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.