TY - JOUR T1 - Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2020-001282 VL - 8 IS - 2 SP - e001282 AU - Joshua E Reuss AU - Valsamo Anagnostou AU - Tricia R Cottrell AU - Kellie N Smith AU - Franco Verde AU - Marianna Zahurak AU - Mara Lanis AU - Joseph C Murray AU - Hok Yee Chan AU - Caroline McCarthy AU - Daphne Wang AU - James R White AU - Stephen Yang AU - Richard Battafarano AU - Stephen Broderick AU - Errol Bush AU - Malcolm Brock AU - Jinny Ha AU - David Jones AU - Taha Merghoub AU - Janis Taube AU - Victor E Velculescu AU - Gary Rosner AU - Peter Illei AU - Drew M Pardoll AU - Suzanne Topalian AU - Jarushka Naidoo AU - Ben Levy AU - Matthew D Hellmann AU - Julie R Brahmer AU - Jamie E Chaft AU - Patrick M Forde Y1 - 2020/09/01 UR - http://jitc.bmj.com/content/8/2/e001282.abstract N2 - Background We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab.Methods Patients with resectable stage IB (≥4 cm)–IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint.Results While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations.Conclusions Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response. ER -