Nivolumab after cyclophosphamide and doxorubicin induction chemotherapy in previously treated patients with EGFR or ALK wild type non-squamous cell non-small cell lung cancer with less than 10% of PD-L1 expression

Purpose To investigate whether cyclophosphamide (C) and adriamycin (A) induction therapy (IT) prior to nivolumab could enhance the efficacy of nivolumab in previously treated patients with non-squamous (NSQ) non–small-cell lung cancer (NSCLC) with less than 10% PD-L1 expression. Methods Patients received four cycles of CA-IT (C,500 mg/m2 and D, 50 mg/m2) every 3weeks. Nivolumab was given 360 mg every 3 weeks from the second cycle. After 4 cycles of CA-IT, nivolumab 480 mg was administered every 4 weeks. We collected blood samples for next-generation sequencing, fluorescence-activated Cell Sorting (FACS) to characterize immune cells, and liquid chromatography-tandem mass spectrometry to identify potential biomarkers. Results A total of 22 patients were enrolled. The median progression-free and overall survivals were 2.4 months (95% CI, 1.3–3.5) and 11.6 months (95% CI, 5.3–18.0), respectively. Two patients with a partial response received nivolumab for 2 years without disease progression. FACS revealed the lowest ratio of myeloid-derived suppressor cells (MDSCs) to CD8 + T-cell throughout the treatment in responders. Proteomic analysis identified a consistent upregulation of extracellular matrix-receptor interactions and phagosome pathways in the responders. Among the differentially expressed proteins, the transferrin receptor protein (TRFC), which mediates ferroptosis and phagocytosis, was higher in responders than in non-responders before treatment. Conclusions CA-IT did not improve nivolumab efficacy in NSQ-NSCLCs with low PD-L1 expression. However, CA-IT induced deceasing MDSC resulted in durable response. Higher baseline TRFC levels may predict favorable response to nivolumab in NSCLC with low PD-L1 expression. Trial Registration: NCT03808480