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      Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer

      brief-report
      1 , 2 , 1 , 2 , 1 , 2 , 3 , 1 , 1 , 1 , 2 , 2 , 4 , 1 , 5 , 1 , 1 , 6 , 1 , 6 , 1 , 6 , 1 , 6 , 1 , 6 , 1 , 6 , 7 , 8 , 9 , 10 , 1 , 5 , 1 , 2 , 1 , 1 , 5 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 4 , 10 , 1 , 2 , 4 , 10 , 1 , 2 ,
      Journal for Immunotherapy of Cancer
      BMJ Publishing Group
      immunotherapy, lung neoplasms, tumor microenvironment, clinical trials as topic, tumor biomarkers

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          Abstract

          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.

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          Most cited references12

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          Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial

          Approximately 25% of all patients with non-small-cell lung cancer present with resectable stage IB-IIIA disease, and although perioperative chemotherapy is the standard of care, this treatment strategy provides only modest survival benefits. On the basis of the activity of immune checkpoint inhibitors in metastatic non-small-cell lung cancer, we designed a trial to test the activity of the PD-L1 inhibitor, atezolizumab, with carboplatin and nab-paclitaxel given as neoadjuvant treatment before surgical resection.
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            Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC

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              Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC)

              Background Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic ‘tumor’ measurements were also assessed. Results We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation—dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death—cholesterol clefts; and (iii) tissue repair—neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P  < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop ‘Immune-Related Pathologic Response Criteria’ (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%–29%) versus 10% (0%–58%), P  = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P  = 0.002). Conclusions irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
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                Author and article information

                Journal
                J Immunother Cancer
                J Immunother Cancer
                jitc
                jitc
                Journal for Immunotherapy of Cancer
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2051-1426
                2020
                13 September 2020
                : 8
                : 2
                : e001282
                Affiliations
                [1 ]departmentDepartment of Oncology , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins , Baltimore, Maryland, USA
                [2 ]The Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University , Baltimore, Maryland, USA
                [3 ]departmentDepartment of Radiology , Johns Hopkins , Baltimore, Maryland, USA
                [4 ]departmentThoracic Oncology Service , Memorial Sloan Kettering Cancer Center , New York, New York, USA
                [5 ]departmentDepartment of Pathology , Johns Hopkins , Baltimore, Maryland, USA
                [6 ]departmentDepartment of Surgery , Johns Hopkins , Baltimore, Maryland, USA
                [7 ]departmentThoracic Surgery Service , Memorial Sloan Kettering Cancer Center , New York, New York, USA
                [8 ]departmentDruckenmiller Center for Lung Cancer Research , Memorial Sloan Kettering Cancer Center , New York, New York, USA
                [9 ]departmentParker Institute for Cancer Immunotherapy , Memorial Sloan Kettering Cancer Center , New York, New York, USA
                [10 ]Weill Cornell Medical College , New York, New York, USA
                Author notes
                [Correspondence to ] Dr Patrick M Forde; Pforde1@ 123456jhmi.edu
                Author information
                http://orcid.org/0000-0002-6401-9080
                http://orcid.org/0000-0002-3470-8686
                Article
                jitc-2020-001282
                10.1136/jitc-2020-001282
                7488786
                32929052
                8b34e89f-2587-4868-9f41-8afc720952aa
                © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 05 August 2020
                Funding
                Funded by: Memorial Sloan Kettering Cancer Center;
                Award ID: P30 CA008748
                Funded by: FundRef http://dx.doi.org/10.13039/100002491, Bristol-Myers Squibb;
                Award ID: International Immuno-Oncology Network
                Funded by: FundRef http://dx.doi.org/10.13039/100000982, Conquer Cancer Foundation;
                Award ID: 90083528
                Funded by: Johns Hopkins University Cancer Center;
                Award ID: P30 CA006973
                Funded by: Eastern Cooperative Oncology Group - American College of Radiology Imaging Network;
                Funded by: Swim Across America;
                Funded by: The Allegheny Health Network – Johns Hopkins Research Fund and the Maryland Department of Health and Mental Hygiene Cigarette Restitution Fund Program;
                Funded by: The Commonwealth Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/100002192, LUNGevity Foundation;
                Funded by: The V Foundation;
                Funded by: Lung Cancer Foundation of America;
                Funded by: Macmillan Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: CA006973
                Award ID: CA121113
                Award ID: CA180950
                Award ID: CA233259
                Award ID: R01 CA142779
                Award ID: T32 CA009071-38
                Award ID: T32 CA193145
                Funded by: FundRef http://dx.doi.org/10.13039/100009730, Stand Up To Cancer;
                Award ID: American Cancer Society Lung Cancer Dream Team
                Award ID: SU2C-AACR-DT1012
                Funded by: Bloomberg-Kimmel Institute for Cancer Immunotherapy;
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                immunotherapy,lung neoplasms,tumor microenvironment,clinical trials as topic,tumor biomarkers

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