192TiP: NEPTUNE: A global, phase 3 study of durvalumab (MEDI4736) plus tremelimumab combination therapy versus standard of care (SoC) platinum-based chemotherapy in the first-line treatment of patients (pts) with advanced or metastatic NSCLC

Mok, Tony; Schmid, Peter; Aren, Osvaldo Rudy; Arrieta, Óscar; Gottfried, Maya; Jazieh, Abdul Rahman; Ramlau, Rodryg; Timcheva, K.; Martín, Claudio; McIntosh, Stuart

doi:10.1016/s1556-0864(16)30301-x

Cited by 32 publications

(26 citation statements)

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“…However, 36% of the 102 patients had TRAEs, and 28% discontinued treatment because of severe TRAEs, among which three deaths were related to the treatment . The assessment of the safety and clinical activity of the combination of durvalumab and tremelimumab versus platinum‐based chemotherapy is still ongoing .…”

Section: Pd‐1/pd‐l1 Blockade Therapy In Advanced Nsclcmentioning

confidence: 99%

PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions

2019

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This article summarizes the latest clinical applications of PD‐1/PD‐L1 blockade therapy in advanced non‐small cell lung cancer (NSCLC) worldwide and in China, reporting the bottlenecks related to the use of this therapy in clinic. An exploration of the underlying mechanism of PD‐1/PD‐L1 blockade therapy and biomarker identification will maximize the application of immune checkpoint inhibitors in advanced NSCLC and facilitate bedside‐to‐bench studies in cancer immunotherapy.

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Section: Pd‐1/pd‐l1 Blockade Therapy In Advanced Nsclcmentioning

confidence: 99%

PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions

2019

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“…A phase I study of nivolumab plus ipilimumab for first-line treatment of advanced NSCLC indeed found an ORR of 38% to 47% with a duration of response of 11.8 to 12.8 months (13). In the same way, durvalumab was studied in combination with the anti-CTLA-4 tremelimumab in the first-line setting in the MYSTIC (14) and NEPTUNE (15) trials and in the second-line setting in the ARCTIC (16) phase III trial. In the MYSTIC trial, patients are randomized to receive Durvalumab (20 mg/kg Q4W) plus Tremelimumab (1 mg/kg Q4W) or durvalumab alone versus platinum-based chemotherapy in advanced NSCLC.…”

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confidence: 99%

Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer

Antonia

2019

N Engl J Med

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Immune Check Point inhibitors (ICIs) have demonstrated efficacy in advanced stage solid tumors including nonsmall cell lung cancer (NSCLC), CTLA4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors being the most studied drugs.Durvalumab, previously known as MEDI4736, is a fully human monoclonal IgG1κ antibody directed against PD-L1 (1). Durvalumab binds with high affinity and specificity to the PD-L1 receptor expressed on tumor cells.Therefore, durvalumab blocks the interaction between PD-L1 and its ligands (PD-1 and CD-80) expressed on immune cells, and restores T-cells cytotoxic function. However, PD-L1 is also expressed on effector T-cells and studies have shown that PD-L1 blocking antibodies are able to trigger the PD-L1 intracellular signaling pathway in CD8+ T cells in addition to their role in blocking PD-L1/PD-1 interaction (2). This intracellular signaling pathway would be likely to trigger apoptosis of T-cells and therefore produce a paradoxical effect.In the phase I study (3), durvalumab was administered IV every 2 or 3 weeks in a 3+3 dose escalation in 26 patients with various malignancies including NSCLC. Durvalumab induced 4 partial responses and 5 additional minor responses. Moreover, durable disease control was obtained in almost half of patients. Treatment-related adverse events (AEs) occurred in 34% of all patients, with a limited toxicity of grade 1 to 2. Side effects consisted mainly of diarrhea, fatigue, rash and vomiting.The phase IB study of durvalumab (10 mg/kg IV Q2W) alone in advanced NSCLC (3) confirmed its clinical significance. Overall, 304 patients were treated. The objective response rate (ORR) was 25% for patients with PD-L1 positive tumors and 6% for patients with PD-L1 negative tumors (respectively 29%, 26%, and 22% after first-, second-and third-line treatment in the PD-L1+ group and 11%, 4% and 6% in the PD L1-group). In addition, median overall survival (OS) was 17.8 months in second-line for PD-L1+ NSCLC and 8.2 months for PD-L1-NSCLC. In the third-line setting, median OS reached 13 months for PD-L1+ NSCLC and 7.1 months for PD L1-NSCLC. All grade AEs and grade ≥3 AEs were reported in 57% and 10% of patients, respectively, with 5% of AEs leading to the discontinuation of treatment (mainly related to pneumonitis and colitis).Furthermore, the ATLANTIC (4) trial assessed durvalumab (10 mg/kg Q2W) for the third-line treatment of patients with advanced PD-L1+ NSCLC. The ORR were 7.5%, 16.4% and 30.9% in patients with PD-L1 expression of <25%, >25% and >90%, respectively. Overall, 10.2% of patients had at least grade 3 treatment-related AEs and 2.7% had treatment-related AEs leading to discontinuation.Initially, ICIs have been approved by the FDA (Food Editorial Durvalumab after chemoradiotherapy in stage III non-small cell lung cancer

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“…4,6 Durvalumab (MEDI4736) is a selective human IgG1 mAb blocker of PD-L1. 4,7 PD-L1 and PD-L2 are co-inhibitory molecules whose interaction with the PD-1 receptor on the T cell surface triggers an intracellular signalling cascade. This cascade results in inhibition of T cell proliferation, activation, cytokine production, and down-regulation of anti-apoptotic and growth-regulatory molecules such as Bcl-xL and mTOR.…”

Section: Discussionmentioning

confidence: 99%

“…4 Recent and ongoing clinical trials have attempted to exploit potential synergistic effects by directing therapy toward both of these pathways simultaneously. 4,5,7,8 Both of these medications work to suppress immune-evading mechanisms used by tumour cells, which generates an immune response to destroy the tumour. Previous reports of immune-related side effects from anti-CTLA-4 monoclonal antibodies (mAbs) have commonly included dermatitis, hepatitis with transaminitis, colitis, diarrhoea, and fatigue.…”

Section: Discussionmentioning

confidence: 99%

A Case Report of Drug-Induced Myopathy Involving Extraocular Muscles after Combination Therapy with Tremelimumab and Durvalumab for Non-Small Cell Lung Cancer

Carrera

Baartman

Kosmorsky

2017

Neuro-Ophthalmology

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Recently developed anti-tumour therapies targeting immune checkpoints include tremelimumab and durvalumab. These agents have incompletely characterised side effect profiles. The authors report a 68-year-old man treated for non-small cell lung cancer (NSCLC) with a combination of tremelimumab and durvalumab. After treatment he developed diplopia, ptosis, fatigue, weakness, and an inflammatory myopathy affecting the extraocular muscles requiring hospitalisation. Electromyography (EMG) testing and muscle biopsy suggested inflammatory myopathy without sign of myasthenia. Within 1 month of withdrawal of cancer therapies and initiation of oral steroid therapy, ocular and systemic symptoms had resolved. This notable adverse effect has not been previously described for these drugs administered singly or in combination, and ophthalmologists should be aware of this presentation in patients treated with these agents.

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192TiP: NEPTUNE: A global, phase 3 study of durvalumab (MEDI4736) plus tremelimumab combination therapy versus standard of care (SoC) platinum-based chemotherapy in the first-line treatment of patients (pts) with advanced or metastatic NSCLC

Cited by 32 publications

References 0 publications

PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions

PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions

Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer

A Case Report of Drug-Induced Myopathy Involving Extraocular Muscles after Combination Therapy with Tremelimumab and Durvalumab for Non-Small Cell Lung Cancer

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