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

Abstract

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.

Conflict of interest statement

Declaration of interests

MCG received personal fees for advisory board participation from AstraZeneca, Roche, Bristol-Myers Squibb, and Merck Sharp and Dohme during this study. JV received an institutional research grant from AstraZeneca and served AstraZeneca in an advisory capacity during this study. HL received personal fees from AstraZeneca, Roche, Merck Sharp and Dohme, Bristol-Myers Squibb, Pfizer, Novartis, Lilly, and Amgen, and non-financial support from AstraZeneca, Roche, Merck Sharp and Dohme, Bristol-Myers Squibb, Pfizer, Lilly, and Amgen, all outside the submitted work. JEG received a research fund grant from AstraZeneca and personal fees for advisory services, outside the submitted work. JP received clinical trial funding from AstraZeneca during this study; received clinical trial funding from Genentech, Bristol-Myers Squibb, Curis, Corvus, EMD Serono, and Macrogenics outside the submitted work; reports DSMC and speakers’ bureau participation with Bristol-Myers Squibb outside the submitted work; reports speakers’ bureau participation with Genentech and Merck outside the submitted work; has a patent T-cell immunotherapy development pending; is a founder and owner of BioCytics, which is a clinical research laboratory developing T-cell immunotherapy; and has previously bought stock in the T-cell companies LionBiotech, Juno, Blue Bird, Kite Pharma, and ZioPharm. CC has received fees during the past 5 years for attending scientific meetings, speaking, organising research, and providing consulting services from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche, Sanofi-Aventis, Lilly, Novartis, Merck Sharp and Dohme, Bristol-Myers Squibb, and Amgen, outside the submitted work. PB participated in advisory boards for Eli Lilly, Bristol-Myers Squibb, and Boehringer Ingelheim, outside the submitted work. PW-P received personal fees for advisory board participation from AstraZeneca, Merck, Bristol-Myers Squibb, and Lilly, outside the submitted work. RAS received a research grant from AstraZeneca and personal fees from AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Lilly, Pfizer, Roche, Taiho, and Bristol-Myers Squibb, outside the submitted work. YH, CW, and PAD are employees of AstraZeneca and hold shares in AstraZeneca. NAR received personal fees from Merck, Bristol-Myers Squibb, Roche, Novartis, Pfizer, and Lilly, outside the submitted work. All other authors declare no competing interests.

Copyright © 2018 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

Of the 1980 enrolled patients, 85 were counted twice because they were rescreened because of programmed cell death ligand-1 (PD-L1) expression results not being obtained within the screening window. EGFR+=EGFR tyrosine kinase mutations. ALK+=anaplastic lymphoma kinase (ALK) rearrangements. EGFR−=EGFR wild type. ALK−=ALK rearrangement negative. *Most screen failures occurred because of the protocol amendment to include only patients with at least 25% of tumour cells with PD-L1 expression (patients with <25% of tumour cells with PD-L1 expression enrolled before the amendment who had not started treatment did not go on to receive treatment). †Patients met the independent central review conditions, but did not have measurable disease at baseline according to the investigator; a protocol deviation was reported for each patient. ‡Patients were not evaluable for response per independent central review because they did not have measurable disease at baseline according to the independent central review.

Figure 2:. Best change from baseline in tumour size over time

(A) Cohort 1 (EGFR+/ALK+ non-small-cell lung cancer [NSCLC]) patients with less than 25% of tumour cells expressing programmed cell death ligand-1 (PD-L1). (B) Cohort 1 patients with at least 25% of tumour cells expressing PD-L1. (C) Cohort 2 (EGFR−/ALK− NSCLC) patients with less than 25% of tumour cells expressing PD-L1. (D) Cohort 2 patients with at least 25% of tumour cells expressing PD-L1. (E) Cohort 3 (EGFR−/ALK− NSCLC) patients with at least 90% of tumour cells expressing PD-L1. Dashed reference lines at −30% and +20% indicate thresholds for partial response and disease progression. Values greater than 100% or less than −100% are displayed as 100% and −100%. The charts show patients evaluable for response per independent central review (all treated patients who had a baseline tumour assessment and had measurable disease at baseline according to the independent central review; patients also had to have at least one post-baseline tumour assessment to be included in the analysis). EGFR+=EGFR tyrosine kinase mutations. ALK+=anaplastic lymphoma kinase (ALK) rearrangements. EGFR−=EGFR wild type. ALK−=ALK rearrangement negative.

Figure 3:. Progression-free survival

(A) Cohort 1 (EGFR+/ALK+ non-small-cell lung cancer [NSCLC]; full analysis set). (B) Cohort 2 (EGFR−/ALK− NSCLC; full analysis set). (C) Cohort 3 (EGFR−/ALK− NSCLC with ≥90% tumour cells with programmed cell death ligand-1 [PD-L1] expression; full analysis set). EGFR+=EGFR tyrosine kinase mutations. ALK+=anaplastic lymphoma kinase (ALK) rearrangements. EGFR−=EGFR wild type. ALK−=ALK rearrangement negative. *In patients with less than 25% of tumour cells expressing PD-L1, the number of patients at risk is per independent central review and therefore smaller than the total number of patients in the full analysis set.

Figure 4:. Overall survival

(A) Cohort 1 (EGFR+/ALK+ non-small-cell lung cancer [NSCLC]; full analysis set). (B) Cohort 2 (EGFR−/ALK− NSCLC; full analysis set). (C) Cohort 3 (EGFR−/ALK− NSCLC with ≥90% tumour cells with programmed cell death ligand-1 [PD-L1] expression; full analysis set). EGFR+=EGFR tyrosine kinase mutations. ALK+=anaplastic lymphoma kinase (ALK) rearrangements. EGFR−=EGFR wild type. ALK−=ALK rearrangement negative.