{ "abstract": "Background Primary (intrinsic) resistance to immune checkpoint inhibitor (ICI) therapy remains a major challenge in clinical oncology. For patients with metastatic non-small cell lung cancer (NSCLC) lacking actionable genomic alterations, platinum doublet chemotherapy is the standard treatment following progression on dual ICI therapy. 1 Several mechanisms may cause primary resistance to ICI, including insufficient neoantigen presentation and an immunosuppressive tumor microenvironment.2 Chemotherapy may mitigate some of these factors by promoting the release of neoantigens and by reducing soluble and membrane-bound factors that inhibit tumor-infiltrating T-cells.3 In this arm of the trial, we investigated the role of the addition of platinum doublet therapy to Ipilimumab (I) and Nivolumab (N) for primary resistance to I+N therapy.Methods Immunotherapy-naïve patients with metastatic NSCLC were treated with ipilimumab and nivolumab per the LONESTAR trial ( NCT03391869). Patients who experienced radiologic progression within 12 weeks were enrolled in Cohort 2 and received two cycles of histology-specific platinum doublet chemotherapy, combined with ipilimumab (1 mg/kg every 6 weeks) and nivolumab (360 mg every 3 weeks), followed by maintenance I+N therapy according to the CheckMate 9LA protocol. The primary endpoint was progression-free survival (PFS) according to RECIST v1.1, measured from the initiation of chemotherapy to radiologic progression. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), duration of response (DoR), and overall survival (OS).Results Ten patients were included in this cohort (median age: 70); Seven (70%) had adenocarcinoma and three (30%) had non-adenocarcinoma histology. The median duration of initial I+N therapy leading to primary ICI failure was 2.5 months. The median PFS to platinum doublet with I+N therapy was 3.2 months. ORR was 30%, and DCR was 90%, with three (30%) partial responses and 6 (60%) stable disease. The median duration of response (DoR) was 4 months (range: 62–389 days). Treatment discontinuation due to toxicity occurred in one patient (10%) (grade 3 pneumonitis). The median overall survival (OS) was 12 months (range: 111–759 days).Conclusions In patients with primary resistance to ipilimumab and nivolumab, the addition of platinum-doublet chemotherapy was feasible and achieved a high disease control rate. However, responses were generally short-lived (<6 months), highlighting the unmet need for the investigation of novel therapy strategies to overcome primary ICI resistance.Trial Registration ClinicalTrials.gov identifier: NCT03391869References Heinhuis KM, Ros W, Kok M, et al. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumor. Ann.Onc.2019;30:219–235Jenkins R, Barbie D, Flaherty K. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118:9–16Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:198-211.Ethics Approval The protocol and all amendments were approved by the MD Anderson Cancer Center Institutional Review Board (#2017-0311).Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.", "authors": [ { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Mehmet Altan" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Saumil Gandhi" }, { "affiliations": [ "Department of Thoracic and Cardiovascular surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Mara Antonoff" }, { "affiliations": [ "Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Natalie I Vokes" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Stephen G Swisher" }, { "affiliations": [ "Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "J Jack Lee" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Mike Hernandez" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Hai Tran" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Carl Gay" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Jianjun J Zhang" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Tina Cascone" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Ferdinandos Skoulidis" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "George R Blumenschein" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Janet Tu" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "Bingnan Zhang" }, { "affiliations": [ "The University of Texas MD Anderson Cancer Center, Houston, TX, USA" ], "name": "John V Heymach" } ], "title": "507 Clinical outcomes of platinum doublet chemotherapy combined with dual checkpoint inhibitors after primary resistance to dual checkpoint inhibitor therapy: results from the LONESTAR study", "uid": "8d5d96f7-b7dc-5091-9bb0-40ccdcce342c" }