Accurately detecting lung tumours and their margins is important for disease outcomes.1,2 However, detection is challenging due to the use of minimally invasive surgery and current localization techniques, such as computed tomography (CT)-guided and endobronchial interventions, which add significantly to procedure time and risk of complications.3 Intraoperative imaging using a targeted agent to optically fluoresce cancerous cells may address these problems, in addition to locating previously unknown tumours and determining tumour margins.4
The fluorescent imaging agent pafolacianine binds and accumulates in folate receptor–positive tissues, visually highlighting these tissues intraoperatively when under a near–infrared lighting system.5 As the majority of pulmonary malignancies continue to express the folate receptor after chemotherapy,6,7 the phase 3 ELUCIDATE trial (ClinicalTrials.gov identifier: NCT04241315) investigated the use of pafolacianine in detecting lung tumours.8 In this expert interview, Professor Linda Martin discusses challenges in intraoperative imaging of lung nodules, and the ELUCIDATE trial of pafolacianine.
Q. What are the challenges in intraoperative imaging of lung nodules?
Some of the challenges come from the desire to make surgery even more minimally invasive, which makes it harder for the surgeon to feel or palpate nodules within the lung to help localize them and determine the margins. So, we were looking for ways to improve our technology so that we can accurately find and remove small nodules while maintaining a minimally invasive surgical approach.
Q. Following approval in ovarian cancer, what was the rationale for investigating pafolacianine in lung cancer detection?
The idea for intraoperative imaging is based on previous practice. In the past, when looking for a small nodule, patients would be sent for an additional invasive procedure to inject a dye or a tracer, allowing for imaging of the nodule during surgery. However, this meant additional risk and cost, as well as introducing a human element into the imaging. The pulmonologist or radiologist was required to estimate where to inject the dye or tracer, which would sometimes result in the dye ending up in the wrong place, for example in the pleural space, or result in the patient getting a pneumothorax. Additionally, this method would not allow for the estimation of nodule margins because it was just an estimate of the location of the nodule. The novel idea was to take this previous imaging practice but use intraoperative molecular imaging, where a tracer is given intravenously and only accumulates in cancerous tissue. This provides an accurate location of the nodule, and in a substantial number of patients, second and even third nodules that were previously unknown are also located. Overall, this provides much more information at the time of surgery.
Q. What were the aims, design and inclusion criteria of the phase 3 ELUCIDATE trial?
The ELUCIDATE trial aimed to confirm the efficacy of intraoperative molecular imaging with pafolacianine to localize lung nodules, identify additional tumours and assess tumour margins during pulmonary resection. The trial had a phase 3 design, where all patients received a single intravenous infusion of pafolacianine (0.025 mg/kg) 24 hours before surgery. Patients were randomized 1:10 to intraoperative molecular imaging using an infrared camera or traditional methods of white light and palpation of nodules. The primary study endpoint was to assess the number of clinically significant events, defined in the following three ways: 1. Did we identify the nodule in question? 2. Did we find a second nodule? 3. Were we able to assess the nodule margins based on this technology? Overall, rather than assess longer-term outcomes such as survival following the procedure, this study just aimed to test the technology.
Q. Could you give us an overview of the clinical data supporting the approval of pafolacianine in this indication?
Patients eligible for the ELUCIDATE trial included those with diagnosed or suspected lung cancer. In total, 54% of patients in the intraoperative molecular imaging group (n=100) had at least one clinically significant event. This included 19 patients whose tumour could not be located by white light, 9 patients who had additional previously unknown nodules identified, and 38 patients who had close (≤10 mm) margins. There were no drug-related serious adverse events. Based on these results, pafolacianine is now approved by the US Food and Drug Administration to assist in the identification of known or suspected lung tumours.9
Q. What impact will this approval have on the treatment paradigm for thoracic surgery, and in which patients will pafolacianine be considered?
In my opinion, this study will have a large impact, as it expands our ability to safely perform surgery with fewer steps and interventions for patients with small lung nodules of unclear origin. This is particularly important given the increased adoption of lung cancer screening, which has created a conundrum in instances where we find small lung nodules. In these instances, the malignancy of nodules is unknown, locating them is very challenging, and there is a need to remove them in an as minimally invasive manner as possible. Intraoperative molecular imaging with pafolacianine provides a technique for greater accuracy in determining margins, with the added benefit of finding unknown nodules and without the need for a separate invasive procedure.