes Often nodal disease just out of field of treatment from pelvic radiotherapy Smallest node detected (literature): 2.4mm

42 Ga-68 PSMA PET CT in Primary Staging 70 patients - results: Meyrick, Asokendaran, Skelly, Lenzo, Henderson. Nuc Med Comm 2017 PSMA-avid disease outside of the prostate gland (distant) detected: Gleason 7 or below: 18.2% (4/22) Gleason 8: 31.6% (6/19 - all PSA 10 or more) Gleason 9 and above: 47.8% (11/23) PSA less than 5: 9% (1 /11) PSA 5-10: 25% (6/24) PSA less than 10: 20% (7/35); PSA over 10: 45.7% (16 /35) 11 patients had both a PSA over 10 and Gleason 9 or more: 7 of these (63.6%) had distant PSMA-avid disease. Of these 7 positive subjects: 5 to lymph nodes, 1 to skeleton and 1 to skeleton + lymph nodes.

43 Mr B 70 yo man with Gleason 9 prostate cancer. PSA 24. Standard preop inx. CT pelvis localised disease. Bone scan - NAD

44 Mr B

45 Mr B

46 Mr B

In high risk patients (Gleason 9+ and PSA>10) PSMA avid disease was found distant to the

47 Ga-68 PSMA PET CT in Primary Staging Conclusions: 68Ga-PSMA PET CT appears to have the potential for improving staging of primary prostate cancer. In high risk patients (Gleason 9+ and PSA>10) PSMA avid disease was found distant to the prostate in 64% of this group. This may have significant impact in patient management. Meyrick, Asokendaran, Skelly, Lenzo, Henderson. Nuc Med Comm 2017

48 Ga-68 PSMA PET in DXRT Planning

49 Ga-68 PSMA PET in DXRT Planning

50 Mr C 63 yo man pt3a Gleason 7 margin -ve prostate cancer. Had RP 22/5/2008. Post-op PSA nadir Slowly rose to 0.21 March 2010 & 0.33 June Re-staging investigations - NAD. Salvage XRT to prostatic bed alone in Oct PSA dropped to nadir of 0.08 Oct Since then PSA slowly rising. Last PSA=1.87 in June Had various staging scans last 2 years and all NAD. NEVER had ADT during the follow up.

51 Mr C

52 Mr C

53 SBRT in 2015

54 PSMA scan 8/8/16

55 Role of Ga-68 PSMA in Prostate Cancer EANM 2018 Consensus Statement I. Biochemical recurrence following definitive therapy PSA >0.5 ug/l II. Primary staging in newly diagnosed high risk prostate cancer (PSA>10; Gleason >8) III. For radiotherapy planning IV. For possible aid in guiding site of targeted biopsy STILL UNDER INVESTIGATION V. Monitoring treatment response - STILL UNDER INVESTIGATION Pro-PSMA Trial Australia

56 Lu-177 PSMA in Ga-68 PSMA Avid Metastatic PCa

57 Systemic radioligand therapy with 177Lu-PSMA-I&T in patients with metastatic castration-resistant prostate cancer. H. Wester & M. Schwaiger Munich March 2016 Material and Methods 22 mcrpc patients treatment failure with both chemotherapy and novel androgenreceptor targeted therapy treated 8-weekly with up to 4 cycles of 177Lu-PSMA-I&T. Results First 3 patients treated with a lower activity of 3.7 GBq in their first cycle. Due to a favourable safety profile the activity was increased to 7.4 GBq in 19 subsequent patients who completed a total of 40 cycles. With higher activity no grade 3/4 toxicities were observed. Main non-hematologic and hematologic grade 1/2 toxicities were dry mouth in 7 (37%), anemia in 6 (32%) and thrombopenia in 5 (25%) patients. Proportion of patients achieving a maximum PSA-decline of 30%, 50% and 90% was 56%, 33% and 11%, respectively. Combined assessment of bone and soft-tissue metastases showed a complete remission in 5%, stable disease in 63% and progressive disease in 32% of patients. ECOG performance status improved or was stable in 74% of patients. Of men with bone pain, 58% achieved complete resolution or reduced pain. Conclusion Radioligand therapy with 177Lu-PSMA-I&T appears to be safe and active in heavily pretreated mcrpc patients.

58 58 Lu-177 PSMA in Treatment 177Lu-PSMA has been used safely in advanced metastatic prostate cancer patients (>3000 worldwide mostly Germany) with promising results. Theranostics Australia Hollywood Private Hospital and Macquarie University Hospital Sydney - ~150 patients treated. Currently treat 10 patients a week. Compassionate basis under TGA SAS. Number of studies now published: largest >500 patients in castrate resistant metastatic prostate cancer who have failed ALL treatment options. After 3-4 cycles Lu-177 PSMA: 40% show >50% reduction in PSA 30% show 0-50% reduction in PSA 30% show progression despite treatment Progression free survival of 6-21 months Overall survival benefit of 6-14 months

59 59 Lu-177 PSMA Side Effects 10-15% nausea (day after therapy for up to 3-4 days) 10-15% bone flare especially if widespread bone disease treat with 7-10 days steroids Transient mouth dryness lasts 1-2 weeks but 8-10% permanent if >4 cycles of therapy Tiredness from few days to few weeks Bone marrow suppression dependent on previous treatments and extent of bone marrow involvement

60 Mr J 82 yo man. Dx prostate cancer in 2004 (Gleason 8). Rising PSA July ADT & prostatic bed radiation (74 Gy) Further PSA rise. CT and bone scan August 2015 no metastatic disease. PSMA PET scan Sir Charles Gardner Hospital September extensive PSMA avid nodal metastasis. Previous ADT- very symptomatic memory, depression, fatigue. Last PSA= 40 ng/ml Oct PSMA nodal and prostatic bed disease. Renal impairment egfr 35 ml/min not a chemotherapy candidate Treated with 3 cycles 6.5 GBq, 5.5 GBq, 5 GBq Lu-177 PSMA (last dose May 2016) Unwell after 1 st cycle reviewed on request of oncologist E. Coli UTI (stricture)

61 Mr J 3 cycles: 17 GBq

62 Mr J 3 cycles: 17 GBq

63 Mr J 3 cycles: 17 GBq

64 Mr J 3 cycles: 17 GBq

65 Mr J 82 yo man. Dx prostate cancer in 2004 (Gleason 8). Rising PSA July ADT & prostatic bed radiation (74 Gy) Further PSA rise. CT and bone scan August 2015 no metastatic disease. PSMA PET scan Sir Charles Gardner Hospital September extensive PSMA avid nodal metastasis. Previous ADT- very symptomatic memory, depression, fatigue. Last PSA= 40 ng/ml Oct PSMA nodal and prostatic bed disease. Renal impairment egfr 35 ml/min not a chemotherapy candidate Treated with 3 cycles 6.5 GBq, 5.5 GBq, 5 GBq Lu-177 PSMA (last dose May 2016) Unwell after 1 st cycle reviewed on request of oncologist E. Coli UTI (stricture) egfr now 41 ml/min; PSA 1.6 ng/ml. Has had stricture repair Jan 2017 Has had spinal surgery (stenosis) May 2017 and ankle repair Sept 2017

66 Mr Y 65 yo Singapore based Japanese businessman Gleason 9 prostate ca 2004; radical prostatectomy undetectable PSA 2007 rising PSA- commenced ADT 2013 second line ADT bicalutamide/nicalutamide 2015 radiotherapy Docetaxol peripheral neuropathy Refused further chemotherapy July Weight loss, nocturnal tumour fever PSA 3900, Hb 97 Treated with 3 cycles Lu-PSMA: 4 GBq Aug 7, 4 GBq Sep 17, 5 GBq Nov 17

67 Mr Y

68 7000 Mr Y PSA Patient Cycle 2 28-Sep Cycle 3 16-Nov Cycle 1 03-Aug Jul Aug Sep Oct Nov Dec Jan Feb Mar-18 Baseline Post Cycle 1 Post Cycle 2 Post Cycle 3

69 Mr G 70 yo Californian businessman Diagnosed with metastatic prostate ca Sep 2014 ADT then second line ADT then chemotherapy Rising PSA PSMA PET scan: Diffuse bone involvement, extensive adenopathy, PSMA disease in prostate November 2016 PSA cycles of Lu-177 PSMA in Germany 3 rd cycles of Lu-177 PSMA at Theranostics Australia Sydney

70 Mr G 450 PSA Patient Cycle 1 (Germany) Cycle 2 (Germany) Cycle 3 (TA - Sydney) /11/2016 1/12/2016 1/01/2017 1/02/2017 1/03/2017 1/04/2017 1/05/2017 1/06/2017 1/07/2017 1/08/2017 1/09/2017 1/10/2017 1/11/2017

71 First U.S. Multi-center Investigational Clinical Trial of 177 Lu PSMA- 617 Targeted Radioligand Therapy in Metastatic Castration Resistant Prostate Cancer Receives FDA Clearance February 06, :00 ET Source: RadioMedix Inc. November 2017 Endocyte Announces Exclusive Worldwide License of Phase 3 Ready PSMA-Targeted Radioligand Therapy for Development in Prostate Cancer January 2018 ANZUP Australian TheraP Trial: A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer (ANZUP Protocol 1603)

in most patients on PSA and molecular imaging criteria.

72 72 Lu-177 PSMA in Treatment 177Lu-PSMA in small series appears well tolerated with minimal short term sideeffects 177Lu-PSMA can be provided safely in an outpatient private hospital setting with improvements in most patients on PSA and molecular imaging criteria. More clinical trials required to determine clinical utility THERA-P Trial: Lu-177 PSMA vs Cabazetaxel chemotherapy PSA 55 ng/ml PSA 4 ng/ml Oct 2015 May 2016

73 FUTURE - Actinium-225 PSMA Lu-177 PSMA failure Before PSA 420 PSA <0.1 After

74 FUTURE - Actinium-225 PSMA Lu-177 PSMA failure PSA 3000 PSA <0.1

75 Future:? Ga/Lu-PSMA in Glioblastoma

76 Ga/Lu-PSMA in Glioblastoma

77 Lu-PSMA in Glioblastoma

78 Ga-68/Lu-177 octreotate A number of tumours exhibit somatostatin receptor (SSTR) overexpression Neuroendocrine tumours Meningioma** Merkel cell tumours Small cell lung cancer Thymic cancer Hepatocellular carcinoma Sarcoma Some Lymphoma Some Squamous cell cancers Some Medullary and Follicular thyroid cancers and Hurthle cell tumours Some Breast cancers

79 Ga-68/Lu-177 Octreotate in Merkel Cell Tumour FDG PET Ga-Octreotate PET

80 Mr R 70 yo businessman skin lesion removal June Pathology- Merkel cell. Wide local excision and axillary SLN biopsy small volume nodal disease July 2016 (Average survival metastatic merkel cell 9 months) Radiotherapy to site and axilla. 6 cycles Pembrolizumab immunotherapy Sept 2016-Feb Mass in right axilla FDG and Ga octreotate PET revealed mets in axilla and sternum 3 cycles of Lu-octreotate: March 3.6 GBq, May 7.3 GBq, July 7.3 GBq Complete remission on FDG and Ga octreotate Repeat scans Nov 2017 new subcut deposit and recurrence at sternum; FDG reveals several new FDG avid liver mets For 3 cycles Lutate + capecitabine + temozolamide with lanreotide (drives SSTR expression). 1 st cycle Dec 2017; 2 nd cycle Feb 2018

81 Mr R January 2018

82 Summary Long history of theranostics in nuclear medicine (I-131) Molecular targets coupled with standardised and simplified production of diagnostic and therapeutic radiopharmaceuticals is expanding potential imaging and therapeutic options Ga-68 octreotate/lutate for NET is now an established theranostic paradigm Ga-68 PSMA becoming standard imaging test for prostate cancer & Lu-177/Act-225 PSMA promising new targeted treatments Gallium-68/Lutetium-177 combination offers great promise for theranostic approaches to a number of cancers Theranostics Australia with Genesis Care starts at Waratah Private Hospital in March 2018

83 Questions: 1. Which imaging modality is most sensitive for carcinoid tumour staging a. CT scan b. Ultrasound c. FDG PET d. Gallium octreotate PET scan 2. Which patient is suitable for Lutetium-octreotate treatment: a. Metastatic colon cancer b. Metastatic kidney cancer c. Metastatic carcinoid (neuroendocrine tumour) d. Metastatic prostate cancer 3. Which imaging modality is most sensitive for restaging prostate cancer in the setting of biochemical recurrence a. CT scan b. FDG PET c. MRI pelvis d. Gallium PSMA PET scan 4. The THERA-P Trial is an Australian phase III study: a. Assessing Lutetium-177 PSMA in early prostate cancer recurrence b. Assessing Lutetium-177 PSMA in end stage prostate cancer c. Assessing Lutetium-177 PSMA vs Cabazetaxel chemotherapy in patients who have failed docetaxel d. Assessing Lutetium-177 PSMA in metastatic carcinoid tumours

84 Metastatic Gastro-pancreatic NET

85 Acknowledgements: Prof Harvey Turner & Dr Phil Claringbold (Fremantle) Mr Philip Calais Physicist (Fremantle Hospital & FSH) Dr Joe Cardaci, Dr Danielle Meyrick, Dr Sharon Yeo, Ms Julie Crouch Oceanic Molecular/Perth Radiological Clinic Team - in particular Dr Andrew Henderson Ms Laura Skelly and Dr Marcus Askondrian Dr Tee Sin Lim and Genesis Care Prof Hans Wester, Munich & Dr Ken Herrmann, Wurzburg Mr Peter Eu Pharmatopes Melbourne ANSTO

86 FREMANTLE HARBOUR

Lutetium-177 PSMA (LuPSMA) Theranostic Phase II trial: Efficacy, safety and QoL in patients

Lutetium-177 PSMA (LuPSMA) Theranostic Phase II trial: Efficacy, safety and QoL in patients with castrate-resistant prostate cancer treated with LuPSMA M. S. Hofman, S. Sandhu, P. Eu, P. Jackson, T. Akhurst,