www.thelancet.com/oncology Published online September 24, 2020 https://doi.org/10.1016/S1470-2045(20)30453-8 1 Articles Lancet Oncol 2020 Published Online September 24, 2020 https://doi.org/10.1016/ S1470-2045(20)30453-8 Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain (M Provencio MD, A Royuela PhD, M Casarrubios MSc, C Salas Antón MD, V Calvo MD, R Laza-Briviesca MSc, A Romero PhD, A Cruz-Bermúdez PhD); Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Institute of Health Carlos III, Madrid, Spain (A Royuela); Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona, Spain (E Nadal MD); Fundación INCLIVA, Hospital Clínico Universitario de Valencia, Valencia, Spain (A Insa MD); Hospital Universitario A Coruña, A Coruña, Spain (M R García-Campelo MD); Hospital Universitario de Vigo, Pontevedra, Spain (J Casal-Rubio MD); Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain (M Dómine MD); Hospital de la Santa Creu I Sant Pau, Barcelona, Spain (M Majem MD); Hospital Insular de Gran Canaria, Las Palmas, Spain (D Rodríguez-Abreu MD); Hospital Universitario e Instituto de Oncología Vall d´Hebron (VHIO), Barcelona, Spain (A Martínez-Martí MD); Hospital Universitario La Paz, Madrid, Spain (J De Castro Carpeño MD); Hospital Universitario Regional de Málaga, Málaga, Spain (M Cobo MD); Hospital Universitario Cruces, Barakaldo, Spain (G López Vivanco MD); Hospital Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial Mariano Provencio, Ernest Nadal, Amelia Insa, María Rosario García-Campelo, Joaquín Casal-Rubio, Manuel Dómine, Margarita Majem, Delvys Rodríguez-Abreu, Alex Martínez-Martí, Javier De Castro Carpeño, Manuel Cobo, Guillermo López Vivanco, Edel Del Barco, Reyes Bernabé Caro, Nuria Viñolas, Isidoro Barneto Aranda, Santiago Viteri, Eva Pereira, Ana Royuela, Marta Casarrubios, Clara Salas Antón, Edwin R Parra, Ignacio Wistuba, Virginia Calvo, Raquel Laza-Briviesca, Atocha Romero, Bartomeu Massuti, Alberto Cruz-Bermúdez Summary Background Non-small-cell lung cancer (NSCLC) is terminal in most patients with locally advanced stage disease. We aimed to assess the antitumour activity and safety of neoadjuvant chemoimmunotherapy for resectable stage IIIA NSCLC. Methods This was an open-label, multicentre, single-arm phase 2 trial done at 18 hospitals in Spain. Eligible patients were aged 18 years or older with histologically or cytologically documented treatment-naive American Joint Committee on Cancer-defined stage IIIA NSCLC that was deemed locally to be surgically resectable by a multidisciplinary clinical team, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received neoadjuvant treatment with intravenous paclitaxel (200 mg/m²) and carboplatin (area under curve 6; 6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was progression-free survival at 24 months, assessed in the modified intention-to-treat population, which included all patients who received neoadjuvant treatment, and in the per-protocol population, which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Safety was assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03081689, and is ongoing but no longer recruiting patients. Findings Between April 26, 2017, and Aug 25, 2018, we screened 51 patients for eligibility, of whom 46 patients were enrolled and received neoadjuvant treatment. At the time of data cutoff (Jan 31, 2020), the median duration of follow-up was 24·0 months (IQR 21·4–28·1) and 35 of 41 patients who had tumour resection were progression free. At 24 months, progression-free survival was 77·1% (95% CI 59·9–87·7). 43 (93%) of 46 patients had treatment- related adverse events during neoadjuvant treatment, and 14 (30%) had treatment-related adverse events of grade 3 or worse; however, none of the adverse events were associated with surgery delays or deaths. The most common grade 3 or worse treatment-related adverse events were increased lipase (three [7%]) and febrile neutropenia (three [7%]). Interpretation Our results support the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable stage IIIA NSCLC. Neoadjuvant chemoimmunotherapy could change the perception of locally advanced lung cancer as a potentially lethal disease to one that is curable. Funding Bristol-Myers Squibb, Instituto de Salud Carlos III, European Union’s Horizon 2020 research and innovation programme. Copyright © 2020 Elsevier Ltd. All rights reserved. Introduction Non-small-cell lung cancer (NSCLC) accounts for 80–85% of all lung cancer cases. Approximately 20% of patients with NSCLC are diagnosed with stage IIIA (N2) disease. 1 Outcomes remain poor for this subset of patients, even in patients with potentially operable tumours, with a median progression-free survival of 13 months and a 3-year overall survival of 30%, with no major treatment advances made in the past 25 years. 2 Pathological response to neoadjuvant treatment is a potential surrogate endpoint for survival; however, considering the low proportion of patients who achieve complete pathological response with induction chemo- therapy (median 4%; range 0–16%), a definitive asso- ciation has been difficult to establish, and has not been validated in NSCLC. 3 In a 2018 study, neoadjuvant administration of two doses of nivolumab was associated with major pathological response in nine (45%) of 20 evaluable patients with NSCLC tumours, with two (10%) of 20 patients achieving a complete pathological response. 4 Furthermore, in a 2020 study of neoadjuvant chemoimmunotherapy, 17 (57%) of