A Phase 2 Multicenter Clinical Trial of Intraoperative Molecular Imaging of Lung Cancer with a pH-Activatable Nanoprobe

Abstract

Purpose: Intraoperative molecular imaging (IMI) uses tumor-targeted optical contrast agents to improve identification and clearance of cancer. Recently, a probe has been developed that only fluoresces when activated in an acidic pH, which is common to many malignancies. We report the first multicenter Phase 2 trial of a pH-activatable nanoprobe (pegsitacianine, ONM-100) for IMI of lung cancer.

Methods: Patients with suspected or biopsy-confirmed lung cancer scheduled for sublobar resection were administered a single intravenous infusion of pegsitacianine (1 mg/kg) one to three days prior to surgery. Intraoperatively, the patients underwent a white light thoracoscopic evaluation, and then were imaged with an NIR thoracoscope to detect tumor fluorescence. The primary study endpoint was the proportion of patients with a clinically significant event (CSE) which was defined as an intraoperative discovery during IMI that led to a change in the surgical procedure. Possible CSEs included (i) localizing the index lung nodule that could not be located by white light, (ii) identifying a synchronous malignant lesion, or (iii) recognizing a close surgical margin (< = 10 mm). Secondary endpoints were sensitivity, specificity, NPV, and PPV of pegsitacianine in detecting tumor-containing tissue. The safety evaluation was based on adverse event reporting, clinical laboratory parameters, and physical examinations.

Results: Twenty patients were confirmed as eligible and administered pegsitacianine. Most of the patients were female (n = 12 [60%]), middle-aged (mean age 63.4 years), and former smokers (n = 13 [65%], 28.6 mean pack years). Mean lesion size was 1.9 cm, and most lesions (n = 17 [85%]) were malignant. The most common histologic subtype was adenocarcinoma (n = 9). By utilizing IMI with pegsitacianine, one patient had a CSE in the detection of a close margin and another had localization of a tumor not detectable by traditional surgical means. Six of 19 (31.6%) malignant lesions fluoresced with mean tumor-to-background ratio (TBR) of 3.00, as compared to TBR of 1.20 for benign lesions (n = 3). Sensitivity and specificity of pegsitacianine-based IMI for detecting malignant tissue was 31.6% and 33.3%, respectively. Positive predictive value (PPV) and negative predictive value (NPV) of pegsitacianine-based IMI was 75% and 7.1%, respectively. Pegsitacianine-based imaging was not effective in differentiating benign and malignant lymph nodes. From a safety perspective, no drug-related serious adverse events occurred. Four patients experienced mild pegsitacianine-related infusion reactions which required discontinuing the study drug with complete resolution of symptoms.

Conclusions: Pegsitacianine-based IMI, though well tolerated from a safety perspective, does not consistently label lung tumors during resection and does not provide significant clinical benefit over existing standards of surgical care. The biology of lung tumors may not be as acidic as other solid tumors in the body thereby not activating the probe as predicted.

Keywords: Activatable probe; Intraoperative molecular imaging; Lung cancer.

Fig. 1

Pegsitacianine labeling of a visually occult, nonpalpable tumor. The top row shows the representative preoperative CT and PET images of a right upper lobe lung nodule from a patient in the clinical trial. The bottom row shows paired white light, near infrared (NIR), and overlay intraoperative images showing pegsitacianine fluorescence. The nodule is not apparent on white light imaging, but is clearly demarcated by pegsitacianine

Fig. 2

Pegsitacianine labeling of a close resection margin. The top row shows the representative preoperative CT and PET images of a central right lung mass from a patient in the clinical trial. The bottom row shows paired white light, near infrared (NIR), and overlay images showing pegsitacianine fluorescence in the resection specimen ex vivo. Fluoroscence is noted in the very near proximity of the resection margin, and the close margin was confirmed by pathologic analysis

Fig. 3

Representative images of a nonfluorescent lesion (false negative) in the study. The top row shows the representative preoperative CT and PET images of a left upper lobe lung nodule from a patient in the clinical trial. The bottom row shows paired white light, near infrared (NIR), and overlay intraoperative images. Neither brightfield nor NIR imaging delineated the nodule in question, which required a thoracotomy for identification. Final pathology returned as adenocarcinoma

Fig. 4

Patterns of distribution of pegsitacianine fluorescence in resected tumors. A. Representative white light, near-infrared (NIR), and overlay images of an ex vivo tumor section showing pegsitacinine fluorescence at the tumor periphery (arrow) but minimal fluorescence in the center of the tumor. B. NIR heatmaps of tumor samples taken from the periphery and center of a tumor, again showing pegsitacianine fluorescence preferentially distributed a the tumor border. C. Mean fluorescence intensity of tissue taken from the peripheral borders of tumors compared with tissue taken from the center of tumors. ** represents p < 0.01