Intraoperative Molecular Imaging With Pafolacianine in Resection of Occult Pulmonary Malignancy in the ELUCIDATE Trial

Lung: Research Intraoperative Molecular Imaging With P a f o l a c i a n i n ei nR e s e c t i o no fO c c u l t Pulmonary Malignancy in the ELUCIDATE Trial David Rice, MBBS, 1 Sunil Singhal, MD, 2,3 Emma Niemeyer, BA, 2,3 Inderpal Sarkaria, MD, MBA, 4 Linda W. Martin, MD, MPH, 5 Michael I. Ebright, MD, 6 Brian E. Louie, MD, 7 Tommy Lee, MSHS, 8 and Jarrod D. Predina, MD, MTR 2,3 ABSTRACT BACKGROUND Clinical studies have demonstrated that intraoperative molecular imaging (IMI) with pafolacianine identi fies occult pulmonary lesions that are not identi fied by preoperative computed tomography or by intraoperative inspection techniques in w20% of patients. This study describes occult lesion clinical data and evaluates characteristics so that surgeons can better incorporate this emerging technology into clinical decision making. METHODS Participants (n [ 100) enrolled in a phase 3 trial of IMI with pafolacianine during pul- monary resection (Enabling Lung Cancer Identi fication Using Folate Receptor Targeting [ELUCIDATE]; NCT04241315) were identi fied. Participants underwent preoperative computed tomography with 1.25-mm slices. Patient and lesion characteristics were analyzed. Positive predictive value and false positive rates were tabulated for IMI fluorescent lesions, with predictors of malignant vs benign occult lesions described. RESULTS IMI identi fied 29 occult lesions in 23 (23%) participants. Seventeen of 29 (58%) lesions were identified within the same lobe as known lesions; 12 of 29 (42%) were identi fied in a different lobe from the suspicious nodule known by preoperative assessment. Twenty-three of 29 (79%) of occult lesions found by IMI were resected with an additional wedge resection. Ten of 29 (34%) lesions identified by IMI were malignant. There was no additional morbidity in participants with lesions resected. With pafolacianine, 7 participants had a synchronous primary stage I lung cancer identi fied, and 1 participant had additional metastases identi fied. CONCLUSIONS IMI with pafolacianine identi fies occult malignant lesions during pulmonary resection despite thorough preoperative imaging and intraoperative assessment by experienced surgeons. (Ann Thorac Surg 2024; -:---) ª 2024 Published by Elsevier Inc. on behalf of The Society of Thoracic Surgeons I ntraoperative molecular imaging (IMI) is an emerging technique that involves systemic delivery of targeted, optical contrast agents that selectively accumulate in tumors and result in intraoperative tumor fluorescence.1 This technique has been developed to improve intraoperative decision making by providing real-time, visual feedback to the surgeon. 1-5 In 2022, pafolacianine (On Target Laboratories) received approval from the U.S. Food and Drug Accepted for publication Oct 7, 2024. Presented at the Advances in Quality & Outcomes: A Data Managers Meeting of The Society for Thoracic Surgeons, Nashville, TN, Sept 11-13, 2024. 1MD Anderson Cancer Center, Houston, Texas; 2Center for Precision Surgery, Perelman School of Medicine at the University of Pennsylvania, Phila- delphia, Pennsylvania; 3Division of Thoracic Surgery, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Phila- delphia, Pennsylvania; 4University of Texas Southwestern Medical Center, Dallas, Texas; 5Section of Thoracic Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia; 6Columbia University Irving Medical Center, New York, New York; 7Swedish Cancer Institute and Medical Center, Seattle, Washington; and 8On Target Laboratories, Inc, West Lafayette, Indiana Address correspondence to Dr Predina, Center for Precision Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104; email: [email protected]. ª 2024 Published by Elsevier Inc. on behalf of The Society of Thoracic Surgeons 0003-4975/$36.00 https:/ /doi.org/10.1016/j.athoracsur.2024.10.001 1 Administration as an adjunct for intraoperative identification of pulmonary lesions, thereby extending the original indication for ovarian le- sions initially approved in 2021. Speci fically for lung nodules, a multicenter phase 3 randomized trial (Enabling Lung Cancer Identi fication Using Folate Receptor Targeting [ELUCIDATE]; NCT04241315) demonstrated that pafolacianine, in combination with standard of care minimally invasive pulmonary resection (video-assisted thoracoscopic surgery and robotic-assisted thora- coscopic surgery), affected 53% of participants randomized to IMI. 6 These clinically signi ficant events (CSEs) included identi fication of inadequate margins (38% of participants), improvements of lesion localization (19%), and discovery of otherwise occult synchronous malignant lesions (8%). Of note, 10% of participants had more than 1 CSE in this phase 3 trial cohort. These findings validated results found in an earlier nonrandomized, multicenter phase 2 trial of pafolacianine (OTL38 Injection for Intraoperative Imaging of Folate Receptor Positive Lung Nodules; NCT02872701) involving a similar cohort of participants in which 26% of participants with non-small cell lung cancer (NSCLC) experienced CSEs. 7 Although the impact of rapid identi fication of positive margins and reliable localization of subtle subsolid or ground-glass opacities is fairly obvious, the bene fits of discovering radiographi- cally occult, synchronous cancers are less clear without long-term data. One could make the argument that resection of such lesions could result in overtreatment. For example, it is fairly common practice for thoracic surgeons to treat only evolving lesions in patients with multifocal ground-glass opacities 8,9 or in certain scenarios associated with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. 10 These approaches appear to minimize morbidity, maximize parenchymal preservation, and have little impact on overall survival. On the other end of this debate, removal of additional lesions may represent proper execution of one the primary tenants of oncologic surgery, which is to achieve “complete local control. ”1 Survival and recurrence data were beyond the study goals of the phase 2 and phase 3 protocols, which evaluated IMI with pafolacianine as a real- time targeted visualization tool, and were there- fore not collected. Additionally, retrospective collection would be of limited value because me- dian postsurgical follow-up is currently less than 2 years. With recent Food and Drug Administration approval and the seemingly rapid implementation of this technology, the goal of this report is to summarize and further analyze data from the ELUCIDATE trial that pertain to intraoperative discovery of occult lesions. We seek to provide granularity regarding occult lesion location, size, histology, and test characteristics (positive pre- dictive value). In addition, we seek to understand which clinical variables may predict malignancy in lesions identi fied solely with IMI. This infor- mation will be critical for thoracic surgeons using pafolacianine and will allow for improved incor- poration of IMI into established intraoperative decision-making algorithms. MATERIAL AND METHODS DATA SOURCE. The data for this report were derived from the original ELUCIDATE trial database and listings generated from iMedidata Rave software version 2021.1.3 (Medidata Solutions). STUDY DESIGN. This is a post hoc analysis involving prospectively collected data from ELUCIDATE, which was a multicenter, randomized phase 3 trial aimed at evaluating the clinical utility of IMI with pafolacianine during pulmonary resection. 6 The trial protocol was approved by an Institutional Review Board (November 25, 2019, # Pro00040361). The study was approved by the Institutional Review Board at each enrolling center as part of the original clinical trial agreements. The full protocol can be found in the trial report. 6 Written informed consent, including consent for data publication, was obtained from each participant before initiating screening procedures. Brie fly, participants receiving pafolacianine and undergoing IMI were identified from the ELUCIDATE database. Participants received 0.025 mg/kg of pafolacianine delivered intravenously over 60 minutes within 1 to 24 hours before surgery and IMI. All participants underwent a high-resolution computed tomographic (CT) scan with at least 1.25-mm axial cuts before enrollment. Otherwise, occult lesions identi fied exclusively by IMI were tallied. Occult lesions were de fined as nodules that were not identi fied on preoperative imaging or by traditional intraoperative techniques, such as visual inspection or palpation techniques. All preoperative imaging was reviewed by institutional radiologists and underwent independent central review by a quali fied thoracic surgeon. Variables that could possibly 2 RICE ET AL PAFOLACIANINE IDENTIFIES OCCUL T LESIONS Ann Thorac Surg 2024;-:--- predict malignancy in occult lesions were incorporated into multivariable models and included age at the time of resection, sex, preoperatively known tumor location, preoperatively known tumor size, clinical stage, occult lesion size, occult lesion location, pathologic stage, and history of previous cancers. STATISTICAL ANALYSIS. This is primarily a descriptive report with data expressed in median values with interquartile ranges or percentages, unless other- wise noted. Positive predictive value and false positive rate were tabulated for lesions based on fluorescence alone. Finally, predictors of malig- nant occult lesions (true positives) versus benign occult lesions (false positives) were examined. Statistical analyses were performed using Sigma Plot for Windows Version 15. RESUL TS PARTICIPANT CHARACTERISTICS. A total of 100 partici- pants who received pafolacianine in ELUCIDATE and were randomized to near-infrared (NIR) imaging were included. A comprehensive summary of participant and primary lesion characteristics is provided in Table 1 . Most participants had stage I or II NSCLC (n ¼ 64), with a median primary tumor size of 13 mm in greatest dimension. The next most common diagnosis was metastatic disease to the lungs (n ¼ 21). Preoperative CT scans were completed at an average of 6.77 weeks (range, 2-15 weeks) before surgery. OCCUL T LESION CHARACTERISTICS. In 23 participants, 29 occult lesions were resected after being iden- tified exclusively by IMI ( Figure). Twenty-one participants had a single additional lesion identified and resected, 1 participant had 2 additional lesions, and 1 participant had 4 lesions ( Tables 2, 3 ). Most occult lesions were less than 1 cm (n ¼ 15; 53%); however, they ranged in size from 0.2 cm to 2.0 cm (median, 0.5 cm). Those resected lesions that contained no identi fiable disease process on final pathologic review were not measured ( Table 3 ). TABLE 1 Characteristics of Phase 3 Participants From the ELUCIDATE Trial Who Received Pafolacianine and Underwent Intraoperative Molecular Imaging Variables n (%) Sex Male 39 (39) Female 61 (61) Age, y ‡65 64 (64) <65 36 (36) Preoperatively identi fied primary lesion size by CT, cm ‡2.0 29 (29) ‡1t o <2.0 49 (49) <1.0 21 (21) Not measured 1 (1) Histopathologic diagnosis of primary lesion NSCLC 64 (64) Metastasis 21 (21) Atypical carcinoid 1 (1) Benign lesion 11 (11) Other 3 (3) Pack-year smoking history, y ‡20 54 (76) <20 17 (24) Smoking status Active 19 (19) Former 52 (52) Never 29 (29) Any cancer history other than lung Yes 50 (50) No 50 (50) Any lung cancer history Yes 22 (22) No 78 (78) Race Asian 2 (2) Black or African American 8 (8) White 88 (88) Unknown 1 (1) Other 1 (1) CT, computed tomography; ELUCIDATE, Enabling Lung Cancer Identi fication Using Folate Receptor Targeting; NSCLC, non-small cell lung cancer. FIGURE Intraoperative molecular imaging with pafola- cianine. The primary nodule shown here was visualized under near-infrared light in the right upper lobe of the lung and measured 5.2 mm 3 in greatest length. Ann Thorac Surg 2024;-:--- RICE ET AL PAFOLACIANINE IDENTIFIES OCCUL T LESIONS 3 Seventeen (58%) of those 29 occult lesions identified solely with IMI were within the same lobe as primary nodules identi fied by preopera- tive CT scans, and 12 (42%) were found in a different lobe ( Table 2 ). These otherwise occult lesions were most commonly resected with an additional wedge resection (23 of 29 lesions; 79%). The remaining (6 of 29 occult lesions; 21%) were included in a single resection, which also included the known lung lesion (5 lobectomies, 1 segmentectomy) ( Table 3 ). On review of the investigator questionnaire, there was no clear perioperative morbidity associated with resection of occult lesions and no increase in pulmonary complications, as determined by safety event data review. On histopathologic review of the 29 lesions identified by IMI, 7 (24%) were invasive pulmo- nary adenocarcinoma, 3 (10%) were metastases from other primary sites, 1 (3%) was adenocarci- noma in situ, and 18 (62%) were benign lesions (Table 3 ). Of the 7 occult NSCLCs identi fied, 4 measured greater than 1.0 cm (1.0 cm, 1.1 cm, 1.8 cm, and 2.0 cm), and each of these lesions had predominantly lepidic histologic features. Of the 18 benign lesions, 15 (83%) were benign tissue, 2 (11%) were granulomas, and 1 (6%) was organizing pneumonia. Four of 8 participants with malignant occult lesions found by IMI had lesions located in a different lobe, and all these lesions were removed by wedge resection ( Table 2 ). The other 4 participants had occult malignant lesions within the same lobe as the known tumor; 2 lesions were managed with wedge resection, and 2 lesions were included during lobectomy. An independent central review of the preoper- ative CT scan was completed for participants with a malignant occult lesion. Of the 10 malignant lesions discovered with pafolacianine, none were found in retrospective review by the independent reviewer and further were not identi fied in the original radiology report and by the surgeon re- view of the scans. TEST CHARACTERISTICS. The true positive rate of fluorescence predicting malignancy (invasive NSCLC or metastases from a distant primary tu- mor) was found to be 37%, with 1 lesion identi fied as true positive for adenocarcinoma in situ. The positive predictive value was 38% of malignancy in occult lesions identi fied with IMI. True negative and false negative rates could not be calculated because otherwise healthy tissue was not resected for purposes of establishing a negative control. PREDICTORS OF OCCUL T MALIGNANCY. Univariate anal- ysis was performed to understand better which participant and primary lesion variables predicted malignancy in occult lesions identi fied by IMI. We found no signi ficant relationships between any pair of variables analyzed ( Table 4 ). COMMENT IMI is an emerging technique that provides real- time, visual information to improve intra- operative decision making by the surgeon. In this report, we expand on the previously described ELUCIDATE trial, which is a stage 3 multicenter trial involving IMI with the folate receptor – targeted agent, pafolacianine. We provide further analysis pertaining to those additional, nontarget lesions identi fied exclusively by IMI, and not by traditional preoperative and intra- operative techniques —“ occult lesions. ” The goal of this report is to provide data so that thoracic surgeons can understand the clinical relevance of such fluorescent lesions more clearly and, in turn, can better incorporate IMI data into established decision-making algorithms and clinical acumen. TABLE 2 Characteristics of Occult Lesions Identi fied by Intraoperative Molecular Imaging With Pafolacianine Variables All Occult Lesions, n or n (%) Malignant Occult Lesions, n or n (%) Sample size Lesions 29 10 Participants 23 8 Size on pathologic examination, cm ‡1t o £2.0 4 (14) 4 (40) <1.0 12 (41) 6 (60) No measurable lesion 13 (45) 0 (0) Histopathologic type NSCLC 7 (24) 7 (70) Metastasis from nonpulmonary location (chordoma) 3 (10) 3 (30) Adenocarcinoma in situ 1 (3) 1 (10) Benign lesion 18 (62) 0 (0) Location Within same lobe as primary lesion 17 (59) 6 (60) Within a different lobe from the primary lesion 12 (41) 4 (40) Any previous lung cancer history Yes 7 (24) 3 (37) No 22 (76) 5 (63) Any previous nonlung cancer history Yes 19 (65) 4 (50) No 10 (35) 4 (50) NSCLC, non-small cell lung cancer. 4 RICE ET AL PAFOLACIANINE IDENTIFIES OCCUL T LESIONS Ann Thorac Surg 2024;-:--- TABLE 3 Case Summary of 23 Participants With 29 Occult Lesions Identi fied by Intraoperative Molecular Imaging ID Age, y Sex Other Previous Cancer Hx Previous Lung Cancer Hx Primary Lesion Synchronous Lesion Size, cm Location Histologic Type Resection Performed Size, cm Location Histologic Type Resection Performed 1 64 F No Yes 0.9 RLL Parenchyma Lobe 0.6 RLL Parenchyma Lobe 2 58 M Yes No 2.2 RUL Adeno Wedge NM NM RLL RLL Parenchyma Parenchyma Wedge Wedge 3 72 F No No 1.0 RUL Adeno Wedge NM RUL Parenchyma Wedge 4 78 F Yes Yes 4.2 RUL Adeno Lobe 2.0 RLL Adeno in situ Wedge 5 63 M No No 3.4 LUL Adeno Wedge NM NM LLL LUL Parenchyma Parenchyma Wedge Wedge 6 47 M Yes No 1.4 LLL Met (chordoma) Wedge 0.5 0.6 0.1 0.3 LLL LLL LLL LUL Chordoma Chordoma Parenchyma Chordoma Wedge Wedge Wedge Wedge 7 83 F No No 2.0 LLL Adeno Lobe 2.0 LUL Adeno Wedge 8 62 F No No 0.8 RUL Adeno Lobe 1.1 RUL Adeno Lobe 9 60 F No Yes 0.9 LUL Adeno Wedge 0.5 LUL Adeno Wedge 10 61 M Yes No 1.8 RLL Solid fibrous tumor Wedge NM RUL Parenchyma Wedge 11 68 F Yes No 2.5 LUL Atypical carcinoid segment 0.3 LUL Adeno segment 12 69 F Yes No 0.7 RLL Met (melanoma) Wedge 0.2 RML Granuloma Wedge 13 71 F No No 1.4 LUL Adeno Wedge 0.5 LLL Organizing pneumonia Wedge 14 79 M Yes No 1.5 LLL Met (prostate) Wedge NM LUL Parenchyma Wedge 15 72 F Yes No 0.9 LUL Adeno Wedge NM LUL Parenchyma Wedge 16 77 M Yes Yes 1.1 RUL Met (pancreatic) Wedge NM RUL Parenchyma Wedge 17 66 F No No 1.1 LLL Adeno Wedge 0.2 LUL Adeno Wedge 18 68 F No No 1.2 LLL Adeno Wedge 0.2 LLL Granuloma Wedge 19 71 F Yes No 1.7 RUL Adeno Wedge NM RUL Parenchyma Wedge 20 50 M Yes Yes 1.0 LUL Met (colorectal) Wedge NM NM LUL LLL Parenchyma Parenchyma Wedge Wedge 21 54 M Yes Yes 1.0 RUL Met (colorectal) Wedge NM RUL Parenchyma Wedge 22 61 F No No 1.0 RUL Adeno Lobe 1.0 RUL Adeno Lobe 23 63 F Yes Yes NM RUL Parenchyma Wedge 0.45 RUL Adeno Wedge Adeno, adenocarcinoma; F, female; Hx, history; ID, identi fication; LLL, left lower lobe; LUL, left upper lobe; M, male; Met, metastasis; NM, no measurement (no lesion) on final pathologic examination; RLL, right lower lobe; RUL, right upper lobe. Ann Thorac Surg 2024;-:--- RICE ET AL PAFOLACIANINE IDENTIFIES OCCUL T LESIONS 5 Previous data from clinical experiences with pafolacianine-based IMI for NSCLC suggested that 26% to 53% of patients derive clinical bene fits.6,7 These bene fits have fallen into 3 general categories marked by improvements in the following: (1) localization of small, subpleural, or subsolid lesions; (2) detection of close or positive margins during sublobar resection; and (3) identification of otherwise occult malignant lesions at the time of resection. In this report, we reexamine the ELUCIDATE cohort and further describe data on occult le- sions that were identi fied exclusively by IMI. In this cohort of 100 participants, 23 participants were found to have additional lesions. Twenty- nine lesions were found in total, 10 (34%) of which represented additional malignancies. Seven lesions were considered synchronous primary lung cancers (adenocarcinoma), and 3 were metastatic lesions from a patient with a history of a chordoma. Occult lesions were most frequently initially m anaged with wedge resec- tion (26 of 29), which was found to add negligible morbidity on review of trial questionnaires and analysis of safety data. For incidentally identi- fied NSCLC in the same lobe as the preopera- tively known lesion (T3 lesions), surgeons participating in ELUCIDATE used lobectomy (n ¼ 2) or wedge resection (n ¼ 2). For NSCLC in a different lobe (n ¼ 4) than that of preoperatively known lesions (T4 lesions), the additional lesion was managed by sublobar resection ( Table 3 ). Although this was the observed trend, we recognize that management of occult malignant lesions identi fied by IMI will be nuanced and patient-speci fic. In those circumstances in which occult lesions were metastases originating from distant sites or benign lesions, wedge resection was typically performed. Unfortu- nately, we could not identify predictors of ma- lignancy in our univariate analysis, likely because the initial trial design of ELUCIDATE was not powered for such analyses. Given the lack of predictors of malignancy in occult le- sions, surgeons identifying occult lesions will need to make management decisions on the ba- sis of clinical risk factors and frozen section analysis. The finding of additional malignant occult le- sions in ELUCIDATE in 8% of patients was similar to the experience observed in the phase 1 trial, 11 which found occult lesions in 10% of patients, and was closely matched to the multicenter phase 2 trial,7 which found malignant occult lesions in 8% of patients. Furthermore, a recent “real-world” experience from the University of Pittsburgh Medical Center (Pittsburgh, PA) reported that malignant occult lesions were identi fied in 8% of patients.12 The rate of detection for occult malignant lesions in ELUCIDATE and in other experiences reported with pafolacianine falls within the frequency of occult lesion rates of 8% to 9% reported in the literature. 13 Although IMI with pafolacianine indeed does identify otherwise occult malignancies, it is important to acknowledge that the clinical impact of resection remains uncertain. Previous human experiences involving IMI are limited. For example, phase 1 and phase 2 trials were non- randomized experiences focused on feasibility, and it is therefore dif ficult to draw objective conclusions on the basis of improvements in overall or disease-free survivorship. 1,4,7 With regard to the randomized phase 3 trial (ELUCIDATE), the median follow-up period is only 2 years. 6 In the absence of these critical data, it is unclear whether resection of additional lesions is of oncologic bene fit, particularly in the case of identifying synchronous NSCLC. Interestingly, there is a recent report involving indocyanine green, a similar, but nonspeci fic, NIR imaging agent, which suggests that resection of additional lesions improves disease- free survival during metastasectomy. 14 In terms of practicality, IMI with pafolacianine requires only minor modi fications to standard TABLE 4 Characteristics of 23 Participants With Malignant Occult Non- Small Cell Lung Cancer Lesions Identi fied by Intraoperative Molecular Imaging Characteristics Participants With Malignant Occult Lesion(s) Participants With Benign Occult Lesion(s) Number of patients 8 14 Sex Female 8 7 Male 0 7 Age, y Mean (SD) 67.6 (± 8.5) 66.4 (± 8.4) Median [IQR] 64.5 [60-83] 68.5 [50-79] Pack-year smoking history, y Mean (SD) 29.5 (± 15.1) 23.9 (± 18.4) Median [IQR] 33.5 [0-45] 25.5 [0-50] Size of largest primary lesion Mean (SD) 17.9 (± 12.4) 14.1 (± 7.1) Median [IQR] 11 [8-42] 11.5 [7-34] IQR, interquartile range. 6 RICE ET AL PAFOLACIANINE IDENTIFIES OCCUL T LESIONS Ann Thorac Surg 2024;-:--- workflow. In most scenarios, pafolacianine was delivered preoperatively in the holding area, with 95% of patients completing the infusion. Toxicity was minimal, as previously noted. 6 Intraoperatively, molecular imaging required a median time of 2 minutes (maximum, 23 minutes). During traditional video-assisted thor- acoscopic surgery, most participating surgeons used an NIR camera, thus no additional ports were required. For those surgeons using robotic-assisted thoracoscopic surgery techniques, in general participating surgeons initially identi fied and marked lesions using the specialized NIR camera systems and then proceeded with robotic resection. Newer-generation cameras and robots will have the added ability to identify and detect pafolacianine. Although IMI with pafolacianine provides a safe and practical approach to identify otherwise occult malignancies at the time of pulmonary resection, long-term bene fits are unclear at this time. As such, we think it is important to emphasize that IMI was developed to provide additional data to the surgeon, and not to replace surgeon’s decision making. Intraoperative fluo- rescent feedback with IMI should serve as a sup- plement to traditional modalities such as preoperative imaging, intraoperative cues, and clinical variables. Potential bene fits of resecting additional malignant lesions must be balanced with considerations of unnecessary parenchymal resection in circumstances of “false positives” and the extent of additional resection required. In addition, the surgeon should consider the clinical impact when the primary diagnosis is early-stage lung cancer vs pulmonary metastases. This report provides additional data so that the sur- geon can better determine whether resection of additional lesions identi fied by IMI is warranted. The authors wish to thank the patients and their families for participa- tion in this study, as well as all investigators and clinical study site staff who supported the study. The authors also wish to acknowledge pa- thology services of Mof fitt Cancer Center Tissue Core and the Total Cancer Care program and manuscript writing and editing support from Kerri Pierz, PhD (Elucidate Health, LLC) and H.B. Slade, MD (Chisholm Clinical Research Services, LLC). FUNDING SOURCES Moffitt Cancer Center is a National Cancer Institute – designated Comprehensive Cancer Center under grant number P30-CA076292. Funding for the ELUCIDATE study was provided by On Target Labora- tories, Inc. This report includes data generated from a randomized multicenter phase 3 trial sponsored by On Target Laboratories. All participating authors were investigators in the sponsored trial and report financial support, administrative support, article publishing charges, equipment, drugs, or supplies, statistical analysis, and writing assistance provided by On Target Laboratories LLC. DISCLOSURES Linda W. Martin reports a relationship with Bristol Myers Squibb that includes: consulting or advisory. Michael I. Ebright reports a relationship with On Target Laboratories that includes: consulting or advisory; and with Medtronic that includes: consulting or advisory. T ommy Lee reports a relationship with On Target Laboratories LLC that includes: employ- ment and equity or stocks. Jarrod D. Predina reports a relationship with On Target Laboratories LLC that includes: consulting or advisory; and with Olympus that includes: consulting or advisory. All other authors declare that they have no con flicts of interest. REFERENCES 1. Predina JD, Fedor D, Newton AD, et al. 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