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      Can Ipilimumab restore immune response in advanced NSCLC after progression on anti‐PD‐1/PD‐L1 agents?

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          Abstract

          Anti‐PD‐1/PD‐L1 agents play a crucial part in the treatment of non‐small cell cancer (NSCLC) demonstrating improved overall response rate (ORR) and overall survival (OS). Recent studies evaluating combination treatment with anti‐PD‐1 and anti‐CTLA‐4 suggests improved outcome but also increased toxicity. Evidence is scarce regarding subsequent treatment with immune checkpoint inhibitors (ICPI) after progression on anti‐PD‐1/PD‐L1. A total of 15 patients were treated with a combination of anti‐PD1 agent and ipilimumab after confirmed progression of disease on anti‐PD1/PDL1 alone during 2017. Clinical data were retrieved retrospectively. Disease control rate (DCR) was defined as partial response (PR) or stable disease (SD). The overall DCR was 33.3% ( n = 5); two patients with PR and three patients with SD, three of whom had prior documented disease control on anti‐PD1. The immune‐related adverse event (irAE) rate was 40% ( n = 6); two patients had grade 3 AE and one patient died of pneumonitis. While the median time to progression was two months (range 0.5–16), four of the five patients with PR/SD experienced durable benefit for 8–16 months. This small retrospective cohort of heavily pretreated unselected patients suggests ipilimumab might reboost the immune response in patients with advanced NSCLC following progression of disease on anti‐PD1 therapy, while delaying exposure to the higher toxicity rates associated with upfront combination therapy. This strategy should be explored prospectively.

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          Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

          Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
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            Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non–Small Cell Lung Cancer

            Introduction With expanding indications for programmed death 1 (PD-1) axis inhibitors in non–small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients. Methods Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either Response Evaluation Criteria in Solid Tumors v1.1 or immune-related response criteria. Results Twenty-six patients with AR to PD-1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; the 2-year survival rate from AR was 70% (95% confidence interval: 0.53–0.92). Twenty patients (77%) experienced AR in lymph nodes (LNs), including 11 patients with LN-only progression. Twenty-three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD-1 axis inhibitor therapy beyond progression. Three patients were re-challenged with the same PD-1 axis inhibitor after holiday from and progression off therapy, 2 again responded. Fifteen patients (58%) received local therapy to site(s) of AR, 11 continued respective PD-1 axis inhibitor after local therapy. The 2-year survival rate from AR among these 15 patients was 92% (95% confidence interval: 0.77–1). Conclusions Acquired resistance to PD-1 axis inhibitors is often limited to one or two sites when local therapy and continuation of PD-1 axis inhibitor therapy can result in prolonged benefit. LN metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD-1 axis inhibitor, re-challenge can again lead to tumor regression.
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              Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control.

              Ipilimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) that has been shown to improve survival in patients with pretreated, advanced melanoma in a phase III trial. Some patients in this study who initially responded to ipilimumab treatment but later progressed were eligible for retreatment with their original randomized regimen. Here, outcomes for these patients concerning baseline characteristics, best overall response, and disease control rate are assessed and considered with respect to the overall study population. In the phase III study, 676 pretreated patients were randomly allocated to treatment with ipilimumab 3 mg/kg plus gp100 vaccine, ipilimumab 3 mg/kg plus placebo, or gp100 vaccine alone. Of these patients, 32 had a partial or complete objective response or stable disease after treatment and met the eligibility criteria for retreatment, although a total of 40 patients were retreated. Best overall response rates (complete responses plus partial responses) for 31 retreatment-eligible patients in the ipilimumab plus gp100 and ipilimumab plus placebo groups were 3 of 23 (13.0%) and 3 of 8 (37.5%), respectively, and disease control rates were 65.2% and 75.0%. No new types of toxicities occurred during retreatment and most events were mild-to-moderate. Ipilimumab provided durable objective responses and/or stable disease in qualifying patients who received retreatment upon disease progression with a similar toxicity profile to that seen during their original treatment regimen.
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                Author and article information

                Contributors
                michalst3@clalit.org.il , avrahami.michal@gmail.com
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                16 June 2020
                August 2020
                : 11
                : 8 ( doiID: 10.1111/tca.v11.8 )
                : 2331-2334
                Affiliations
                [ 1 ] Davidoff Cancer Center Rabin Medical Center Petah Tikva Israel
                [ 2 ] Sackler School of Medicine Tel Aviv University Tel Aviv Israel
                [ 3 ] The Legacy Heritage Oncology Center Soroka Medical Center Beer‐Sheva Israel
                [ 4 ] Ben Gurion University of Negev Beer‐Sheva Israel
                Author notes
                [*] [* ] Correspondence

                Michal Sternschuss, Davidoff Cancer Center, Rabin Medical Center, Kaplan St., Petah Tikva 49100, Israel.

                Tel: +972 3 9378007; +972 528526844

                Fax: +972 3 9378044

                Email: michalst3@ 123456clalit.org.il , avrahami.michal@ 123456gmail.com

                Author information
                https://orcid.org/0000-0003-2985-4483
                Article
                TCA13502
                10.1111/1759-7714.13502
                7396365
                32548905
                14f29b96-3404-4203-9184-05a3a5c21bd6
                © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 January 2020
                : 06 May 2020
                : 07 May 2020
                Page count
                Figures: 1, Tables: 2, Pages: 4, Words: 2323
                Categories
                Brief Report
                Brief Reports
                Custom metadata
                2.0
                August 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.6 mode:remove_FC converted:02.08.2020

                immune‐related adverse events,ipilimumab,nivolumab,nsclc

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