Background: Adoptive cell therapy with TIL has demonstrated durable complete responses in immunogenic tumors with high mutational burden. Durvalumab, which enhances T-cell antitumor cytotoxicity through blockade of the PD-1/PD-L1 axis, has demonstrated clinical activity in NSCLC. Despite recent advances in the treatment of NSCLC using checkpoint inhibitors, the majority of patients do not respond, leaving an unmet need to improve therapeutic outcomes, warranting this investigation of TIL therapy alone and in combination with durvalumab. IOV-LUN-201 is a phase 2 multicenter, open-label study designed to evaluate the efficacy and safety of autologous LN-145 therapy alone or in combination with durvalumab, for previously-treated, anti-PD-1/PD-L1-naïve NSCLC patients. Methods: LN-145 is a preparation of TIL extracted from surgically-resected tumors and manufactured in a 22-day process at a central GMP facility. LN-145 infusion is preceded by a non-myeloablative lymphodepletion regimen of cyclophosphamide and fludarabine, and followed by up to 6 infusions of IV IL-2. Cohort 1 patients receive LN-145 therapy alone. Patients in Cohort 1 who do not receive LN-145 or those who progress following LN-145 therapy can receive durvalumab 1500 mg IV Q4W until progression or unacceptable toxicity. Cohort 2 patients receive durvalumab 2 weeks prior to and 2 weeks after tumor harvest, and then following LN-145 infusion resume durvalumab 1500 mg IV Q4W until progression or unacceptable toxicity. Patients unable to receive LN-145 are allowed to receive durvalumab alone. Patients ≥ 18 years of age must have confirmed stage III/IV NSCLC and have received ≥1 line of prior systemic therapy, excluding anti-PD-1/anti-PD-L1. Other major eligibility criteria include: minimum of 2 tumor lesions, adequate organ function, and ECOG PS 0 or 1. Primary endpoints are efficacy as defined by ORR and safety of LN-145 as a single agent or in combination with durvalumab; secondary endpoints are DOR and PFS per RECIST 1.1, and OS. Key exploratory objectives include CR rate, DCR, immune correlates of response, and HRQoL. Clinical trial information: NCT03419559