Choline PET/CT Robert S. Bridwell MD MBA Founder and CMO Appian 360 Medical Advisor to Zevacor Pharma, Inc.

Disclosure/Disclaimer This presentation has been prepared and delivered at the request of Zevacor Pharma, Inc. for which the author/speaker has received an honorarium. Any opinions, findings, conclusions or recommendations expressed in this presentation are those of the author. The information is designed for educational purposes only and is not engaged in rendering medical advice or professional services.

Prostate cancer as a target

Three PET isotopes to target prostate CA FDG NAF Choline/Amino Acid imaging

Prostate Cancer 65yo male with history of 8/10 Gleason Prostate Cancer The patient presents one year after initial treatment with elevated ALK, bone pain and elevated PSA Bone scan and FDG PET/CT ordered to restage the patient

FDG PET/CT

Case study 69yo male with a history of prostate cancer, Gleason 8/10 initially treated with radiation therapy Now presenting with rapidly elevated PSA, asymptomatic NAF PET/CT ordered for assessment of osseous involvement

Impact of NAF PET/CT NAF PET/CT revealed multifocal osteoblastic metastatic disease Not one of the lesions was noted on the CT study

NAF PET/CT for Prostate Cancer Kjolhede et al. Combined F-fluorocholine and NAF PET/CT imaging for staging of high risk prostate cancer. BJU Apr 2012 90 patients with initial staging evaluation, negative planar bone scan and PSA between 20-99ng/ml and/or Gleason score 8-10 tumors Patients initially considered for curative therapy Compared clinical impact of PET/CT in patients with a negative or equivocal bone scan

NAF PET/CT Prostate Cancer For 50/90 patients one or both PET/CT scans indicated metastases F-Fluorocholine PET/CT indicated lymph node and/or bone metastases in 35 (39%) of patients NAF PET/CT was consistent with bone mets in 41% of patients In 20% of cases NAF found diffuse metastatic disease and changed therapy from curative to non curative

NAF PET/CT Of the patients with a positive scan 74% had a Gleason score 8-10 All patients with boney metastatic disease on the F choline study were detected on the NAF PET/CT

Tc99m MDP F-Choline NAF

Case study 68yo male with a history of prostate cancer He now presents with rapid increase in PSA The patient is asymptomatic A CT and bone scan (NAF PET/CT), along with FDG PET/CT was ordered

NAF FDG

Impact of PET/CT NAF PET/CT revealed multiple areas of increased osteoblastic activity consistent with widespread osseous metastatic disease Every site of abnormal uptake is FDG negative This illustrates that FDG PET/CT has limited impact (sensitivity) in some patients compared to bone scanning (NAF PET/CT)

FDG versus NAF for Prostate Cancer Jadav et al. Prospective evaluation of NAF and FDG PET/CT in detection of occult metastatic disease in biochemical recurrence of prostate cancer. Clin Nuc Med Jul 2012 37 med with PSA relapse (range 0.5-40.2 ng/ml, median 3.2 ng/ml) after definitive therapy with negative conventional imaging underwent FDG and NAF imaging Reference standard imaging and clinical follow up

FDG vs. NAF Primary Gleason score Less than 7 in 7 patients 7 or higher in 27 patients Unattainable in 3 Patients with a positive NAF PET/CT PSA range was 1.9 to 5.8 ng/ml

FDG vs. NAF FDG PET/CT positive in 2 patients for nodal disease True positive detection rate for NAF imaging was 16.2% NAF positivity tends to associated with increasing PSA level

Case study 65yo male with high risk prostate cancer The patient was staged with CT and bone scan which were negative for regional or distant disease NAF PET/CT was performed prior to definitive management to improve the sensitivity of bone scintigraphy

Case study

Impact of NAF PET/CT NAF PET/CT revealed multifocal uptake in the axial skeleton, which was undetected on conventional bone imaging Findings were consistent with metastatic disease Patient management decision, therefore, was based on more accurate information

Case study 72yo male with a history of prostate cancer treated with definitive radiation therapy Now the patient presents with elevated PSA and hip pain Bone scan ordered to assess for metastatic disease

Case study

Case study

FDG PET/CT Relatively poor sensitivity for prostate cancer Low metabolic rate High false negative rate Sensitivity dependent on the PSA doubling time and or absolute PSA Only reimbursed for restaging by CMS Limited clinical utilization due to poor sensitivity

NAF PET/CT Pros Cons A better, faster bone scan Higher diagnostic accuracy to assess osteoblastic metastatic disease Cons Cost Cannot assess soft tissue metastatic disease Prostate bed recurrence Nodal disease Interpreters’ false positive rate

C-11Choline 20 minute half-life Indication for patient restaging Logistically and technically different patient flow when compared to FDG/NAF Indication for patient restaging Biochemical failure after definitive therapy for prostate cancer Sensitive for early PSA failure PSA< 1.5 ng/ml There is data for staging (off label indication) Mechanism of action parallels choline metabolism

Choline metabolism

Value of Choline PET Different physiologic mechanism compared to FDG and NAF Higher diagnostic accuracy to assess soft tissue than CT or MRI - finding disease within normal sized structures Power of fusion to minimize false positives Sensitivity may be preserved for low PSA recurrences-PSA <1.0 Already in the NCCN guidelines for restaging

NCCN

C-11 Choline Technical considerations 20 minute half-life Early imaging of the pelvis to avoid urine excretion into the bladder Late imaging to improve sensitivity (especially if the PSA is low) Injection between 10-15 mCi Depends on equipment Depends on PSA value and anticipation for delayed imaging Fasting for at least six hours - similar to FDG

C-11 Choline Collect clinical history prostate cancer Prior definitive therapy PSA value at the time of the study PSA values over time What type of therapy is the patient on? ADT? When did it start? Clinical history other tumor types Type of cancer Any prior therapy-surgery/radiation Contrast considerations Oral and iv

Acquisition Massaro et al. Optimizing F-18 Choline PET/CT acquisition protocol in prostate cancer. N Am J Med Sci Sep 2012 30 patients with biochemical relapse of prostate cancer Five scan protocols Early dynamic Early static scan pelvis Early whole body scan Delayed static scan of the pelvis Delayed whole body scan

Acquisition Blinded interpretation Assess quantitatively which study provided the highest sensitivity and specificity Histologic confirmation in all positive lesions

Acquisition One hour delayed scan provided the highest diagnostic accuracy about prostate bed, local nodal recurrences and distant metastatic disease The early static scan provided important information regarding urine from loco regional recurrence

Choline PET/CT

Case 3 72yo male with a history of prostate cancer. He was definitively treated with external beam radiation therapy 3 years ago. The patient has had a recent rise in his PSA over the last year 12 months ago 0.5ng/ml 6 months ago 0.8 ng/ml 2 months ago 2.2 ng/ml The patient is asymptomatic and has had negative CT of the abdomen and pelvis and bone scan

Impact of Choline PET/CT PET/CT with choline revealed two areas of abnormal focal accumulation consistent with recurrent disease Choline PET/CT improved the sensitivity of anatomical and other functional imaging modalities

Review article Evangelista L et al. Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis. Clin Nuc Med May 2013 53 complete articles - 19 articles met criteria for inclusion A total of 1555 patients Pooled sensitivity-85.6%, specificity 92.6% for all sites

Review article Pooled sensitivity of 75.4% (95% CI: 66.9%-82.6%) and pooled specificity of 82% (95% CI: 68.6%-91.4%) for prostatic fossa recurrence Pooled sensitivity of 100% (95% CI: 90.5%-100%) and pooled specificity of 81.8% (95% CI: 48.2%-97.7%) for lymph node metastases.

Restaging prostate cancer Castellucci P et al. Early biochemical relapse after radical prostatectomy: which prostate cancer patients from a restaging C-11 Choline PET/CT scan before salvage radiation therapy? J Nucl Med Sep 2014 605 patients treated for cure and a biochemical relapse being considered for S-RT PSA values were > 0.2 ng/ml and < 2.0 ng/ml All patients classified as N0 after RP

Restaging Prostate Cancer 17/605 received adjuvant RT 148/605 were receiving ADT at the time of the PET/CT PSA, PSA kinetics, Gleason score, age, time to biochemical relapse, ADT and tumor stage were correlated with positive study on C-11 Choline

Restaging Prostate Cancer C-11 choline was positive in 28.4% of patients. 83/605 positive only in the pelvis 72/605-positive for distant metastatic disease 17/605 positive for both local and distant disease At multivariate analysis, PSA, PSA doubling time (PSAdt), and ongoing ADT were significant predictors for positive scan results

Case Study 72yo male with prior history of prostate cancer s/p prostatectomy The patient is now asymptomatic and presents with biochemical failure PSA 12 months ago 0.1ng/ml PSA 6 months ago 0.5 ng/ml PSA now 1.0 ng/ml Prior CT and bone scan negative for evidence of recurrence C-11 Choline ordered to improve the sensitivity of anatomical based imaging and bone scan

Impact of PET/CT with Choline Positive choline finding disease within normal sized lymph nodes in the pelvis in a multifocal pattern Hilar nodes are inflammatory in etiology

Literature review Wondergen M et al. A literature review of 18F fluoride PET/CT and 18F-choline or C-11 choline PET/CT for detection of bone metastases in patients with prostate cancer Nucl Med Commun Oct 2013 13 articles

On a lesion basis, we found a sensitivity and specificity of 84 On a lesion basis, we found a sensitivity and specificity of 84.0 and 97.7% for C-choline and F-choline and 88.6 and 90.7% for F-fluoride, respectively. On a patient basis, the sensitivity and specificity were 85.2 and 96.5% for C-choline and F-choline and 86.9 and 79.9% for F-fluoride, respectively. No significant differences were found between the sensitivity and specificity of C-choline or F-choline and F-fluoride.

Choline Predicts Survival Giovacchini G et al. C-11 choline PET/CT predicts cancer specific survival in patients with biochemical failure during androgen-deprivation therapy. J Nucl Med Feb 2014 Retrospective study of 195 patients s/p RP with biochemical failure (PSA> 0.2ng/ml) on ADT. Disease specific survival was correlated with positive or negative Choline study

Survival C-11 choline was positive in 57% of the patients The median PCa specific survival was 16.4y in patients with a negative C-11 choline study The median PCa specific survival was 11.2 years in patients with a positive C-11 choline study Patients with disease in the nodes had a longer survival than those with skeletal metastatic disease

Case Study 75yo male with a history of prostate cancer He has had a prior prostatectomy and now presents two years after surgery with an elevated PSA of 15 ng/ml The patient is asymptomatic and has had a negative CT and bone scan C-11 Choline PET/CT ordered to improve the sensitivity of anatomical based imaging

Impact of Choline PET/CT C-11 Choline PET/CT revealed multifocal metastatic disease both within soft tissue lymph nodes and osseous metastatic disease

Choline for Restaging Prostate Cancer Chondrogiannis S et al. Role of F-choline PET/CT in suspicion of relapse following definitive radiotherapy for prostate cancer. Eur J Nucl Med Mol Imaging. Sep 2013 46 patients previously treated by definitive radiotherapy presenting with biochemical failure 12 treated with brachytherapy 34 with external beam radiation therapy

Restaging Prostate Cancer Overall positive detection rate was 80.4% The detection rate increased with increasing trigger PSA There was no statistical difference between those on ADT and those not Detection 59% of the patient had local relapse only 22% of the patients had distant relapse only 19% showed local and distant disease

C-11 Choline PET/CT Performance Castellucci P et al. Is there a role for C-11 Choline PET/CT in the early detection of metastatic disease in surgically treated prostate cancer patients with a mild PSA increase < 1.5ng/ml. Eur J Nucl Med Mol Imaging Jan 2011;38(1):55-63 102 patients previously treated with RP and who presented during FU with a mild increase of PSA serum level <1.5ng/ml (mean 0.86 ng/ml, range 0.2-1.5). C-11 choline was used as the first imaging examination at the time of PSA detection

C-11 PET/CT Performance 86 patients were not receiving any pharmaceutical intervention and 16 were under anti-androgenic therapy Gold standard was tissue or follow up for at least 12 months or alternative imaging

C-11 PET/CT Performance C-11 Choline was positive in 29-102 patients (28%). Choline detected local relapse in 7 patients, bone metastases in 13 patients and lymph node metastases in 9 patients. Performance Sensitivity 93% Specificity 74% PPV 60% NPV 96%

Case Study 64yo male with prostate cancer s/p definitive therapy with radioactive seed implantation. The patient has an asymptomatic biochemical failure with PSA of 2.0 ng/ml Anatomical imaging negative for recurrent disease C-11 Choline ordered to improve the sensitivity of CT

Impact of Choline PET/CT Choline PET/CT revealed increased uptake the prostate bed consistent with local recurrence No distant nodal or osseous disease is noted

Restaging of Prostate Cancer Beheshti M et al. Impact of 18F-choline PET/CT in prostate cancer patients with biochemical relapse: influence of androgen deprivation therapy and correlation with PSA kinetics. J Nucl Med Jun 2013. Prospective study 250 patients Mean PSA was 46.9 ng/ml and 55 % of patients were receiving ADT Histopathology or consensus was the gold standard

Restaging Prostate Cancer F-18 choline was able to correctly detect malignant lesions in 74% The sensitivity of the (18)F-FCH PET was significantly higher (P = 0.001) in patients with ongoing ADT (85%; confidence interval, 80%-91%) than in patients without ADT (59.5%; confidence interval, 50%-69%) (18)F-FCH PET sensitivity was 77.5%, 80.7%, 85.2%, and 92.8% for the trigger PSA levels of more than 0.5, 1.0, 2.0, and 4.0 ng/mL, respectively

Scan sensitivity was 33% in patients with a trigger PSA level of less than 0.3 ng/mL and 77% in patients with a trigger PSA level of greater than 0.3 ng/mL, respectively (P = 0.001). Using a binary logistic regression analysis model, we showed trigger PSA and ADT to be the only significant predictors of positive PET findings.

ADT and Choline Imaging Chondrogiannis S et al. Is the detection rate of 18-F-Choline PET/CT influenced by androgen-deprivation therapy? Eur J Nucl Med Mol Imaging July 2014 Retrospective study of 325 consecutive patients with biochemical relapse after definitive therapy Two groups PSA trigger between 0.1 and 80 ng/ml PSA trigger between .5 ng/ml and 5 ng/ml

ADT and Choline imaging Overall detection rate of Choline was 58.2% In group A Trigger PSA and ADT were significantly correlated with detection rate. The detection rate was higher in patients under ADT compared to those not under ADT In group B only trigger PSA was correlated with the detection rate

Choline imaging History - PSA level, PSA doubling time, Type of initial treatment, current therapy (ADT or not), Acquisition Delayed imaging may improve sensitivity Acquisition consideration given your equipment Sensitivity tied to PSA trigger level and PSA doubling time-know what you are looking for

ADT The potential impact of ADT Hormone naïve prostate CA If the ADT was just started and the PSA is dropping it may have a negative impact on Choline sensitivity Patient progressing through ADT If the patient’s PSA is rising on ADT therapy suggest a de-differentiated prostate ca. Choline PET/CT will show a higher sensitivity.

Training and support Up front clinical training Educating your market After deployment support

The future Competitive product pipeline Accuracy Blue Earth Diagnostics F18-Fluciclovine-Currently in Phase 3 Synthetic amino acid Indication is the same as Choline Restaging of prostate cancer with biochemical failure Accuracy For disease in the prostate bed Sensitivity 90% and specificity 40% For extraprostatic disease Sensitivity of 55% and specificity of 96.7% Compared to ProstaScint 25.7% of patients were upstaged

[F18]DCFPyl (DCFPyl) Small molecule PSMA inhibitor

Regional distribution of Fluciclovine Sorensen et al. Regional distribution and kinetics of F-18 fluciclovine, a tracer of amino acid transport, in subjects with primary prostate cancer. Eur J Nuclear Med Dec 2012 Six patients with biopsy proven prostate CA PET/CT performed between 1-15 minutes and sequentially to 120 minutes post injection

Comparison Nanni C et al., 18F-Fluciclovine PET/CT for the detection of prostate cancer relapse: A comparison to C-11-Choline PET/CT. Clin Nucl Med Aug 2015 50 patients previously treated for prostate cancer and presenting with biochemical failure All patients were off of hormonal therapy Both Choline and Fluciclovine obtained within a week

On a patient basis F-fluciclovine was superior to C-choline P>0.000001 Lymph nodes, bone, and local relapses There was no significant difference in terms of target to background between C-choline and F-Flucicclovine When patients were divided into groups with different PSA F-fluciclovine had superior detection rate for low, intermediate and high PSA levels.

First clinical study Szabo Z, et al., Initial Evaluation of [18F]DCFPyL for Prostate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer. Mol Imaging Biol. 2015 Apr 21 9 patients with prostate cancer Radiation dose similar to that of other PET/CT tracers

Comparison PSMA imaging Dietlein et al. Comparison of F-18 DCFPyl and Ga68-PSMA-HBED-CC for PSMA PET imaging in patients with relapsed prostate cancer. Mol Imaging Biol 2015 17:575-584. 14 patients with biochemical relapse of prostate cancer Patients had both studies

Comparison All suspicious lesions identified by the galliun tracer were also detected by FDCFPyl. In three patients F18-DCFPyl detected additional lesions The SUVmax was higher with the F-18 DCFPyl tracer Higher target to background was also noted

F-18 DCFPyl Ga-68-PSMA-HBED-CC

Choline versus PSMA Afshar-Oromieh et al. Comparison of PET imaging with Ga68-labelled PSMA ligand and F-18 choline based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2013 37 patients with biochemical relapse of prostate cancer. Mean PSA 11.1 range of 0.01-116. The patients had both studies within 30 days

Choline versus PSMA 78 lesions characteristic for prostate cancer were detected in 32 patients with Ga68 PSMA imaging 56 lesions in 26 patients were detected with choline imaging Higher detection rate of PSMA was statistically significant p=0.04 GA68 PSMA uptake was >10% higher in 62-78 lesions-tumor to background was higher in 74-78 lesions

Conclusion Choline PET/CT Well researched First PET/CT agent approved to assess for soft tissue metastatic disease in restaging prostate CA Already in NCCN guidelines Competitive to NAF market for restaging prostate CA Non specific for prostate CA Challenge will be 20 minute half-life There is a learning curve for interpretation

Competitive pipeline Amino acid molecules-F-18 labeled FABC - will be here first PETNet In limited studies appears more accurate than choline F-18 distribution and workflow Not specific for prostate CA F-labelled PSMA PET/CT molecules Specific imaging of the PSMA found on prostate CA More accurate than GA labelled PSMA compounds

Competitive products Ga68 labeled PSMA compounds Specific imaging Long half-life/wide distribution Maybe less accurate than F-labeled PSMA product in limited comparison studies PSMA more accurate than Choline in comparable studies

Utilization Distribution Interpretive confidence Cost Availability

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