Patterns of Failure in Resectable Stage I-IIIA NSCLC Treated with Neoadjuvant Immunotherapy Combinations, a Secondary Analysis of a Prospective Trial

Abstract

<h3>Purpose/Objective(s)</h3> The impact of neoadjuvant immune checkpoint inhibitor (ICI)-based therapies on mediastinal recurrence patterns after resection for non-small cell lung cancer (NSCLC) is unknown. We describe patterns of mediastinal failure after receipt of neoadjuvant ICI and provide a descriptive analysis of patients who experienced a mediastinal recurrence. <h3>Materials/Methods</h3> Between August 2015 and August 2021, patients with stage I-IIIA NSCLC treated with nivolumab-based therapies prior to resection on the clinical trial NA_00092076 were identified. Patient, tumor, treatment, pathological, recurrences, and post-operative therapy data were obtained from the trial. Variables including central location, initial mediastinal node involvement were obtained via chart review. <h3>Results</h3> Of the 23 NSCLC patients identified: median age was 66 years (range: 48-78), 68% (n= 15) were male, and 39% (n=9) and 35% (n=8) had stage II and III NSCLC, respectively at initial diagnosis. Histological subtypes included adenocarcinoma (50%) and squamous (36%). ICI therapies included: nivolumab (48%, n=11), nivolumab/ipilimumab (17%, n=4), nivolumab with carboplatin/paclitaxel (4%, n=1). A majority of patients received a lobectomy (70%, n=16) and had a margin negative resection (95%, n=22). The median follow-up was 41 months (range: 1 – 74). A majority (70%, n=13) of patients had centrally located tumors. Nodal involvement included: 57% (n=13) N0, 35% (n=7) N1, and 13% (n=3) N2 disease. Two patients developed mediastinal recurrence, both with initial stage III disease. Of the 3 patients with cN2 disease, none received post-operative radiation (RT) after resection and 33% (n=1/3) developed mediastinal recurrence. Of the two patients who experience a mediastinal recurrence: Patient 1 (initial T1N2 disease) achieved major pathologic response (MPR) and overall tumor downstaging to ICI. Locoregional recurrence included the initially involved 4R node. The patient is without evidence of disease 4 years after salvage chemoRT. Patient 2 (initial T3N1 disease) had no MPR nor tumor down staging to ICI. This patient developed mediastinal and distant metastases after declining post-op RT after a R1 pneumonectomy. Both patients received neoadjuvant ICI alone and had initial tumor disease within 2 cm of central airways. <h3>Conclusion</h3> In this analysis, we provide the first report of patterns of mediastinal failure in patients with resectable stage I-IIIA NSCLC who have received neoadjuvant ICI-based therapies. Patients with MPR may still have risk of mediastinal recurrence. The patients who developed mediastinal failure in this cohort had initial N2 disease, lack of response to therapy, and R1 resection. These variables may be associated with mediastinal failure risk after neoadjuvant ICI-based therapies. Multi-institutional efforts are needed to better characterize the risk factors associated with mediastinal recurrence after neoadjuvant ICI.