Background: NAP is a chimeric protein composed of a superantigen (SAg) and a Fab targeting common tumor antigen 5T4, which is highly expressed in NSCLC. Its therapeutic effect is associated with activation, expansion, and tumor infiltration of SAg-binding specific T cells. Docetaxel is important therapeutic component in the treatment of advanced-stage NSCLC and SOC after failure of chemo-immunotherapy. We present initial results from this open label single arm trial, with advanced/metastatic NSCLC pts previously treated with at most 2 prior systemic therapies, including platinum-based chemotherapy and CPI, were treated with NAP and docetaxel. Methods: Patients were treated with NAP at 10 mcg/kg and docetaxel at a standard dose (75 mg/m2) in 21 day cycles for up to 2 years. If docetaxel was discontinued, NAP could be continued as monotherapy in 28 day cycles. Obinutuzumab pretreatment prior to cycle 1 used to inhibit anti-drug antibodies (ADAs) to NAP. Primary objective was overall response rate (ORR) and duration of response (DOR) based on institutional iRECIST review. Secondary objectives included safety, progression free survival (PFS) and overall survival (OS). Results: The trial enrolled 38 pts, 36 received NAP, 32 had post baseline imaging and were evaluable for response. Median age 66 yrs (33-85), 55% male, ECOG 0 in 26% and 1 in 74%. Eight pts (21%) had CNS involvement at baseline but brain MRI was not initially required, but implemented later in the trial. All pts received platinum-based chemotherapy and CPI, with a median of 2 (1-4) prior regimens. Nine pts (24%) received 2 CPI containing regimens. NAP safety was acceptable and consisted of mostly grade 1-2 infusion related reactions, were generally easily manageable and rapidly reversable that were in line with previous reports. Pts received median of 4 combination cycles and 14 pts (39%) continued NAP as monotherapy. NAP treatment was discontinued due to toxicities in 2 pts (5%). Five pts had PR, 2 of them unconfirmed, ORR 16%. Two pts had prolonged responses: one lasted for 22 m and the second had CR in target lesions lasted for 24 m with progression in brain treated with radiation, which did not compromise pts systemic response. One pt had initial pseudo-progression in target lesions with a subsequent PR, suggesting a possible immune response. Mean response duration was 7.3 m (1.3 - 20.8). Mean PFS was 4.6 m, 18 pts (56%) had SD, disease-control rate (DCR) was 72%, with mean duration of 5.3 m. Median OS was 8 months with 11 pts (34%) still alive at database lock and 3 pts receiving NAP under individual expanded access protocol. Conclusions: These preliminary results of NAP + docetaxel show potential evidence of activity with acceptable safety in heavily pre-treated NSCLC pts. Further trials of NAP in combination, including CPIs are planned. Clinical trial information: NCT04880863.