ArticlesDurvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study
Introduction
Treatment options for patients with advanced non-small-cell lung cancer (NSCLC) have expanded over the past 15 years. Targeted therapies have radically changed the treatment paradigm for patients with EGFR tyrosine kinase mutations and anaplastic lymphoma kinase (ALK) rearrangements (EGFR+/ALK+). For patients without targetable EGFR or ALK genetic aberrations (EGFR−/ALK−), chemotherapy has long been the cornerstone of treatment, with moderate outcomes.1 However, over the past 3 years, immune checkpoint inhibitors have become another important treatment modality for advanced NSCLC.2, 3 Despite these developments, standard options are not available for patients with NSCLC who have disease progression after two lines of therapy. Only erlotinib is indicated in third-line treatment and beyond, with minor and debatable activity, particularly in the EGFR− population.4 Gemcitabine and vinorelbine are often administered in advanced lines in clinical practice because of their acceptable safety profile; however, the benefit of this treatment is unclear.
The inhibitory programmed cell death-1 (PD-1)–programmed cell death ligand-1 (PD-L1) pathway plays a major role in controlling T-cell activation and is used by tumour cells to evade antitumour responses.5, 6 The anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab, and the anti-PD-L1 monoclonal antibody atezolizumab have received approval from the European Commission in the EU and by the US Food and Drug Administration for the treatment of metastatic NSCLC.7, 8, 9 Meta-analyses in advanced NSCLC suggest that patients with higher tumour PD-L1 expression achieve improved responses to treatment with anti-PD-1 and anti-PD-L1 agents, compared with patients with lower PD-L1 expression.10, 11 Retrospective analyses suggest that EGFR+/ALK+ tumours respond less well to these treatments than EGFR−/ALK− tumours.12, 13
Durvalumab is a selective, high-affinity human immunoglobulin G1 κ monoclonal antibody that has been engineered to reduce antibody-dependent cell-mediated cytotoxicity.14 It blocks PD-L1 binding to PD-1 (half maximum inhibitory concentration [IC50] 0·1 nmol/L) and CD80 (B7.1; IC50 0·04 nmol/L), allowing T cells to recognise and kill tumour cells.15 Durvalumab is approved in the USA for the treatment of post-platinum locally advanced or metastatic urothelial carcinoma and unresectable, stage III NSCLC that has not progressed following concurrent platinum-based chemotherapy and radiation therapy, and has shown encouraging antitumour activity in a phase 1–2 clinical study across multiple advanced solid tumours,16 including NSCLC.17 Compared with patients who had tumours with less than 25% of tumour cells expressing PD-L1, a larger proportion of patients with advanced NSCLC with at least 25% of tumour cells expressing PD-L1 (assessed using the Ventana PD-L1 [SP263] Assay [Ventana Medical Systems, Tucson, AZ, USA]18) achieved an objective response, and their overall survival was longer.17
We report findings from the phase 2 ATLANTIC study, which evaluated the clinical activity and safety of third-line and later treatment with durvalumab in advanced NSCLC. The study included three independent patient cohorts defined by EGFR/ALK status and tumour PD-L1 expression.
Section snippets
Study design and participants
ATLANTIC was a phase 2, open-label, single-arm study done at 139 study centres across Asia, Europe, and North America. Patients were aged 18 years and older, had either histologically or cytologically documented NSCLC (stage IIIB or IV) or recurrent or progressive disease following multimodal therapy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1,19 a life expectancy of at least 12 weeks at day 1, and a WHO performance status score of 0 or 1. Patients
Results
Patients were enrolled between Feb 25, 2014, and Dec 28, 2015. The first protocol amendment to include only patients with at least 25% of tumour cells expressing PD-L1 was implemented on May 13, 2014, and the second protocol amendment to add cohort 3 was implemented on Nov 28, 2014. In cohorts 1 and 2, 38 and 167 patients were enrolled under the original protocol and a further 35 and 92 were enrolled under amendment 1. 1980 patients were enrolled and screened; after exclusions, (mainly for
Discussion
The results of the ATLANTIC study show that the anti-PD-L1 monoclonal antibody durvalumab has clinical activity and an acceptable tolerability profile in heavily pretreated patients with advanced NSCLC. Durable responses and encouraging overall survival data were observed across cohorts of patients with NSCLC defined by EGFR and ALK status and tumour PD-L1 expression. Our findings confirm preliminary results from a previous phase 1–2 study of durvalumab in patients with advanced NSCLC,17 and
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