Lumicell Direct Visualization System (DVS)

P230014 · Lumicell, Inc. · SAW · Apr 17, 2024 · General, Plastic Surgery

Device Facts

• Record ID: P230014
• Device Name: Lumicell Direct Visualization System (DVS)
• Applicant: Lumicell, Inc.
• Product Code: SAW · General, Plastic Surgery
• Decision Date: Apr 17, 2024
• Decision: APPR
• Device Class: Class 3
• Attributes: AI/ML

AI Performance

Output	Algorithm	Acceptance	Observed	Dev DS	Dev Readers	Test DS	Test Readers
Residual breast cancer detection	Proprietary Patient Calibrated Tumor Detection Software	Lower bound of 95% CI > 3%	7.6% (95% CI: 5.0%, 10.8%)	Phase B Study (n=45) and initial 83 subjects of Phase C Study (Training Set).	—	Pivotal Study CL0007 (NCT03686215): 357 patients.	—
Tissue-level sensitivity	Proprietary Patient Calibrated Tumor Detection Software	Lower bound of 95% CI > 40%	49.1% (95% CI: 36.4%, 61.9%)	Phase B Study (n=45) and initial 83 subjects of Phase C Study (Training Set).	—	Pivotal Study CL0007 (NCT03686215): 357 patients.	—
Tissue-level specificity	Proprietary Patient Calibrated Tumor Detection Software	Lower bound of 95% CI > 60%	86.5% (95% CI: 84.5%, 88.3%)	Phase B Study (n=45) and initial 83 subjects of Phase C Study (Training Set).	—	Pivotal Study CL0007 (NCT03686215): 357 patients.	—

Indications for Use

The combination product consists of an optical imaging agent, LUMISIGHT (pegulicianine) for injection (NDA 214511), and a fluorescence imaging device, the Lumicell Direct Visualization System (DVS). The Lumicell Direct Visualization System is intended for use in adults with breast cancer as an adjunct for the intraoperative detection of cancerous tissue within the resection cavity following removal of the primary specimen during lumpectomy surgery. The Lumicell DVS is used with LUMISIGHT for fluorescence imaging of the lumpectomy cavity.

Device Story

Lumicell DVS is a fluorescence imaging system used as an adjunct to breast-conserving surgery (lumpectomy). The system comprises a workstation and a handheld probe. Patients receive an intravenous injection of the optical imaging agent LUMISIGHT (pegulicianine) 2-6 hours prior to surgery. During the procedure, the surgeon uses the handheld probe to scan the lumpectomy cavity. The probe delivers 630 nm excitation light and captures fluorescence emission (662.5–737.5 nm) from activated LUMISIGHT. Data is processed by the workstation's proprietary Patient Calibrated Tumor Detection Software to highlight suspicious regions on a touchscreen. Surgeons use this real-time visual feedback to guide the removal of additional tissue (LUM-guided shaves) from the cavity. This process aims to detect residual cancer that standard-of-care pathology might miss, potentially reducing the need for second surgeries and improving surgical completeness. The device is operated by surgeons in an operating room setting.

Clinical Evidence

Pivotal study (CL0007) enrolled 357 patients in the treatment arm. Primary endpoints: removal of residual cancer (7.6% success rate, 95% CI: 5.0%-10.8%, meeting >3% goal), tissue-level sensitivity (49.1%, 95% CI: 36.4%-61.9%, did not meet >40% goal), and tissue-level specificity (86.5%, 95% CI: 84.5%-88.3%, met >60% goal). 14.5% of patients with positive margins after standard-of-care surgery were converted to negative margins via LUM-guided shaves. Safety profile included 1.5% hypersensitivity rate (0.6% anaphylaxis) and 90.4% chromaturia.

Technological Characteristics

System consists of a workstation and handheld probe connected via optical fiber. Excitation: 630 ± 5 nm light. Detection: fluorescence emission via 662.5–737.5 nm bandpass filter. Software: proprietary Patient Calibrated Tumor Detection Software. Connectivity: USB data transfer. Sterilization: Reusable handheld probe (validated cleaning/sterilization) and single-use sterile covers.

Indications for Use

Indicated for adults with breast cancer as an adjunct for intraoperative detection of cancerous tissue within the resection cavity following primary specimen removal during lumpectomy. Contraindicated in patients with hypersensitivity to pegulicianine.

Regulatory Classification

Identification

The combination product consists of an optical imaging agent for injection, and a fluorescence imaging device. The product is intended for use in adults with breast cancer as an adjunct for the intraoperative detection of cancerous tissue within the resection cavity following removal of the primary specimen during lumpectomy surgery. The imaging device is used with the imaging drug for fluorescence imaging of the lumpectomy cavity.

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

# I. GENERAL INFORMATION

Device Generic Name: Fluorescence imaging for breast cancer detection

Device Trade Name: Lumicell Direct Visualization System (DVS)

Device Procode: SAW

Applicant's Name and Address: Lumicell, Inc.
275 Washington Street, Suite 200
Newton, MA 02458

Date(s) of Panel Recommendation: N/A

Premarket Approval Application (PMA) Number: P230014

Date of FDA Notice of Approval: April 17, 2024

Breakthrough Device: Granted breakthrough device status on March 28, 2018, because the device meets the Breakthrough criteria. The Lumicell DVS is indicated for use in patients undergoing a breast conserving surgery (lumpectomy) to remove breast cancer. The Lumicell DVS is intended to be used whenever breast tissue is removed, histopathology evaluation of the tissue is the standard of care and/or it is essential that the tissue margins be examined for completeness of removal using standard surgical procedures. The Lumicell DVS is to be used in vivo following the excision of the main lumpectomy specimen to assist in locating residual abnormal tissue.

# II. INDICATIONS FOR USE

The combination product consists of an optical imaging agent, LUMISIGHT (pegulicianine) for injection (NDA 214511), and a fluorescence imaging device, the Lumicell Direct Visualization System (DVS). The Lumicell Direct Visualization System is intended for use in adults with breast cancer as an adjunct for the intraoperative detection of cancerous tissue within the resection cavity following removal of the primary specimen during lumpectomy surgery.

The Lumicell DVS is used with LUMISIGHT for fluorescence imaging of the lumpectomy cavity.

LUMISIGHT Indications for Use: LUMISIGHT is an optical imaging agent indicated for fluorescence imaging in adults with breast cancer as an adjunct for the intraoperative detection of

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cancerous tissue within the resection cavity following removal of the primary specimen during lumpectomy surgery.

## III. CONTRAINDICATIONS

There are no known contraindications for the Lumicell DVS. LUMISIGHT is contraindicated in patients with a history of hypersensitivity reaction to pegulicianine. Reactions have included anaphylaxis. Refer to LUMISIGHT's Prescribing Information for full safety information.

## IV. WARNINGS AND PRECAUTIONS

The warnings and precautions for the Lumicell DVS can be found in the Lumicell DVS Instructions for Use. The warnings and precautions for LUMISIGHT (pegulicianine) for injection can be found in the LUMISIGHT Prescribing Information (PI) (refer to NDA 214511, and Appendix I).

## V. DEVICE DESCRIPTION

LUMISIGHT and Lumicell Direct Visualization System is a combination product indicated as an adjunct for the intraoperative detection of cancerous tissue within the resection cavity following removal of the primary specimen during lumpectomy surgery and consists of:

- Device constituent: Lumicell Direct Visualization System (DVS) fluorescence imaging device
- Drug constituent: LUMISIGHT (pegulicianine) for injection optical imaging agent

LUMISIGHT is provided as a sterile, dark blue lyophilized powder in a clear vial which contains 40 mg of pegulicianine, 39.5 mg of mannitol, 3.8 mg of monobasic sodium phosphate monohydrate and 3.2 mg of dibasic sodium phosphate heptahydrate. Please refer to the LUMISIGHT Prescribing Information for details.

The Lumicell Direct Visualization System (DVS) consists of a Workstation and a Handheld Probe (Figure 1). The Handheld Probe connects to the Workstation's Light Source via an optical fiber cable. These components are used together to excite the optical imaging agent, LUMISIGHT, and capture and display real-time fluorescence images. During surgery, the Handheld Probe is used to scan the lumpectomy cavity for activated LUMISIGHT by delivering 630 ± 5 nm excitation light and measuring the fluorescence emission signal using a camera after filtering through a 662.5 – 737.5 nm bandpass filter. The resulting data is transferred to the Workstation's Touchscreen via USB cable. The data is analyzed in real-time via Lumicell's proprietary Patient Calibrated Tumor Detection Software to highlight regions within the lumpectomy cavity that are suspicious of containing residual cancer.

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The Lumicell DVS will be packaged and sold separately from LUMISIGHT. Each will be co-labeled with instructions for the use of the drug and device constituents to combination usage.

Figure 1. Lumicell Direct Visualization System (DVS). Left: Workstation, right: Handheld Probe with cables


# A. Changes Between the Clinical and Commercial Product

There were some changes implemented to the Lumicell DVS between the pivotal study and commercial versions. The changes were primarily for manufacturability, usability, and sterilizability of the hand-held probe. There were no changes to the device principles of operation or performance. Key device changes are noted in Table 1 below.

Table 1. Key Changes between Clinical Study Device and Commercial Device

| Probe and Cable | Enclosure improved, no changes to optics or performance |
| --- | --- |
| Sterile Cover | Added second layer, changed to rolled configuration with applicator |
| Computer | Changed to medical grade all-in-one touchscreen computer |
| Software | Improved user interface, no change to image analysis algorithm |

Results from system-level equivalence testing show that all key performance parameters were within specification. Equivalency testing included fluorescence detection sensitivity, signal linearity, field of view, magnification, distortion, spatial resolution, depth of field, signal uniformity, and excitation light crosstalk. All results met prespecified acceptance criteria and it was concluded that optical performance between the clinical study and commercial versions of the Lumicell DVS were equivalent.

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VI. ALTERNATIVE PRACTICES AND PROCEDURES

Currently, no FDA-approved intraoperative technology is available that directly examines the lumpectomy cavity for residual cancer after the main specimen is removed in Breast-Conserving Surgery (BCS; partial removal of breast tissue or lumpectomy). Moreover, no in-vivo imaging products or modalities are available to assist breast cancer surgeons in examining the lumpectomy cavity for a signal of residual cancer, which would facilitate excision of cancer that remains in-situ during and after the initial surgery. One available technology uses radiofrequency spectroscopy intraoperatively, but it is used to examine the excised specimen, which can present challenges translating the suspected location containing cancer from the excised specimen to the corresponding location within the cavity. There are multiple alternative intraoperative breast cancer diagnosis options, including specimen X-ray, intraoperative sonography, etc. There are several non-intraoperative alternatives for breast cancer diagnosis, including clinical breast examination, mammography, color and power Doppler, strain and shear wave elastography, magnetic resonance imaging, and molecular breast imaging. There is an alternative breast cancer surgical intervention - removal of the entire breast (mastectomy). Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

VII. MARKETING HISTORY

LUMISIGHT and Lumicell DVS have not previously been marketed in the United States or any foreign country.

VIII. POTENTIAL ADVERSE EFFECTS OF THE COMBINATION PRODUCT ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of LUMISIGHT and the Lumicell DVS.

Serious hypersensitivity reactions, including anaphylaxis, have been reported following administration of LUMISIGHT (see the Boxed Warning and the Warnings and Precautions in the LUMISIGHT Prescribing Information in the Appendix).

Adverse reactions occurring in ≥ 1% of patients receiving LUMISIGHT were hypersensitivity (1.4%, including anaphylaxis [4 out of 726]) and chromaturia 85%). Chromaturia resolved within 48 hours after administration in 93% of patients, with the longest time to resolution of 15 days.

Adverse reactions occurring in < 1% of patients were skin discoloration after extravasation, nausea, dyspnea, pyrexia, and vomiting.

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Patients should be informed that if extravasation of LUMISIGHT occurs, it may result in blue discoloration of the skin at the injection site that will be evident for several weeks.

No serious adverse device effects have been observed to date in any of the clinical trials using the Lumicell DVS. While not related to the Lumicell DVS, common surgical-related adverse events are anticipated. These may include but are not limited to surgery site infection, seroma, hematoma, and delayed wound healing. These events are anticipated to occur at an equivalent rate to standard of care surgery.

For the specific adverse events that occurred in the clinical studies, please see Section X below.

## IX. SUMMARY OF NONCLINICAL STUDIES

### A. System Level Testing

System level testing was done for: hardware safety, electromagnetic compatibility (EMC), software and hardware verification & validation, cleaning, packaging and shipping validation, usability, performance equivalency between clinical and commercial systems, and biocompatibility. Testing for the system ensured that the Lumicell DVS met established specifications for the planned commercial product. These tests are summarized in Table 2.

Table 2: Summary of system-level testing

| Test | Purpose | Method | Result |
| --- | --- | --- | --- |
| Hardware Safety Test | Test basic safety and essential performance of medical electrical equipment with endoscopic functionality and a light source | According to ANSI AAMI ES60601-1:2005/(R)2012 & A1:2012, C1:2009/(R)2012 & A2:2010/(R)2012 (Cons. Text) Medical electrical equipment - Part 1: General requirements for basic safety and essential performance
IEC 60601-2-18 Ed. 3.0 b:2009 Medical electrical equipment - Part 2-18: Particular requirements for the basic safety and essential performance of endoscopic equipment
IEC 60601-2-57 Ed. 1.0 b:2011 Medical electrical equipment - Part 2-57: Particular requirements for the basic safety and essential performance of non-laser light source equipment intended for therapeutic, diagnostic, monitoring and cosmetic/aesthetic use | Passed |
| EMC Test | Test for Electromagnetic Compatibility | IEC 60601-1-2 Ed. 4.1 b:2020 Medical electrical equipment - Part 1-2: General requirements for basic safety and essential performance - Collateral Standard: Electromagnetic disturbances - Requirements and tests, and related standards | Passed |

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| Test | Purpose | Method | Result |
| --- | --- | --- | --- |
| Software Verification & Validation | Test software unit and system level performance and accuracy, and ensure cybersecurity | IEC 62304 Ed. 1.1 b:2015 General Principles of Software Validation Guidance for Industry and Food and Drug Administration Staff (January 11, 2002)
Off-The-Shelf Software Use in Medical Devices Guidance for Industry and Food and Drug Administration Staff (September 27, 2019)
Content of Premarket Submissions for Management of Cybersecurity in Medical Devices Guidance for Industry and Food and Drug Administration Staff (October 2, 2014)
Guidance for Industry and Food and Drug Administration Staff (October 2, 2014) | Passed |
| Hardware Verification | Ensure system meets requirements | Verification tests were conducted on the system’s hardware to verify that system meets design requirements | Passed |
| Cleaning- Imaging Station | Test cleanability of Imaging Station | Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling Guidance for Industry and Food and Drug Administration Staff (March 17, 2015)
Guidance for Industry and Food and Drug Administration Staff (March 17, 2015)
AAMI TIR30:2011/(R)2016
A compendium of processes, materials, test methods, and acceptance criteria for cleaning reusable medical devices | Passed |
| Packaging and Shipping-Imaging Station | Test that packaging configuration maintains the integrity of the package and product during handling and transportation. | ASTM D4169-22 Standard Practice for Performance Testing of Shipping Containers and Systems
ASTM F2825-18: Climatic Stressing of Packaging Systems for Single Parcel Delivery | Passed |
| Usability | Test usability of system | Applying Human Factors and Usability Engineering to Medical Devices Guidance for Industry and Food and Drug Administration Staff (February 3, 2016)
IEC 62366-1 Ed. 1.1 b:2020 Medical devices - Part 1: Application of usability engineering to medical devices | Passed |
| System Equivalence | To ensure that the optical performance of the Clinical and Commercial versions perform the same | Tests for sensitivity, signal linearity, field of view, magnification, distortion, spatial resolution, depth of field, signal uniformity, and excitation light crosstalk must meet prespecified acceptance criteria | Passed |

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| Test | Purpose | Method | Result |
| --- | --- | --- | --- |
| Software Equivalence | To ensure that the Clinical and Commercial software versions perform the same | Pivotal study images analyzed by both versions should have same results | Passed |
| Biocompatibility-Lumicell DVS | Assess biocompatibility at the system level | Use of International Standard ISO 10993-1 "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" Guidance for Industry and Food and Drug Administration Staff (September 4, 2020)
ISO 10993-1:2018 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process | Passed |

## B. Component Testing

Component testing included biocompatibility, sterilization, reusability, packaging, and shipping for various components of the Lumicell DVS. Testing for components ensured that they met established specifications for the planned commercial product. These tests are summarized in Table 3.

Table 3: Summary of component testing

| Test | Purpose | Method | Result |
| --- | --- | --- | --- |
| Biocompatibility-Sterile Cover | Test biocompatibility | Use of International Standard ISO 10993-1 "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" Guidance for Industry and Food and Drug Administration Staff (September 4, 2020)
ISO 10993-1:2018 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process
ISO 10993-5:2009 Biological evaluation of medical devices - Part 5: Tests for in vitro cytotoxicity
ISO 10993-10:2021 Biological evaluation of medical devices - Part 10: Tests for skin sensitization
ISO 10993-11:2017 Biological evaluation of medical devices - Part 11: Tests for systemic toxicity
ISO 10993-12:2012 Biological evaluation of medical devices - Part 12: Sample Preparation | Passed |

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| Test | Purpose | Method | Result |
| --- | --- | --- | --- |
| Sterilization-Sterile Cover and Calibration Plate | Validation of sterilization process | ISO 11135:2014+A1:2019 Sterilization of health-care products-Ethylene oxide-Requirements for the development, validation and routine control of a sterilization process for medical devices
ISO 10993-7:2008 Biological Evaluation of medical devices- Part 7: Ethylene oxide residuals | Passed |
| Packaging, Shipping, and Shelf Life-Sterile Cover and Calibration Plate | Test that packaging configuration maintains the sterility of the product, and integrity of the package and product during handling and transportation over its shelf life | ISO 11607-1:2019 Packaging for Terminally Sterilized Devices, Parts 1 and 2
ASTM D4332-14 Standard Practice for Conditioning Containers, Packages, or Packaging Components
ASTM F1886-16 Standard Test Method for Determining Integrity of Seals for Flexible Packaging by Visual Inspection
ASTM F2096-19 Standard Test Method For Detecting Gross Leaks In Medical Packaging By Internal Pressurization (Bubble Test) | Passed |
| Cleaning-Handheld Probe and Sterilization Tray | Validate cleaning instructions for Handheld Probe and Sterilization Tray | Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling
Guidance for Industry and Food and Drug Administration Staff (March 17, 2015)
AAMI TIR30:2011/(R)2016 (Handheld Probe)
ANSI/AAMI ST98:2022 (Sterilization Tray)
A compendium of processes, materials, test methods, and acceptance criteria for cleaning reusable medical devices | Passed |
| Sterilization-Handheld Probe and Sterilization Tray | Validate sterilization instructions for Handheld Probe and Sterilization Tray | ISO 14937 (2009): Sterilization of Health Care Products – General Requirements for Characterization of a Sterilizing Agent and the Development, Validation and Routine Control of a Sterilization Process for Medical Devices
7.2 AAMI TIR No. 12-2020: Designing, Testing, and Labeling Reusable Medical Devices for Reprocessing in Health Care Facilities: A Guide for Medical Device Manufacturers | Passed |
| Reuse-Handheld Probe | Test failures of reuse to inform labeling | Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling
Guidance for Industry and Food and Drug Administration Staff (March 17, 2015)
ISO 17664-1:2021 Processing of health care products - Information to be provided by the medical device | Passed |

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| Test | Purpose | Method | Result |
| --- | --- | --- | --- |
| | | manufacturer for the processing of medical devices – Parts 1 and 2 | |
| Packaging and Shipping-Handheld Probe | Test that packaging configuration maintains the integrity of the package and product during handling and transportation. | ASTM D4169-16 Standard Practice for Performance Testing of Shipping Containers and Systems
ASTM F2825-18: Climatic Stressing of Packaging Systems for Single Parcel Delivery | Passed |
| Packaging and Shipping- Light Source | Test that packaging configuration maintains the integrity of the package and product during handling and transportation. | ASTM D4169-16 Standard Practice for Performance Testing of Shipping Containers and Systems
ASTM F2825-18: Climatic Stressing of Packaging Systems for Single Parcel Delivery | Passed |

## C. Animal Studies

Early in the development of LUMISIGHT and the Lumicell DVS, animal studies were conducted. These studies are summarized in Table 4.

Table 4: Summary of animal studies

| Study | Purpose | Result |
| --- | --- | --- |
| Proof-of-Concept Studies in Mouse Models for Cancer | Studied LUMISIGHT labeling of tumors | Demonstrated residual fluorescence within tumor bed |
| Proof-of-Concept Studies in Dog Patients | Studied LUMISIGHT with prototype Lumicell DVS for imaging in dogs with cancer | Correctly distinguished cancer from normal tissue in 92% of biopsies |

## X. SUMMARY OF PRIMARY CLINICAL STUDIES

The Applicant performed a pivotal clinical study (CL0007) in the US to establish a reasonable assurance of safety and effectiveness of LUMISIGHT and Lumicell DVS for use in patients with breast cancer as an adjunct for the intraoperative detection of cancerous tissue within the resection cavity following removal of the primary specimen during lumpectomy surgery (NCT03686215). Data from this pivotal/PMA clinical study is presented below.

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Additionally, a multicenter feasibility study was conducted (termed Phase C Study or CL0006) and is included as a supporting study for the evaluation of safety and effectiveness of LUMISIGHT and the Lumicell DVS (IDE G140195, NCT03321929).

Safety evaluations of LUMISIGHT for these two studies are presented in Section X.D.1 and XI.1, respectively. An overall safety assessment was also conducted in all breast cancer patients and all cancer patients treated across multiple indications from other ongoing and completed clinical studies and is presented in Section XI.2. The safety information of the drug use is analyzed based on all the patients in these trials.

## Pivotal Study (CL0007)

### A. Study Design

Patients were enrolled between 04 November 2019 and 15 September 2021. The database for this PMA reflected data collected through 15 September 2021 and included 406 patients. There were 14 investigational sites in the United States.

The Pivotal Study was a multicenter, two-arm, randomized, study designed to demonstrate the safety and effectiveness of LUMISIGHT and the Lumicell DVS in identifying residual cancer in the lumpectomy cavity of female patients with breast cancer. Eligible patients consented to participate in the study with histologically or cytologically confirmed primary invasive breast cancer, ductal carcinoma in situ (DCIS), or primary invasive breast cancer with a DCIS component.

Prior to randomization, all patients were injected with LUMISIGHT at a dose of 1 mg/kg 2-6 hours prior to the recording of any image. Upon completion of the standard of care (SoC) BCS, it was revealed whether the patient was randomized into the treatment arm or the control arm. In the treatment arm, the surgeon used the Lumicell DVS to scan the lumpectomy cavity to identify and remove regions suspicious of containing residual cancer (a maximum of 2 Lumicell DVS-guided (or LUM-guided) shaves per lumpectomy cavity orientation). In the control arm, the surgeon did not use the Lumicell DVS to guide additional resection of tissue. Randomization to study arms was performed at a ratio of 10:1; that is, on average for every 10 patients randomized to the Lumicell DVS arm, one patient was randomized to the control arm. The control group was included with the intent of reducing potential bias from surgeons that could arise if surgeons knew that the Lumicell DVS was going to be used in all patients. The control arm was not used to compare results with the treatment arm. Also, because the Lumicell DVS is used after the surgeon completes their SoC BCS in the treatment arm, the patients serve as their own control.

All clinical staff were informed whether the patient was randomized to the treatment or control arm after the surgeon completed the planned SoC BCS. Pathologists were blinded to whether the shave undergoing histopathology examination was an SoC shave or a LUM-guided shave.

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The Pivotal study was statistically powered for the three coprimary effectiveness endpoints: removal of residual cancer, tissue-level sensitivity, and tissue-level specificity. For the primary endpoint of the proportion of patients with residual cancer removed in at least one LUM-guided shave, success was declared if the lower bound of the 95% confidence interval (CI) of this proportion was greater than 3%. For the primary endpoints of tissue-level sensitivity and specificity, success was declared if the lower bound of the 95% CI for tissue-level sensitivity was greater than the performance goal of 40%, and if the lower bound of the 95% CI for tissue-level specificity was greater than the performance goal of 60%. All of the three primary endpoints were tested at a one-sided significance level of 2.5%. For further information regarding the clinical endpoints see Section 3 below.

Patients were enrolled until approximately 70 truth standard positive events were reported to achieve the desired statistical power, up to a maximum of 450 patients. The number of truth standard positive events were counted based on the truth standard hierarchical approach.

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the Pivotal Study was limited to patients who met the following inclusion criteria:

- Female, 18 years or older with histologically or cytologically confirmed primary invasive breast cancer, ductal carcinoma in situ (DCIS), or primary invasive breast cancer with a DCIS component
- Patients were scheduled for a lumpectomy for a breast malignancy
- Patients were able and willing to follow study procedures and instructions
- Patients received and signed an informed consent form
- Patients had no uncontrolled serious medical problems except for the diagnosis of breast cancer
- Patients had organ and marrow function within limits as defined below:
- Leukocytes > 3,000/mcL
- Platelets > 75,000/mcL
- Total bilirubin within normal institutional limits
- AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal
- Creatinine ≤ 1.5 mg/dL or creatinine clearance > 60 mL/min/1.73 m² for patients with creatinine levels above institutional normal
- Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Patients were not permitted to enroll in the Pivotal Study if they met any of the following exclusion criteria:

- Patients who had been diagnosed with bilateral breast cancer and were undergoing a bilateral resection procedure
- Patients who were pregnant at the time of diagnosis of their breast cancer; this exclusion is necessary because the teratogenic properties of LUMISIGHT are unknown. Because there is an unknown but potential risk of AEs in nursing infants secondary to treatment

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of the mother with LUMISIGHT, breastfeeding should be discontinued if the mother is treated with LUMISIGHT

- Patients who were sexually active and not willing/able to use two medically acceptable forms of contraception (hormonal, barrier method of birth control, abstinence) upon entering the study and for 60 days after injection of LUMISIGHT. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Breast cancer patients are routinely advised against becoming pregnant during treatment, so this requirement does not differ from SoC
- Patients who had taken an investigational drug within 30 days of enrollment
- Patients who had administration of methylene blue or any dye for sentinel lymph node mapping on the day of the surgery prior to imaging the lumpectomy cavity with the Lumicell DVS
- Patients who had not recovered from AEs due to other pharmaceutical or diagnostic agents
- Patients with uncontrolled hypertension defined as persistent systolic blood pressure > 180 mm Hg, or diastolic blood pressure > 110 mm Hg; those patients with known hypertension should be stable with controlled hypertension while under pharmaceutical therapy
- History of allergic reaction to polyethylene glycol (PEG)
- History of allergic reaction to any oral or intravenous contrast agents
- Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, chronic obstructive pulmonary disease or asthma requiring hospitalization within the past 12 months, or psychiatric illness/social situations that would limit compliance with study requirements
- HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with LUMISIGHT
- Any patient for whom the investigator feels participation is not in the best interest of the patient
- Patients undergoing a second lumpectomy procedure because of positive margins in a previous surgery prior to entering the Pivotal Study
- Patients with post-biopsy hematomas greater or equal to 2 cm that are visible on physical exam or detected during pre-operative observations
- Patients with prior ipsilateral breast cancer surgeries, mastectomies, breast reconstructions, or implants
- Patients with prior ipsilateral reduction mammoplasties (breast reductions) performed less than 2 years prior to enrollment to this study

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- Patients previously treated with systemic therapies to treat the cancer to be removed during this clinical investigation, such as neo-adjuvant chemotherapy or hormonal therapy
- Patients undergoing BCS whose resected specimen (main lump, shaves, or any other resected tissue) will be evaluated with frozen section after the Lumicell DVS-guided removal of shaves.

# 2. Study Procedure and Follow-up Schedule

The study procedure and surgical workflow is depicted in Figure 2 below.

Eligible patients consenting to participate in the study were injected with LUMISIGHT at a dose of $1.0\mathrm{mg / kg}$ 2-6 hours prior to the recording of any image.

Figure 2. Study Procedure Workflow

Once the SoC BCS procedure was completed, it was revealed whether the patient was randomized into the treatment arm or the control arm as below:

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- LUM Imaging Device Arm (or treatment arm): Patients who received $1\mathrm{mg/kg}$ LUMISIGHT, completed SoC BCS and had their lumpectomy cavity imaged with the Lumicell DVS for additional image-guided tissue (LUM-guided shaves)
- Control Arm: Patients who received $1\mathrm{mg/kg}$ LUMISIGHT, completed SoC BCS and had no Lumicell DVS imaging of the lumpectomy cavity.

After surgery was completed for patients in both the LUM Imaging Device Arm and the Control Arm, all resected specimens were sent to the pathology laboratory at each site for margin assessment per SoC.

All patients were observed for safety assessments of LUMISIGHT with standard preoperative, intraoperative, and postoperative monitoring after administration of the LUMISIGHT injection. Patients had a final safety assessment at their first postoperative visit. Final safety assessments for AEs and clinical laboratory evaluations were performed for all patients at the routine (first) postoperative visit as shown in the schedule of events (Table 5). All enrolled patients were followed in the study until their medical team determined that no further surgical intervention was required, and their postoperative follow-up and postoperative blood sample had been completed or until resolution of any reported AE related to the study intervention.

All study visits and assessments are summarized in Table 5.

Table 5. Schedule of Events for Study Visits and Assessments

| | Pre-Enrollment / Screening | Day 1 / Enrollment | ~2 - 14 Days After Surgery | Routine Follow-up Visit | 3-Month PROM Survey Collection | 6-Month PROM Survey Collection |
| --- | --- | --- | --- | --- | --- | --- |
| Informed consent | X | | | | | |
| Medical history | X | | | | | |
| Radiologic evaluationa | X | | | | | |
| Physical exam (Ht, Wt, VS) | X | | | | | |
| Pregnancy test (serum or urine) | Xb | | | | | |
| CBC with differentials | X | | | X | | |
| Serum chemistryc | X | | | X | | |
| Concomitant medications | X | X | | X | | |

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| | Pre-Enrollment / Screening | Day 1 / Enrollment | ~2 - 14 Days After Surgery | Routine Follow-up Visit | 3-Month PROM Survey Collection | 6-Month PROM Survey Collection |
| --- | --- | --- | --- | --- | --- | --- |
| Adverse event/adverse device effect evaluation | | X | | X | | |
| Patient Reported Outcome Measures Survey^{d} | | X^{d} | | X | X | X |
| LUMISIGHT administration | | X | | | | |
| Randomization | | X | | | | |
| Intraoperative imaging^{e} | | X | | | | |
| Margin assessment | | | X | | | |

Abbreviations: CBC = complete blood count; Ht = height; PROM = Patient Reported Outcome Measure; VS = vital signs; Wt = weight

a Radiologic evaluations are not required if not part of the patient’s medical history
b Serum or urine pregnancy test (women of childbearing potential).
c Albumin, alkaline phosphatase, total bilirubin, blood urea nitrogen, calcium, chloride, glucose, potassium, total protein, aspartate transaminase (AST/SGOT), alanine transaminase (ALT/ SGPT), sodium and creatinine/creatinine clearance
d PROMs were optional for enrollment. The Baseline evaluation could be completed by the patient at any time prior to the lumpectomy procedure. A validated survey tool, the Breast-Q, was used to collect the majority of the PROMs.
e If patient is randomized into the Device Arm.

3. Clinical Endpoints

Safety Endpoints

To provide evidence of safety for LUMISIGHT and the Lumicell DVS, adverse events (AEs) and serious adverse events (SAEs) stratified by severity and relatedness to drug/device were evaluated.

Primary Effectiveness Endpoints

To provide evidence of effectiveness, three co-primary endpoints were used in the Pivotal Study:

- Removal of Residual Cancer: the proportion of patients who have residual cancer found in at least one LUM-guided shave

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- Diagnostic performance measure of tissue-level sensitivity
- Diagnostic performance measure of tissue-level specificity

The Pivotal Study performance goal criteria for all three primary effectiveness endpoints were as follows:

- Removal of Residual Cancer: the performance goal selection for this endpoint was pre-specified as greater than 3% for the lower bound of the 95% CI of this proportion
- Tissue-level sensitivity: the performance goal was pre-specified at greater than 40% for the lower bound of the 95% CI of the tissue-level sensitivity
- Tissue-level specificity: the performance goal was prespecified greater than 60% for the lower bound of the 95% CI of the tissue-level specificity

## B. Accountability of PMA Cohort

At the time of database lock, 406 patients had enrolled in the PMA study and received a single intravenous dose of LUMISIGHT. A total of 392 patients were randomized to either the LUM Imaging Device Arm (n = 357) or Control Arm (n = 35). Fourteen (14) patients were withdrawn from the study after injection of LUMISIGHT but before randomization (Figure 3).

The evaluation of effectiveness was based on the 357 patients randomized to the LUM Imaging Device and the primary analysis set was the modified intent-to-treat (mITT) Population comprising all patients who completed the study procedure (n = 357). Evaluation of safety included all patients that were injected with LUMISIGHT (n = 406).

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Figure 3. Pivotal Study Accountability Tree
*Withdrawals were due to adverse events (n = 7), device system issues (n = 2), physician decision (n = 1), protocol deviations (n = 4).

# C. Study Population Demographics and Baseline Parameters

Patient demographic characteristics are presented in Table 6; and the tumor characteristics are presented in Table 7.

Overall, demographic characteristics data of the enrolled populations were representative of the US population of newly diagnosed patients with breast cancer. The distribution of age, sex, race, ethnicity, and the calculated body mass index (BMI) were found to be very similar between the study populations.

Table 6. Study Population Disposition and Demographics

| Characteristics | LUMISIGHT Injected (Safety Analysis Population) (N = 406) | Modified Intent-to-Treat Population (N = 357) | Control Group (N = 35) |
| --- | --- | --- | --- |
| Sex | | | |
| Female | 406 100.0% | 357 100.0% | 35 (100.0%) |
| Age (years) | | | |
| Mean ± SD (N) | 62.3 ± 9.7 (406) | 62.4 ± 9.6 (357) | 61.6 ± 9.9 (35) |
| Median (Q1, Q3) | 64.0 (56.0, 70.0) | 64.0 (57.0, 70.0) | 62.0 (54.0, 70.0) |
| Range (Min, Max) | (36.0, 83.0) | (36.0, 83.0) | (37.0, 82.0) |

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| Characteristics | LUMISIGHT Injected (Safety Analysis Population) (N = 406) | Modified Intent-to-Treat Population (N = 357) | Control Group (N = 35) |
| --- | --- | --- | --- |
| Race n (%) | | | |
| American Indian or Alaska Native | 1 0.2% | 0 | 1 (2.9%) |
| Asian | 22 (5.4%) | 21 (5.9%) | 1 (2.9%) |
| Black or African American | 26 (6.4%) | 22 (6.2%) | 4 (11.4%) |
| Native Hawaiian or Pacific Islander | 1 0.2% | 1 0.3% | 0 |
| White | 337 83.0% | 297 83.2% | 27 (77.1%) |
| Other | 4 1.0% | 4 1.1% | 0 |
| Unknown or not reported | 15 (3.7%) | 12 (3.4%) | 2 (5.7%) |
| Ethnicity n (%) | | | |
| Hispanic or Latino | 12 (3.0%) | 11 (3.1%) | 1 (2.9%) |
| Non-Hispanic or Latino | 383 94.3% | 336 94.1% | 34 97.1%) |
| Unknown or not reported | 11 (2.7%) | 10 (2.8%) | 0 |
| Body Mass Index (kg/m2) | | | |
| Mean ± SD (N) | 29.9 ± 6.6 (405) | 29.8 ± 6.7 (356) | 31.0 ± 5.9 (35) |
| Median (Q1, Q3) | 29.4 (25.0, 33.8) | 29.2 (25.0, 33.3) | 30.8 (26.1, 36.0) |
| Range (Min, Max) | (16.8, 67.4) | (16.8, 67.4) | (20.0, 42.5) |

Abbreviations: Max = maximum; Min = minimum; Q = quartile; SD = standard deviation

Table 7. Baseline Clinicopathological Findings: Tumor Histology and Receptor Status from Biopsy or Main Specimen

| Characteristics | Safety Analysis Population (N = 406) | Modified Intent-to-Treat Population (N = 357) | Control Population (N = 35) |
| --- | --- | --- | --- |
| Largest Dimension of Tumor in Main Specimen (cm) | | | |
| Mean ± SD (N) | 1.8 ± 1.4 (378) | 1.7 ± 1.3 (344) | 2.2 ± 1.5 (34) |
| Median (Q1, Q3) | 1.5 (0.9,2.2) | 1.5 (0.9,2.1) | 1.9 (1.0,3.1) |
| Range (Min, Max) | (0.1,10.1) | (0.1,10.1) | (0.4,8.3) |
| Tumor Histology (Biopsy and/or Main Lumpectomy Specimen) | | | |

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| Characteristics | Safety Analysis Population (N = 406) | Modified Intent-to-Treat Population (N = 357) | Control Population (N = 35) |
| --- | --- | --- | --- |
| DCIS Only | 78 (19.2%) | 70 (19.6%) | 6 (17.1%) |
| IDC ± DCIS | 284 70.0% | 249 69.7% | 25 71.4%) |
| ILC ± DCIS | 41 (10.1%) | 35 (9.8%) | 4 (11.4%) |
| IDC + ILC | 3 (0.7%) | 3 0.8% | 0 |
| Receptor Status | | | |
| ER (+) | 378 93.1% | 335 93.8% | 30 (85.7%) |
| PR (+) | 311 76.6% | 272 76.2% | 28 (80.0%) |
| HER2 (+) | 23 (5.7%) | 20 (5.6%) | 3 8.6% |
| Triple Negative | | | |
| Yes | 15 (3.7%) | 11 (3.1%) | 3 8.6% |
| No | 391 96.3% | 346 96.9% | 32 (91.4%) |
| Unknown | 0 | 0 | 0 |
| Lymph Nodes | | | |
| Lymph Node (+) | 10 (2.5%) | 9 2.5% | 1 2.9% |
| Lymph Node (-) | 60 (14.8%) | 51 (14.3%) | 7 (20.0%) |
| No Lymph Node Biopsy | 336 82.8% | 297 83.2% | 27 (77.1%) |

Abbreviations: DCIS = ductal carcinoma in situ; ER = estrogen receptors; HER2 = human epidermal growth factor receptor 2; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; Max = maximum; Min = minimum; PR = progesterone receptor; Q = quartile

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of safety was based on the cohort of 406 patients that received an intravenous dose of 1 mg/kg LUMISIGHT. The key safety outcomes for the study are presented below. Adverse event (AE) data are reported in Table 8.

### Adverse Events

A total of 596 AEs were reported in 406 patients in the safety population with 395 AEs reported as related to LUMISIGHT. There were no device related adverse events reported.

Of the 395 AEs related to LUMISIGHT, the most common AE was chromaturia (abnormal color of urine) at an incidence rate of 90.4% (367 of 406 patients). Chromaturia was an expected AE

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due to the blue color of the LUMISIGHT injection solution and resolved between 24 and 48 hours after administration in over 92% of the patients; the longest time for resolution was six days.

Other than chromaturia, 23 patients experienced 28 AEs related to LUMISIGHT, with no event that was determined to be related to the intervention having an incidence rate of more than 1.0%. All AEs for all patients resolved during the study.

No deaths and no unexpected severe events related to LUMISIGHT were reported. No serious or nonserious unanticipated adverse device effects (UADE) were observed in the study.

The second most common adverse reaction was hypersensitivity, occurring in six patients (approximately 1.5%; Table 8). This included one patient who experienced anaphylaxis.

Table 8. Summary of Adverse Reactions by Preferred Term

| Adverse Event Preferred Terma | Patients (%)
(N = 406) |
| --- | --- |
| Chromaturia | 367 90.4% |
| Hypersensitivity | 6 (1.5%) |
| Nausea | 2 (0.5%) |
| Dysgeusia | 1 (0.2%) |
| Dyspnea | 1 (0.2%) |
| Pyrexia | 1 (0.2%) |
| Skin discoloration after extravasation | 1 (0.2%) |
| Vomiting | 1 (0.2%) |

Note: Patients with multiple events in the same category are counted only once in that category.
aMedDRA Version 22.1

## 2. Effectiveness Results

The analysis of effectiveness was based on the 357 evaluable patients in the mITT Population who completed the study. Key effectiveness outcomes are presented in Table 9 to Table 12.

## Primary Endpoint Analysis

### Removal of Residual Cancer

LUMISIGHT and the Lumicell DVS demonstrated success in detecting residual cancer and guiding the removal of the cancerous tissue that would have otherwise remained undetected after SoC BCS in 27 patients (7.6%) in the mITT Population.

- A total of 27 of 357 patients had residual cancer found in at least one LUM-guided shave in the mITT Population (7.6%; 95% CI: 5.0%, 10.8%). The performance goal for the primary endpoint, Removal of Residual Cancer, was met for the LUMISIGHT and

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Lumicell DVS with a lower bound CI of 5.0%, which was greater than the pre-set performance goal of 3% (Table 9).

## Tissue-level Sensitivity and Tissue-level Specificity

The diagnostic performance endpoints of the Lumicell DVS were as follows:

- Tissue-level sensitivity was 49.1% (34 out of 69 truth standard positives; 95% CI: 36.4%, 61.9%)
- Tissue-level specificity was 86.5% (1,940 out of 2,277 truth standard negatives; 95% CI: 84.5%, 88.3%).

The tissue-level sensitivity endpoint did not meet the pre-set performance goal of 40% by 3.6 percentage points at the lower bound of the 95% CI (i.e., 36.4%). The tissue-level specificity endpoint successfully met the pre-set performance goal of 60% by 24.5 percentage points at the lower bound of the 95% CI (i.e., 84.5%). Sensitivity and specificity results were calculated using the generalized estimating equation [GEE] method to account for within-patient correlations (Table 9).

Table 9. Primary Effectiveness Endpoint Results (Pivotal Study)

| Primary Effectiveness Endpoints | Performance Goal (Lower Bound of 95% Confidence Interval) | Results |
| --- | --- | --- |
| Removal of Residual Cancer: Proportion of patients who have residual cancer found in at least one LUM-guided shave among all patients in the LUM Imaging Device Arm (patient-level) | > 3% | 27/357
7.6%
95% CI: 5.0%, 10.8% |
| Tissue-level Sensitivity (GEE method^{a}) | > 40% | 34/69
49.1%
95% CI: 36.4%, 61.9% |
| Tissue-level Specificity (GEE method^{a}) | > 60% | 1,940/2,277
86.5%
95% CI: 84.5%, 88.3% |

Abbreviations: CI = confidence interval; GEE = generalized estimating equations; LUM-guided shaves = Lumicell DVS guided shaves
aGEE method was used to calculate sensitivity and specificity to account for within-patient correlations.

## Other Endpoint Analysis: Secondary Effectiveness Endpoints

A series of secondary effectiveness endpoints were analyzed in the Pivotal Study/PMA clinical study related to meaningful clinical impact. The results of these analyses are presented in Table 10 to Table 12.

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Table 10. Detection and Conversion of Positive Standard of Care Margin by the Lumicell DVS

| | mITT Population (LUM Imaging Device Arm) |
| --- | --- |
| Total Patients | 357 |
| Patients having positive margins after SOC BCS n % | 62 (17.4%) 95% CI:13.6%, 21.7% |
| Detection of all positive margins after SoC BCS on the corresponding orientations in the cavity | |
| Secondary endpoint a: Proportion of patients with positive margins after SoC BCS for whom all the orientations with positive SoC margins were detected in the cavity by the Lumicell DVS n (%) | 16.1% (10/62) 95% CI: 8.0%, 27.7% |
| Conversion of all positive margins after SoC BCS to negative margins by removing LUM-guided shaves | |
| Secondary endpoint b: Proportion of patients with pathology-positive margins after SoC BCS for whom additional Lumicell DVS-guided shaves resulted in pathology-negative margins n (%) | 14.5% (9/62) 95% CI: 6.9%, 25.8% |
| Additional analyses | |
| Detection of at least one positive margins after SoC BCS on the corresponding orientations in the cavity | |
| Proportion of patients with positive margins after SoC BCS for whom at least one orientation with positive an SoC margin was detected in the cavity by the Lumicell DVS n % | 24.2% (15/62) 95% CI: 14.2%, 36.7% |

Abbreviations: BCS = breast-conserving surgery; CI = confidence interval; mITT = modified Intent-to-Treat; SoC = standard of care

Table 11. Removal of Residual Cancer Guided by the Lumicell DVS in Patients with Negative and Positive Margins after Standard of Care Surgery

| | mITT Population |
| --- | --- |
| All Patients | 357 |
| Patients Having All Negative Margins after SoC BCS | 295 |
| Patients Having at Least One Positive Margin after SoC BCS | 62 |
| Patients with negative margins after SoC BCS having tumor found in at least one therapeutic shave | |
| Secondary endpoint d: Ratio of patients with negative margins after the SoC procedure who have residual cancer found in at least one LUM-guided shave among patients with negative margins n (%) | 6.4% (19/295) 95% CI: 3.9%, 9.9% |
| Additional analyses in patients with positive margins after SoC BCS | |
| Patients with positive margin after SoC BCS having tumor found in at least one therapeutic shave | |
| Ratio of patients with positive margins after the SoC procedure who have residual cancer found in at least one LUM-guided shave n (%) | 12.9% (8/62) 95% CI: 5.7%, 23.9% |
| Ratio of patients with positive margins after the SoC procedure who have residual cancer found in at least one LUM-guided shave among all patients n (%) | 2.2% 8/357 95% CI: 1.0%, 4.4% |

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Abbreviations: BCS = breast-conserving surgery; CI = confidence interval; mITT = modified Intent-to-Treat; SoC = standard of care

Table 12. Summary of Tissue Volumes: Lumpectomy, Standard of Care Shaves, LUM-guided Shaves and Contribution to Total Tissue Volume

| | Treatment Arm | | |
| --- | --- | --- | --- |
| | mITT Population | mITT Population and having at least one LUM-guided shave removed | Control |
| All Patients N | 357 | 166 | 35 |
| Lumpectomy Volume (cm3) | | | |
| Mean (SD) | 74.9 (76.5) | 70.5 (55.9) | 82.0 (65.0) |
| Median (2.5%, 97.5%) | 54.0 (9.7, 267.2) | 54.3 (13.3, 208.0) | 66.8 (10.5, 308.0) |
| Median (Min, Max) | 54.0 (5.5, 722.6) | 54.3 (6.0, 463.0) | 66.8 (10.5, 308.0) |
| SoC Shave Volume (cm3) | | | |
| Mean (SD) | 14.1 (36.7) | 16.3 (24.0) | 13.5 (16.8) |
| Median (2.5%, 97.5%) | 7.5 (0.0, 71.2) | 9.8 (0.0, 77.0) | 7.7 (0.0, 71.9) |
| Median (Min, Max) | 7.5 (0.0, 603.0) | 9.8 (0.0, 164.6) | 7.7 (0.0, 71.9) |
| SoC Total Volume (cm3) | | | |
| Mean (SD) | 89.0 (93.7) | 86.8 (70.0) | 95.6 (68.8) |
| Median (2.5%, 97.5%) | 66.4 (15.1, 308.7) | 70.6 (20.6, 253.3) | 76.7 (21.9, 308.0) |
| Median (Min, Max) | 66.4 (5.5, 963.0) | 70.6 (6.0, 601.4) | 76.7 (21.9, 308.0) |
| Secondary Endpoint f: Therapeutic Shave Volume (cm3) | | | |
| Mean (SD) | 10.1 (17.5) | 21.8 (20.1) | 0.0 (0.0) |
| Median (2.5%, 97.5%) | 0.0 (0.0, 61.1) | 15.6 (1.6, 73.5) | 0.0 (0.0, 0.0) |
| Median (Min, Max) | 0.0 (0.0, 126.7) | 15.6 (0.7, 126.7) | 0.0 (0.0, 0.0) |
| Total Volume (cm3) | | | |
| Mean (SD) | 99.1 (97.3) | 108.6 (79.0) | 95.6 (68.8) |
| Median (2.5%, 97.5%) | 77.5 (15.2, 348.1) | 90.0 (28.3, 318.1) | 76.7 (21.9, 308.0) |
| Median (Min, Max) | 77.5 (5.5, 963.0) | 90.0 (13.7, 625.8) | 76.7 (21.9, 308.0) |
| Secondary Endpoint g: Ratio of Therapeutic Shave Contributing to Total Volume | | | |
| Mean (SD) | 9.4% 14.1% | 20.3% (14.5%) | 0% 0% |
| Median (2.5%, 97.5%) | 0.0% (0.0%, 44.7%) | 16.7% (3.3%, 61.9%) | 0.0% 0.0%, 0.0%) |
| Median (Min, Max) | 0.0% (0.0%, 81.3%) | 16.7% (1.7%, 81.3%) | 0.0% 0.0%, 0.0%) |

Abbreviations: CI = confidence interval; Max = maximum; Min = minimum; mITT = modified Intent-to-Treat; SD = standard deviation, SoC = standard of care

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For exploratory analysis, the patient reported outcome measures (PROM) data collected using the validated BREAST-Q survey, module 2, version showed that the majority of the patients responded either "very satisfied" or "somewhat satisfied" across all the time frames pre- and post-surgery. In addition, PROMs were generally similar between those patients with or without LUM-guided therapeutic shaves. No statistically significant difference between the patient overall satisfaction across the two groups was observed.

## Other Endpoint Analysis: Post hoc Effectiveness Endpoints

Total Number of Patients with Residual Cancer Removed in Second Surgeries and Guided by the Lumicell DVS

Overall, after the SoC BCS was complete, 41 subjects had residual cancer removed either by a re-excision surgery or a LUM-guided shave (Table 13). Of these, 14 subjects had residual cancer removed only during the re-excision surgery and seven subjects had residual cancer removed by both LUM-guided shaves and re-excision surgeries. An additional 20 subjects had residual cancer removed only by LUM-guided shaves. Thus, 27 out of 41 subjects (65.9%) had additional cancer resection enabled by the Lumicell DVS, further demonstrating that the combination product can enhance SoC surgery.

Table 13. Number of Subjects with Residual Cancer Removed

| Total subjects with residual cancer removed after SoC BCS (n) | 41 |
| --- | --- |
| Subjects with residual cancer removed only in a re-excision surgery n (%) | 14 (34.1%) |
| Subjects with residual cancer removed by LUM-guided shaves and re-excisions n %) | 7 (17.1%) |
| Subjects with residual cancer removed only by LUM-guided shaves n %) | 20 48.8%) |

Abbreviations: BCS = breast-conserving surgery; SoC = standard of care

## Characteristics of Tumor Detected in LUM-guided Shaves from Standard of Care Negative Margin Orientations

The characteristics of the residual cancer removed by LUM-guided shaves were evaluated, specifically from subjects with orientations that had a negative margin assessment after the SoC procedure. This analysis focused on this subset population because the cancer detected by the Lumicell DVS most likely would have not been removed by any other surgical procedure. This group consisted of 22 subjects including:

- 19 subjects with all SoC negative margins with residual cancer removed guided by the Lumicell DVS

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- Three subjects with SoC positive margins but residual cancer removed guided by the Lumicell DVS from orientations with an SoC negative margin that potentially would not be addressed in a second surgery

These 22 subjects had residual cancer removed that would have not been otherwise detected with the current SoC procedures. The characteristics of the subjects and details of tumor burden, tumor grade, and margin status are presented in Table 14. Of these, 21 subjects (95.0%, 21 out of 22 subjects) had potential clinically significant factors including:

- Residual cancer removed was non-microscopic in size (1 mm to 13 mm)
Tumor was Grade 3, or
- The subject was 70 years of age or older and ER-positive, for which adjuvant radiation may have been omitted according to the American Society for Radiation Oncology (ASTRO) evidence-based guidelines (Smith BD et al. 2018).

In these subjects, the Lumicell DVS detected and guided the removal of residual cancer that otherwise remained undetected by the SoC procedure.

Table 14. Summary of Subjects with Residual Cancer Removed in LUM-guided Shaves by Tumor Burden, Tumor Grade, Age, and Standard of Care Margin Status

| Subject | Largest Tumor Dimension Found in LUM-guided Shavea | Tumor Gradea | Ageb | SoC Margin Statusa |
| --- | --- | --- | --- | --- |
| 01-01-PIV-0012 | Not reportedc | 3 | 58 | Negative |
| 01-01-PIV-0023 | Not reportedc | 3 | 42 | Negative |
| 01-01-PIV-0034 | 1.5 mm | 3 | 51 | Negative |
| 01-01-PIV-0038 | 2 mm | 2 | 65 | Negative |
| 01-01-PIV-0044 | 2 mm | 3 | 58 | Negative |
| 01-01-PIV-0055 | 11 mm | 2 | 76d | Negative |
| 04-01-PIV-0050 | 2 mm | 3 | 36 | Negative |
| 06-01-PIV-0004 | 6.5 mm | 2 | 71d | Negative |
| 13-01-PIV-0019 | 4 mm | 2 | 52 | Negative |
| 14-01-PIV-0011 | 1 mm | 3 | 71d | Negative |
| 14-01-PIV-0022 | 1.5 mm | 1 | 53 | Negative |
| 14-01-PIV-0031 | 1 mm | 2 | 60 | Negative |
| 14-01-PIV-0048 | 11 mm | 3 | 58 | Negative |
| 14-01-PIV-0061 | Not reportedc | 1 | 77d | Negative |
| 18-01-PIV-0013 | 1 mm | 3 | 47 | Negative |
| 22-01-PIV-0003 | 2 mm | 3 | 70d | Negative |

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| Subject | Largest Tumor Dimension Found in LUM-guided Shave ^{a} | Tumor Grade ^{a} | Age ^{b} | SoC Margin Status ^{a} |
| --- | --- | --- | --- | --- |
| 23-01-PIV-0015 | 13 mm | 2 | 52 | Negative |
| 14-01-PIV-0084 | 7 mm | Not reported^{c} | 66 | Negative |
| 14-01-PIV-0056 | 7 mm | 2 | 60 | Positive^{e} |
| 18-01-PIV-0027 | 5 mm | 2 | 65 | Positive^{e} |
| 18-01-PIV-0081 | 8 mm | 2 | 66 | Positive^{e} |
| 13-01-PIV-0004 | Not reported^{c} | 2 | 59 | Negative |

Abbreviations: CI = confidence interval; SoC = standard of care
$^{\mathrm{a}}$ Data from pathology chart
$^{\mathrm{b}}$ Demographic data from Electronic Data Capture
$^{\mathrm{c}}$ Not reported indicates data not entered in the subject’s study Case Report Form.
$^{\mathrm{d}}$ These subjects are at least 70 years old and estrogen-receptor positive
$^{\mathrm{e}}$ These subjects had positive margins but a LUM-guided shave with tumor was removed from a negative margin orientation

## 3. Pivotal Study Safety and Effectiveness Conclusions

Overall, the evaluation of safety in the Pivotal Study showed that the study treatment LUMISIGHT was associated with an incidence of hypersensitivity of approximately 1.5% (6/406), including one patient with anaphylaxis. Refer to the LUMISIGHT prescribing information for additional information, warnings, and recommendations.

- Chromaturia was the most commonly reported and expected AE due to the blue color of the LUMISIGHT injection that resolved completely in approximately 92% of patients within 48 hours.

LUMISIGHT and Lumicell DVS demonstrated success in detecting and guiding the removal of residual cancer that would have otherwise remained after SoC BCS in 27 out of 357 7.6% patients in the mITT Population (95% CI: 5%, 10.8%).

- The performance goal for the primary endpoint Removal of Residual Cancer was met for the Lumicell DVS with a lower bound CI of 5%, which was greater than the pre-set performance goal of 3%.

The primary endpoints that measured diagnostic performance confirmed:

- Tissue-level sensitivity of 49.1% (34 out of 69 truth standard positives; 95% CI: 36.4%, 61.9%; GEE Estimator)
- Tissue-level specificity of 86.5% (1940 out of 2277 truth standard negatives; 95% CI: 84.5%, 88.3%; GEE Estimator).

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The tissue-level sensitivity endpoint did not meet the pre-set performance goal of 40% by 3.6 percentage points at the lower bound of the 95% CI (i.e., 36.4%). The tissue-level specificity endpoint successfully met the pre-set performance goal of 60% by 24.5 percentage points at the lower bound of the 95% CI (i.e., 84.5%).

LUMISIGHT and Lumicell DVS also demonstrated the ability to detect LUM-positive signals corresponding to SoC negative margin orientations.

- In 19 out of 295 (6.4%) patients with negative margins at the end of the SoC procedure, the LUMISIGHT and Lumicell DVS detected and guided the removal of shaves containing residual cancer. This represented 5.3% of the entire mITT Population (19 of 357 patients). Without the use of the Lumicell DVS imaging device, these 19 patients would have completed their initial surgical procedure with cancer remaining in the lumpectomy cavity and would likely have not had an indication for a second surgery to address this remaining cancer.

The combination product also detected LUM-positive signals corresponding to SoC positive margin orientations and converted those orientations into negative margins by removing LUM-guided shaves (mITT Population) with subsequent reductions in positive margins after second surgeries.

- Subset analysis in patients with positive margins after SoC BCS further demonstrated that in 8 of 62 patients (12.9%) who had SoC positive margins identified by pathology, residual cancer was detected by the Lumicell DVS and removed by the surgeon. A total of 9 out of 62 (14.5%) patients with SoC positive margins were converted to having pathology-negative margins after LUM-guided resections. Although residual cancer may be removed in a second surgery due to positive margins in this subset of patients, eliminating it during the initial surgery can avoid the risk of not finding the exact location of residual cancer in a second surgery, in addition to potentially preventing a second surgery and the associated comorbidities with a second surgery.

Overall, 27 patients (out of 357) had residual cancer removed in LUM-guided shaves with 20 of those 27 patients having residual cancer only found by the Lumicell DVS..

A total of 41 patients had residual cancer removed after the SoC BCS was completed, with 65.9% of these patients having additional tumor resection enabled by using the LUMISIGHT and Lumicell DVS as adjunct to SoC BCS, further demonstrating that the device can enhance SoC surgery.

Among the 166 patients with at least one LUM-guided shave excised, the mean total LUM-guided shave volume was 22 cm³ ± 20 cm³, accounting for 20% ± 15% of the total volume of resection. An exploratory Patient Reported Outcome Measure (PROM) based on a module of the BREAST-Q survey indicated there was no significant difference in patient overall satisfaction between patients with or without LUM-guided shaves for each PROM time frame.

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## 4. Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

## E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 62 investigators listed on FDA Form 1572. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions about the reliability of the data.

## XI. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION

Supplemental clinical information includes:

1. Supportive Phase C IDE Feasibility Study CL0006
2. Pooled analyses of safety in clinical studies evaluated
3. Early clinical development: Phase 1 IND, IDE Feasibility Studies Phase A and B

### 1. Supportive Phase C IDE Feasibility Study CL0006

A Phase C Feasibility Study CL0006 was conducted to evaluate the safety and effectiveness of the LUMISIGHT and Lumicell DVS combination product and to train surgeons and clinical staff in preparation for the Pivotal Study. The safety and effectiveness data from this supportive clinical study are provided below. This study was not adequate and well-controlled. The performance data provided a basis for design of the pivotal trial. The performance results were generally aligned with those from the pivotal trial.

#### A. Study Title

Feasibility Study Phase C: Expansion into multiple institutions for training in the use of the Lumicell DVS for intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer.

#### B. Overview of Phase C Feasibility Study CL0006

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In this multicenter, open label, single arm study, patients were enrolled between 06 February 2018 and 15 August 2019. Database lock was on 10 April 2020.

This study was conducted at 16 sites within the United States of America with up to 250 patients planned to be enrolled.

## C. Patient Disposition

A total of 234 patients received a single dose of LUMISIGHT (pegulicianine) in the safety analysis population; four patients were withdrawn prior to imaging with the Lumicell DVS.

A total of 230 patients completed the study in the mITT Population (Table 15).

Table 15. Patient Disposition in Phase C IDE Study CL0006

| Disposition | Number of Patients |
| --- | --- |
| Patients with informed consent form signed | 283 |
| Patients exit prior to LUMISIGHT injection n %) | 49 (17.3%) |
| Screen failure n %) | 42 (14.8%) |
| Withdrawn prior to enrollment n % | 7 (2.5%) |
| Patients with LUMISIGHT injected (SAF population) n (%) | 234 (82.7%) |
| Patients withdrawn prior to LUM imaging procedure completed n (%) | 4 (1.4%) |
| Patients completed with LUM imaging (mITT population) n (%) | 230 (81.3%) |
| Patients with major protocol deviations n (%) | 5 (1.8%) |
| Patients in the per protocol population n (%) | 225 (79.5%) |

mITT = modified intent-to-treat; SAF = safety analysis

## D. Study Objectives

The key objectives of the study were to complete hands-on training of the surgeons and clinical staff who would be participating in the Pivotal Study, to evaluate the safety and effectiveness of LUMISIGHT and Lumicell DVS in breast cancer surgeries, and to identify and address any site-specific or user-specific issues for using the combination product in breast cancer surgeries.

## E. Clinical Endpoints

Safety: All patients were observed to assess the safety of LUMISIGHT with standard preoperative, intraoperative, and postoperative monitoring from the time of injection of LUMISIGHT to the time they were discharged from the hospital. Patients had a final safety assessment at the first postoperative visit, at which time blood and urine laboratory studies were collected. Any reported AEs were followed until resolution.

Effectiveness: As the study was intended as a feasibility study to train surgeons and refine the patient calibrated tumor detection software, no predefined hypothesis-tested effectiveness criteria were used. However, effectiveness metrics were evaluated post hoc based on the Pivotal Study design and are presented in tables comparing the results between the two studies. The endpoints included in this comparative analysis included:

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- Rate of removal of residual cancer at a per-patient level
- Diagnostic performance characterized as sensitivity and specificity at a per-image level
- Rate of detection of positive margins at a per-patient level
- Rate of conversion of positive margins to negative margins at a per-patient level
- Rate of removal of residual cancer in patients having negative SoC margins
- Average volume of LUM-guided shaves and contribution to total excision volume.

## F. Study Design and Methodology

**Design:** Open label, single arm (non-randomized), multicenter clinical study.

**Methodology:** Planned number of patients: 250; total number of patients enrolled: 234.

The assessment for completing the surgical training was done in collaboration between Lumicell and each surgeon. A total of 1-3 surgeons per site were included in the training from 16 sites, with each surgeon allocated five patients per surgeon. Surgeons could enroll more than five patients if needed to complete training, or if more patients were needed to complete the patient calibrated tumor detection software verification.

Patients undergoing a lumpectomy procedure to treat primary breast cancer were injected with LUMISIGHT 2-6 hours prior to surgery at a dose of 1.0 mg/kg. The sequence of events during the surgical procedure varied based on the SoC used by the surgeon.

During surgery, patients received the SoC procedures for each site, including any SoC shaves. Then, the Lumicell DVS was used and Lumicell DVS-positive tissue was removed.

Data were collected to determine the margin assessment after the SoC lumpectomy procedure was completed (SoC margin), after the LUM imaging procedure was completed (final margin), and before the Lumicell DVS was used to guide the resection of additional tissue. All the resected tissue was to be handled and processed for margin assessment following the institution’s practices for breast-conserving surgeries.

## Inclusion and Exclusion Criteria

Enrollment in the Phase C IDE Feasibility Study CL0006 was limited to patients who met the following inclusion criteria:

- Patients must have had histologically or cytologically confirmed primary invasive breast cancer, DCIS, or a combination of invasive breast cancer and DCIS. The protocol accepted methods for obtaining the histological samples were diagnostic core needle biopsies or fine needle biopsies.
- Female, age of 18 years or older. Because no dosing or AE data are currently available on the use of LUMISIGHT in patients <18 years of age, children were excluded from this study.
- Patients must have been scheduled for a lumpectomy for a breast malignancy.

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- Patients must have been able and willing to follow study procedures and instructions.
- Patients must have received and signed an ICF.
- Patients must have had no uncontrolled serious medical problems except for the diagnosis of cancer, as per the exclusion criteria listed below.
- Patients must have had normal organ and marrow function within limits as defined below:
- Leukocytes > 3,000/mcL
- Platelets > 75,000/mcL
- Total bilirubin within normal institutional limits
- AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal
- Creatinine ≤ 1.5 mg/dL or creatinine clearance > 60 mL/min/1.73 m² for patients with creatinine levels above institutional normal.
- Patients must have had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Patients were not permitted to enroll in the Phase C IDE Feasibility Study CL0006 if they met any of the following exclusion criteria:

- Patients who were treated for bilateral breast cancer resection procedure.
- Patients who were pregnant at the time of diagnosis of their breast cancer; this exclusion was necessary because the teratogenic properties of LUMISIGHT are unknown. Because there was an unknown but potential risk of AEs in nursing infants secondary to treatment of the mother with LUMISIGHT, breastfeeding should have been discontinued if the mother was treated with LUMISIGHT.
- Patients who were sexually active and not willing/able to use medically acceptable forms of contraception (hormonal or barrier method of birth control, abstinence) upon entering the study and for 60 days after injection of LUMISIGHT. Should a woman have become pregnant or suspected she was pregnant while participating in this study, she should have informed her treating physician immediately. Breast cancer patients are routinely advised against becoming pregnant during treatment, so this requirement does not differ from SoC.
- Patients who had taken an investigational drug within 30 days of enrollment.
- Patients with prolonged corrected QT interval defined as greater than 480 ms.
- Patients who had administration of methylene blue or any dye for sentinel lymph node mapping on the day of the surgery prior to imaging the lumpectomy cavity with the LUM Imaging Device.
- Patients who had not recovered from AEs due to other pharmaceutical or diagnostic agents.

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- Patients with uncontrolled hypertension defined as persistent systolic blood pressure > 180 mm Hg, or diastolic blood pressure > 110 mm Hg; those patients with known hypertension should have been stable within these ranges while under pharmaceutical therapy.
- History of allergic reaction to polyethylene glycol (PEG) (this criterion was added after the first case of anaphylaxis reported).
- History of allergic reaction to any oral or intravenous (IV) contrast agents (this criterion was added after the first case of anaphylaxis reported).
- Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, chronic obstructive pulmonary disease or asthma requiring hospitalization within the past 12 months, or psychiatric illness/social situations that would limit compliance with study requirements.
- Human immunodeficiency virus positive individuals on combination antiretroviral therapy were ineligible because of the potential for pharmacokinetic interactions with LUMISIGHT.
- Any patient for whom the investigator feels participation was not in the best interest of the patient.
- Patients undergoing a second lumpectomy procedure because of positive margins in a previous surgery prior to entering this study.
- Patients with prior ipsilateral breast cancer surgeries, mastectomies, breast reconstructions, or implants.
- Patients who had undergone a surgical biopsy for any reason in the ipsilateral breast performed less than 2 years prior to enrollment of this study.
- Patients with prior ipsilateral reduction mammoplasties (breast reductions) performed less than 2 years prior to enrollment to this study.
- Patients previously treated with systemic therapies to treat the cancer to be removed during this clinical investigation, such as neo-adjuvant chemotherapy or hormonal therapy.
- Patients undergoing breast conserving surgery whose resected specimen will be evaluated with frozen section.

G. Patient Accountability

At the time of database lock, of 234 patients enrolled in the Phase C IDE Feasibility Study CL0006 and who received a single intravenous dose of LUMISIGHT, 230 (98.3%) were available for analysis at the completion of the study (Table 16).

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Four (4) patients were withdrawn from the study after injection of LUMISIGHT.

Figure 4. Phase C IDE Feasibility Study CL0006 Accountability Tree

To start the feasibility Phase C study, the patient-calibrated tumor detection software developed during the Phase B study was used. After the first 83 subjects were enrolled, the collected pathology results and Lumicell DVS imaging data were used to refine the patient calibrated tumor detection software, while enrollment continued. After a total of 127 subjects had been enrolled in the study, the refined tumor detection software was locked and implemented. The locked software was then used in the final 103 subjects in the feasibility Phase C study and in all the subjects in the pivotal study. As a result, the analysis populations for feasibility Phase C are defined as follows:

- Training Set (n = 83 subjects): consists of the initial 83 subjects enrolled in the feasibility Phase C study whose pathology and imaging data were used to refine the patient calibrated tumor detection software; these subjects used the patient calibrated tumor detection software developed during Phase B
- Extended Training Set (n = 127 subjects): consists of the initial 83 subjects in the Training Set plus 44 subjects enrolled before implementing the refined patient calibrated tumor detection software; all of these 127 subjects used the patient calibrated tumor detection software developed during Phase B
- Validation Set (n = 103): consists of 103 subjects enrolled after the refined and locked patient calibrated tumor detection software was implemented

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- All population $(n = 230)$ : consists of subjects in the Extended Training Set and Validation Set; when efficacy results are presented for this population, the refined algorithm was implemented retrospectively to the Extended Training Set

# H. Study Population Demographics and Baseline Parameters

The patient disposition and demographics of the study population are presented in Table 16 and the baseline clinicopathological findings are presented in Table 17.

Overall, the distribution of age, sex, race, ethnicity, and the calculated BMI were found to be very similar between the study populations.

Table 16. Phase C IDE Feasibility Study CL0006: Population Disposition and Demographics

| Characteristics | Total LUMISIGHT Injected (SAF Population) (N = 234) | Total LUM Imaging Procedure Completed (mITT Population) (N = 230) |
| --- | --- | --- |
| Patient Status | | |
| Screen Failure | 0 | 0 |
| Complete | 230 98.3% | 230 100.0% |
| Withdrawn | 4 (1.7%) | 0 |
| Sex | | |
| Female | 234 100.0% | 230 100.0% |
| Age (Years) | | |
| Mean ± SD (N) | 61.7±9.8 (234) | 61.4±9.7 (230) |
| Median (Q1, Q3) | 62.0 (55.0,69.0) | 62.0 (55.0,69.0) |
| Range (min, max) | (37.0,84.0) | (37.0,84.0) |
| Race | | |
| American Indian or Alaska Native | 0 | 0 |
| Asian | 15 (6.4%) | 15 (6.5%) |
| Black or African American | 21 (9.0%) | 21 (9.1%) |
| White or Caucasian | 187 79.9% | 183 79.6% |
| Multiple races | 2 (0.9%) | 2 (0.9%) |
| Unknown or Not reported | 9 (3.8%) | 9 3.9% |
| Ethnicity | | |
| Hispanic or Latino | 4 (1.7%) | 4 (1.7%) |
| Non-Hispanic or Latino | 220 94.0% | 216 (93.9) |
| Unknown or not reported | 10 (4.3%) | 10 (4.3%) |
| BMI (kg/m2) | | |
| Mean ± SD (N) | 29.0±6.6 (233) | 29.0±6.6 (229) |
| Median (Q1, Q3) | 27.5 (24.3,32.3) | 27.4 (24.3,32.2) |
| Range (min, max) | (17.1,51.3) | (17.1,51.3) |

Table 17. Phase C IDE Feasibility Study CL0006: Baseline Clinicopathological Findings - Tumor Histology and Receptor Status from Biopsy or Main Specimen

| Characteristics | Total LUM Imaging Procedure Completed (mITT Population) (N = 230) |
| --- | --- |
| Largest dimension of tumor in main specimen (cm) | |

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| Characteristics | Total LUM Imaging Procedure Completed (mITT Population) (N = 230) |
| --- | --- |
| Mean ± SD (N) | 1.8±1.5 (171) |
| Median (Q1, Q3) | 1.5 (0.9,2.0) |
| Range (min, max) | (0.0,10.9) |
| Tumor histology (biopsy and/or main lumpectomy specimen)^{1} | |
| DCIS Only | 43 (18.7%) |
| IDC +/- DCIS | 160 69.6% |
| ILC +/- DCIS | 25 (10.9%) |
| IDC + ILC | 2 (0.9% |
| ER (+)^{1} | 209 91.7% |
| PR (+)^{1} | 176 79.6% |
| HER2 (+)^{1} | 18 (9.8% |
| Triple negative | |
| Yes | 10 (4.3) |
| No | 219 (95.2) |
| Unknown | 1 (0.4) |
| At least one LN (+) | 28 (15.2%) |
| All LN (-) | 156 84.8% |
| No LN Biopsy | 46 (20.0%) |

I. Safety Results

Safety: A total of 234 patients were included in the safety analysis population. Overall, 214 patients (91.5%) reported chromaturia (blue-green discoloration of the urine) due to the blue color of the LUMISIGHT injection. In addition to the chromaturia events, 57 AEs observed in 39 patients were reported with four AEs related to the LUMISIGHT treatment Table 18. One serious AE of anaphylaxis was observed during the administration of LUMISIGHT; no deaths or UADEs were reported.

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Table 18. Summary of Adverse Events by Severity and Relatedness to LUMISIGHT Treatment (Safety Population)

| Severity | All | | | Mild | | | Moderate | | | Severe | | Life Threatening | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Adverse Events | All n (%) | Not Related n (%) | Related n (%) | All n (%) | Not Related n (%) | Related n (%) | All n (%) | Not Related n (%) | Related n (%) | All n (%) | Related n (%) | All n (%) | Related n (%) |
| All AE events | 271 | 53 | 218 | 255 | 41 | 214 | 14 | 12 | 2 | 1 | 1 | 1 | 1 |
| Chromaturia | 214 | 0 | 214 | 214 | 0 | 214 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Other AEs | 57 | 53 | 4 | 41 | 41 | 0 | 14 | 12 | 2 | 1 | 1 | 1 | 1 |
| All patients with any AEs | 215 (91.9%) | 33 (14.1%) | 214 (91.5%) | 214 (91.5%) | 25 (10.7%) | 214 (91.5%) | 12 5.1% | 10 4.3% | 2 0.9% | 1 0.4% | 1 0.4% | 1 (0.4%) | 1 (0.4%) |
| All patients with chromaturia | 214 (91.5%) | 0 | 214 (91.5%) | 214 (91.5%) | 0 | 214 (91.5%) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| All patients with Other AEs | 36 (15.4%) | 33 (14.1%) | 3 (1.3%) | 25 (10.7%) | 25 (10.7%) | 0 | 12 5.1% | 10 4.3% | 2 0.9% | 1 0.4% | 1 0.4% | 1 (0.4%) | 1 0.4% |

Abbreviation: AE = adverse event

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J. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The Phase C Feasibility Study included 38 investigators listed on FDA Form 1572. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions about the reliability of the data

K. Safety Conclusions

Safety: No adverse device effects were observed in this study.

The imaging agent, LUMISIGHT, was generally well tolerated by study subjects. No deaths were reported. One serious adverse reaction of anaphylaxis was observed – the subject was treated and recovered and then proceeded to receive standard of care lumpectomy (no imaging with the Lumicell DVS). No allergic reactions were observed in the 230 subjects that were enrolled in the study after the exclusion criteria modification. Most subjects experienced the AE of chromaturia (blue-green urine discoloration) which was expected based on the blue color of the LUMISIGHT imaging agent. The other events experienced by the study subjects were expected based on their underlying disease, change in medications, or were otherwise expected due to the subject undergoing and recovering from surgery.

2. Pooled Analyses of Safety in the Clinical Studies Evaluated

An analysis of pooled safety data was pe…