Use of a Protease Activated System for Real-time Breast Cancer Lumpectomy Margin Assessment

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1 Use of a Protease Activated System for Real-time Breast Cancer Lumpectomy Margin Assessment Barbara L. Smith, MD, PhD Professor of Surgery, Harvard Medical School Division of Surgical Oncology Massachusetts General Hospital

2 No Disclosures MGH Lumicell trials funding Feasibility trial: NCI grant 1R21CA Pivotal trials: NIH 1R44CA , NCI 1R01CA Research nurse support MGH Translational Clinical Research Center NIH grant 1UL1TR Clinical production of LUM015: NCI/NIH Experimental Therapeutics Program funding

3 Breast Conservation vs. Mastectomy 20 year follow-up: lumpectomy and mastectomy provide equivalent survival Local recurrence reduces survival 4:1 ratio 1 excess death for each 4 local failures

4 Lumpectomy: Prevent recurrence Oxford Overview: 1 excess death per 4 local recurrences Clarke Lancet 366: Margins: Negative for invasive, > 2mm for DCIS Radiation with boost Systemic therapy decreases local recurrence

5 Breast duct anatomy is complex Ducts branch in irregular patterns and overlap Tumor growth along ducts unpredictable POSITIVE MARGINS ARE COMMON! 20-40% of patients need a 2 nd surgery for positive margins

6 Current breast lumpectomy margin assessment: Limited real-time tools Specimen imaging Mammography, micro-ct Lumpectomy surface assessment Frozen section, touch prep cytology Specimen surface imaging MarginProbe Bigger lumpectomies Shaved cavity margins 6

7 What is the ideal margin assessment tool? High sensitivity for tumor detection Rapid assessment of the entire cavity Identify residual tumor in the cavity wall rather than on surface of excised specimen Avoid problem of correlating specimen surface findings with location in cavity

8 LUM Imaging System: How it works 1 LUM015 (cathepsin and MMP activated fluorescent optical contrast agent) injected IV 2-6 hours pre-op LUM015 Optical contrast agent 2 After standard lumpectomy, cavity imaged with hand-held imaging device that detects activated LUM015 fluorescence 670nm wavelength Hand-held Imaging Device cm diameter image acquired in <1 second, surgeon excises area of fluorescent signal Real-time decision software

9 MGH Lumicell Feasibility Trial Lanahan, San Antonio Breast Cancer Symposium 2017 Study design 60 breast cancer patients 15 training cases, device, LUM015, standard surgery 45 Lumpectomy + comprehensive shaves + Lumicellguided therapeutic shaves Study goals Safety assessment Standard of care shaves (yellow) Avoid false negatives Refine threshold algorithm Lumicell therapeutic shaves (red) 9

10 Tumor : Normal LUM015 signal ex vivo 15 patient training set Br Ca Res Treat 2018;171:413 IDC + DCIS no LUM015 (T:N signal 1.9) IDC + DCIS 0.5 mg/kg LUM015 (T:N signal 4.8) Normal Tumor Tumor Normal Dose - Tumor histology Average T:N signal ratio No LUM015 (n=3) mg/kg (n=5) mg/kg (n=4) 4.22 Pure DCIS or extensive DCIS, any dose (N=4) 2.61 Invasive +/- DCIS, any dose (n=5) 5.99

11 Feasibility Trial logistics 45 breast cancer lumpectomy patients injected with 1mg/kg LUM hrs before surgery Standard lumpectomy performed Lumpectomy cavity surfaces and excised specimens imaged with hand-held probe Areas of high cavity fluorescence detected, analyzed and excised. Lumicell images and standard histopathology compared 2.6 cm diameter image acquisition, analysis and display required only ~1 second

12 Lumicell Imaging System OR use

13 Study population Patient Characteristics (n=45) Age (yrs) 60 (44-79) Pre- or perimenopausal Heterogeneously or extremely dense Ethnicity 31% 53% Non Hispanic 42 (93%) Hispanic 1 (2%) Unavailable 2 (5%) Race White 38 (85%) Black 5 (11%) Asian 2 (4%)

14 Tumor characteristics Tumor characteristics (N=45) Mean tumor size (range) 1.2 ( )cm Invasive ductal +/- DCIS 59% Invasive lobular 13% Pure DCIS 24% Invasive ductal/lobular +/- DCIS 4% ER+ 90% Nodal Status # Patients Positive 5 (11%) Negative 29 (65%) Not tested 11 (24%)

15 Lumicell Imaging System: In vivo detection of LUM015 dye fluorescence at sites of tumor in lumpectomy cavity walls Lanahan, San Antonio Breast Cancer Symposium 2017 Lumicell images Histopathology of same sites a) 0.5 mg/kg Ex Vivo p=9.3e-05 b) 0.5 mg/kg In Vivo p=0.015 Fluorescent signal intensity of individual cavity surfaces by histology findings c) fluorescence fluorescence 1.0 mg/kg Ex Vivo p=2.4e-06 fluorescence fluorescence d) 1.0 mg/kg In Vivo p=6.3e-10

16 LUM Imaging and histopathology A. In vivo cavity wall with IDC B. Excised tissue from site C. Ex vivo positive IDC, cut specimen D. Lumpectomy histopathology E. Ex vivo DCIS specimen surface F. Histopathology at site A C E B D F

17 Small focus of tumor identified on specimen image and histology

18 MGH Lumicell Feasibility Trial 45 breast cancer pts with 8 relevant positive margins Invasive (lobular and ductal), invasive + DCIS, pure DCIS Excluded neoadjuvant therapy Safety data: Phase 1, Feasibility Trial 70 pts injected with LUM015 - no serious adverse events, 1 IV infiltration with blue dye skin staining 3 months 60 pts imaged in vivo with the LUM Imaging Device with no device adverse events Training for multicenter pivotal trial Anaphylactic reaction in 95 th patient to receive LUM015 18

19 Histopathology - Lumicell correlation 8 of 45 patients had positive final margins by histopathology and had intraoperative cavity margin imaging Patient Standard pathology margin Lumicell cavity read Action taken Tumor found in subsequent tissue Result PHB-0016 DCIS <2mm from ink + LUM shave + Saved 2 nd PHB-0039 DCIS <2mm from ink + LUM shave - surgery PHB-0010 IDC on ink - Re-excision - No tumor PHB-0025 DCIS <2mm from ink - Re-excision - found PHB-0037 IDC on ink + Mastectomy + PHB-0023 DCIS <2mm from ink + Re-excision + PHB-0038 ILC on ink + Mastectomy + PHB-0042 DCIS <2mm from ink + Re-excision - Surgeon declined taking shave 19

20 Lumicell Feasibility Trial: Summary 569 cavity margin surface images evaluated Final cavity margin: 100% sensitivity for tumor <2 mm from margin Final + intermediate margins: 84% Sensitivity 73% specificity Readings not affected by breast density or menopausal status Signal observed in some benign tissue including: Macrophages associated with healing biopsy sites Fibrocystic changes with usual ductal hyperplasia and cysts Threshold algorithm revised

21 Lumicell Feasibility Trial: Summary Correctly identified all positive final margins identified by standard histopathology Correctly predicted negative re-excisions in 2 patients with positive lumpectomy margins on standard histopathology 21

22 Factors affecting system performance Time between injection and imaging Minimum time 101 minutes, fine to at least 6 hrs Contact between probe and surface Smaller probe designed: 1.3 and 2.6 cm Extensive tissue necrosis/hematoma Not affected by: Tumor histology, DCIS detected Breast density Menopausal status

23 Lumicell Feasibility Trial: Conclusions The LUM Imaging system showed: % sensitivity for detection of breast cancer <2mm from a margin Very rapid, large diameter image acquisition Can rapidly image entire cavity Cavity wall imaging rather than excised specimen strategy Allows smaller, targeted excision and verifies removal of suspicious sites

24 LUM015 identifies multiple malignancies Breast cancer Multiple sarcoma types Pancreatic cancer Esophageal cancer Under investigation CNS, lung and GYN tumors

25 Tumor H&E Tumor LUM Image Normal Muscle H&E Normal Muscle LUM Image A Tumor H&E Tumor LUM Image Normal Muscle H&E Normal Muscle LUM Image B Histology and Lumicell fluorescence of tumor and normal tissue (A): Human undifferentiated pleomorphic sarcoma thigh (B): myxofibrosarcoma of the thigh REF: Whitley et al. A Mouse-Human Phase 1 Co-Clinical Trial of a Protease-Activated Fluorescent Probe for Imaging Cancer. Science Transl Medi (2016):320ra4.PMC.

26 Next Steps Breast surgery Multicenter Pivotal trial under way - 20 sites Endpoints: positive margins and re-excisions 5-site R01 supported trial Test system after neoadjuvant therapy Refine algorithms for histological subtypes Assess residual tumor after negative LUM reading