P2.04-90 Nodal Immune Flare (NIF) Following Neoadjuvant Anti-PD-1 and Anti-CTLA-4 Therapy in Non-Small Cell Lung Cancer

Immune checkpoint inhibitors (ICIs) have induced durable responses in selected non-small cell lung cancer (NSCLC) patients. However, ICIs have also shown to induce tumor pseudo-progression in some cases. We report the incidence and consequences of a distinct phenomenon – the apparent radiographic progression of lymph nodes without pathological evidence of tumor – that we define "nodal immune flare" (NIF), following neoadjuvant ICIs in the NEOSTAR phase 2 trial of nivolumab or nivolumab plus ipilimumab for operable NSCLCs. NEOSTAR randomized 44 patients with stage I-IIIA (AJCC 7th edition) to nivolumab (3 mg/kg IV, days 1, 15, 29) or nivolumab/ipilimumab (1 mg/kg IV, day 1) with planned surgery between 3-6 weeks after last dose. Computed tomography (CT) and positron emission tomography (PET-CT) were obtained prior to ICIs and prior to resection. Response Evaluation Criteria in Solid Tumors v1.1 were used to evaluate responses. 44 patients, median age 66 years (range 43-83), 28 (64%) males, 37 (84%) white were randomized to nivolumab (n=23) or nivolumab/ipilimumab (n=21). 26 (59%) had adenocarcinoma, 17 (39%) squamous cell, 1 (2%) adenosquamous carcinoma. 23 (52%) stage I, 12 (27%) stage II, 9 (20%) stage IIIA. 39 (89%) underwent complete resection, 2 off trial, and 5 (11%) were not resected. NIF occurred in 5/44 (11%) patients, 3 post nivolumab (3/23, 13%) and 2 (2/21, 10%) post nivolumab/ipilimumab. All patients had no evidence of malignancy in nodes of interest prior to ICIs. 2 (2/26, 8%) occurred in adenocarcinoma and 3 (3/17, 18%) in squamous cell. 2 (5%) required additional invasive restaging, 3 (7%) change in surgical plan, 1 (2%) declined surgery, 1 (2%) was thought to have disease progression and was treated with chemotherapy plus ICI prior to resection off study, and 1 (2%) underwent planned resection. Pathologic evaluation of the flared nodes revealed no evidence of cancer in all 5 patients, rather demonstrated noncaseating granulomata. In a previous neoadjuvant trial utilizing platinum-based chemotherapy with nintedanib, we did not observe NIF in 21 patients in absence of pathologic evidence of tumor progression (primary or nodal metastases). NIF occurred in 11% of patients following neoadjuvant ICIs and changed treatment plan in 9% of patients. This is the first preliminary report of NIF in operable NSCLCs treated with neoadjuvant single and combined ICIs. Considering the number of ongoing neoadjuvant immunotherapy trials, we highlight the importance of judicious and invasive restaging of sites of suspected progression after neoadjuvant ICIs prior to definitive treatment decisions.