Elsevier

The Lancet Oncology

Volume 19, Issue 4, April 2018, Pages 521-536
The Lancet Oncology

Articles
Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study

https://doi.org/10.1016/S1470-2045(18)30144-XGet rights and content

Summary

Background

Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR−/ALK−), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1.

Methods

ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR−/ALK− NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423.

Findings

Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7–21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8–23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2–43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines.

Interpretation

In patients with advanced and heavily pretreated NSCLC, the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents. Responses were recorded in all cohorts; the proportion of patients with EGFR–/ALK– NSCLC (cohorts 2 and 3) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25% of tumour cells expressing PD-L1 was encouraging, and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted.

Funding

AstraZeneca.

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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