Nodal immune flare mimics nodal disease progression following neoadjuvant immune checkpoint inhibitors in non-small cell lung cancer

Abstract

Radiographic imaging is the standard approach for evaluating the disease involvement of lymph nodes in patients with operable NSCLC although the impact of neoadjuvant immune checkpoint inhibitors (ICIs) on lymph nodes has not yet been characterized. Herein, we present an ad hoc analysis of the NEOSTAR trial (NCT03158129) where we observed a phenomenon we refer to as “nodal immune flare” (NIF) in which patients treated with neoadjuvant ICIs demonstrate radiologically abnormal nodes post-therapy that upon pathological evaluation are devoid of cancer and demonstrate de novo non-caseating granulomas. Abnormal lymph nodes are analyzed by computed tomography and 18F-fluorodeoxyglucose positron emission tomography/computer tomography to evaluate the size and the maximum standard uptake value post- and pre-therapy in NEOSTAR and an independent neoadjuvant chemotherapy cohort. NIF occurs in 16% (7/44) of patients treated with ICIs but in 0% (0/28) of patients after neoadjuvant chemotherapy. NIF is associated with an inflamed nodal immune microenvironment and with fecal abundance of genera belonging to the family Coriobacteriaceae of phylum Actinobacteria, but not with tumor responses or treatment-related toxicity. Our findings suggest that this apparent radiological cancer progression in lymph nodes may occur due to an inflammatory response after neoadjuvant immunotherapy, and such cases should be evaluated by pathological examination to distinguish NIF from true nodal progression and to ensure appropriate clinical treatment planning.

Immune-related dissociated response as a specific atypical response pattern in solid tumors with immune checkpoint blockade

“…This is supported by a recently published study showing a specific ‘nodal immune flare’ phenomenon in which NSCLC patients demonstrate radiologically abnormal nodes due to a pathological inflammatory response after neoadjuvant ICIs (16%), but not after neoadjuvant chemotherapy (0%). 35 Such temporary inflammatory response can be observed in lymph nodes and be misinterpreted as disease progression. Although no data directly show the frequency of responding lesions being seen in lymph nodes while progressive lesions may be in other viscera, avoiding using lymph nodes as target lesions and exclusion of lymph nodes in response criteria for immunotherapy should be considered, to precisely defined patients with DR or other atypical responses.…”

The Evolving Role of Immunotherapy in Stage III Non-Small Cell Lung Cancer

“…This was due to immune-cell infiltration into the tumour, rather than tumour growth [ 39 ]. In an ad hoc analysis of the NEOSTAR trial, a “nodal immune flare” (NIF) phenomenon was observed in which patients treated with neoadjuvant ICIs demonstrate radiologically abnormal nodes post-therapy that upon pathological evaluation were devoid of cancer and demonstrated de novo non-caseating granulomas [ 40 ]. This occurred in approximately 16% of patients treated with ICIs.…”

Pathological Response and Immune Biomarker Assessment in Non-Small-Cell Lung Carcinoma Receiving Neoadjuvant Immune Checkpoint Inhibitors

“…The rationale of using immunotherapy as a neoadjuvant treatment lies in the concept that the administration of an ICI while the primary tumor is still in the patient will result in a better systemic anti-tumor immune response. Preclinical in vivo studies in murine models of breast and lung cancer have shown that neoadjuvant immunotherapy works better than immunotherapy in the adjuvant setting, supporting the hypothesis that ICI therapy would be more efficient in driving the anti-tumor T cell response when the tumor mass contains a high antigen burden to be recognized by host T cells [ 13 , 14 , 15 ].…”

“…This phase 3 clinical trial was preceded by several clinical trials that have shown the feasibility and efficacy of several immunotherapeutic approaches for neoadjuvant therapy alone or in combination in patients with resectable NSCLC Stage IB, II, and III. These studies have shown a low toxicity and a high percentage of patients achieving a major pathological response (MPR) and cPR [ 12 , 13 , 14 , 15 , 16 , 17 ].…”