Characteristics of pneumonitis associated with immune checkpoint inhibitor nivolumab; preliminary report

[Background] A new type of pneumonitis associated with immune checkpoint inhibitor treatment has been reported. We have analyzed clinical and radiological feature of nivolumab related pneumonitis and tried to characterize patterns of immune mediated pneumonitis. [Methods] Based on nationwide post-marketing surveillance of nivolumab in Japan, we collected clinical and radiological data on cases reported as pneumonitis by physicians during or after nivolumab treatment for melanoma or non-small cell lung cancer. Expert review committee consisted of radiologists, pulmonologists and medical oncologists evaluated the clinical course, computed tomography imaging and validity of the diagnosis of pneumonitis in these cases. Radiological patterns were classified into two categories; pneumonitis including ground glass opacity or consolidation showing non-segmental distribution on both sides or dominant in contralateral lung to tumor, which is known as typical pattern associated with chemotherapy or molecular targeted drugs. Another type was categorized with atypical feature including (1) ground glass opacity confined to the area around the tumor named “peritumoral infiltration”, (2) similar pattern to exacerbation of radiation fibrosis, (3) patterns like intensified infections and (4) abnormal opacities almost confined to ipsilateral lung of the tumor. [Results] Among the cases reported, we analyzed 154 cases with sufficient available data. In 136 of those, causal relationship of pneumonitis to nivolumab was evaluated as reasonable possibility by the committee. The findings from 100 (73.5%) among these 136 cases were the known features of typical pneumonitis. Atypical features were observed in the remaining 36 cases including 23 with peritumoral infiltration, 17 with reaggravation of radiation fibrosis, and 3 with intensified infection.Peritumoral infiltration was accompanied with other atypical imaging features in 12 cases, with typical imaging features in 4, alone in 7. The median time upon appearance of peritumoral infiltration was 29 days after the start of treatment (range: 5-139 days). Nivolumab treatment was discontinued in all 23 cases. All 23 cases were treated with corticosteroids, with the outcome being recovery in 11 cases, alleviation in 10 cases and death in 2 cases. [Conclusions] Although this is a preliminary report of an on-going surveillance with several limitations including biased patient selection, clinicians should pay attention to these features unique to nivolumab-associated pneumonitis, in addition to typical features of conventional drug-induced pneumonitis. As brand new pattern “peritumoral infiltration” showed good response to steroid treatment, immunopotentiation may be potential cause of immune checkpoint inhibitor associated pneumonitis.