Elsevier

The Lancet Oncology

Volume 17, Issue 3, March 2016, Pages 299-308
The Lancet Oncology

Articles
Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study

https://doi.org/10.1016/S1470-2045(15)00544-6Get rights and content

Summary

Background

PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC).

Methods

We did a multicentre, non-randomised, open-label, phase 1b study at five cancer centres in the USA. We enrolled immunotherapy-naive patients aged 18 years or older with confirmed locally advanced or metastatic NSCLC. We gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 12 weeks for three doses. The primary endpoint of the dose-escalation phase was safety. Safety analyses were based on the as-treated population. The dose-expansion phase of the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT02000947.

Findings

Between Oct 28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation phase and received treatment. At the time of this analysis (June 1, 2015), median follow-up was 18·8 weeks (IQR 11–33). The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase). The most frequent treatment-related grade 3 and 4 adverse events were diarrhoea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). Discontinuations attributable to treatment-related adverse events occurred in 29 (28%) of 102 patients. Treatment-related serious adverse events occurred in 37 (36%) of 102 patients. 22 patients died during the study, and three deaths were related to treatment. The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative tumours. Investigator-reported confirmed objective responses were achieved by six (23%, 95% CI 9–44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 95% CI 3–60) of nine patients with PD-L1-positive tumours and four (29%, 95% CI 8–58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 staining (four [40%, 95% CI 12–74] of ten patients).

Interpretation

Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status, and was selected as the dose for phase 3 studies, which are ongoing.

Funding

MedImmune.

Introduction

Drugs that block the PD-L1/PD-1 pathway act in the tumour microenvironment and prevent inhibition of T-cell function, whereas drugs that block the CTLA-4 pathway act in the lymphoid compartment to expand the number and repertoire of tumour-reactive T cells.1, 2 Thus, combined blockade of both pathways targets both compartments. The clinical benefit of PD-L1/PD-1 pathway inhibition has been shown in roughly 10–30% of PD-L1 unselected patients with non-small cell lung cancer (NSCLC).3 However, fewer than half of NSCLC patients express PD-L1 on their tumour cells,4 and most patients (including PD-L1-positive and PD-L1-negative) do not respond to PD-1 pathway blockade alone, representing an opportunity for combination treatments. In studies of nivolumab plus ipilimumab for melanoma5 and NSCLC,6 durable responses were reported in both PD-L1-positive and PD-L1-negative patients. Tolerability of this treatment combination seemed to be dose-dependent and schedule-dependent, highlighting the need for optimum dose selection to minimise the toxic effects of combination regimens while maintaining clinical activity.

Research in context

Evidence before this study

We searched PubMed between Jan 1, 2005, and Oct 1, 2015, for published preclinical and clinical research on antibody treatments for cancer, with terms including “anti-PD-L1” or “anti-PD-1” and “anti-CTLA-4”. Most clinical studies were reported in the past 2 years. Patients with advanced non-small cell lung cancer (NSCLC) progressing after first-line treatment have a pronounced unmet need because current treatments have limited clinical use. Early clinical data suggest that blockade of multiple immune checkpoints might have greater antitumour activity than blockade of one checkpoint in melanoma and other tumour types, including NSCLC, although the incidence of adverse events also seems to be higher than with single drugs. Treatment with the PD-L1 inhibitor durvalumab has produced durable responses in patients with advanced NSCLC, with a manageable tolerability profile. We designed a study to investigate the safety and antitumour activity of durvalumab in combination with the CTLA-4 inhibitor tremelimumab in patients with locally advanced or metastatic NSCLC.

Added value of this study

In the dose-escalation part of the study, the combination of durvalumab 20 mg/kg every 4 weeks and tremelimumab 1 mg/kg had a manageable tolerability profile. Clinical activity was recorded irrespective of PD-L1 expression status, including in patients with no PD-L1 staining in the tumour cell membrane.

Implications of all the available evidence

The clinical activity of durvalumab plus tremelimumab noted in patients with PD-L1-negative tumours is an important advance, because this population is less responsive to treatment with single drugs that block the PD-1 checkpoint pathway. Based on findings of this study and previous investigations, the optimum dose of combination treatment with durvalumab and tremelimumab was selected for phase 3 studies, which are ongoing.

Durvalumab is a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80 but does not bind to PD-L2,7 avoiding potential immune-related toxic effects due to PD-L2 inhibition, which has been noted in susceptible animal models.8, 9 In an ongoing phase 1/2 study,10 durvalumab treatment produced durable responses in patients with advanced NSCLC, with a manageable tolerability profile. Furthermore, a maximum tolerated dose was not reached in the dose-escalation phase, and dose-expansion cohorts were initiated with a dose of 10 mg/kg every 2 weeks.10 Tremelimumab is a selective human IgG2 monoclonal antibody inhibitor of CTLA-4.11 It promotes T-cell activity through CTLA-4 inhibition but does not seem to deplete regulatory T cells directly.12 Preclinical data indicate that the PD-L1/PD-1 and CTLA-4 pathways are non-redundant,13 suggesting that targeting both pathways could have additive or synergistic effects.

We designed a phase 1b study to assess the tolerability and antitumour activity of the combination of durvalumab and tremelimumab in patients with advanced NSCLC, irrespective of PD-L1 expression status. In this report, we present results of the dose-escalation phase; the dose-expansion phase is ongoing.

Section snippets

Study design and participants

We did a non-randomised, open-label, phase 1b study at five cancer centres in the USA (appendix p 27). We judged patients eligible for the study if they were aged 18 years or older and had confirmed locally advanced or metastatic squamous or non-squamous NSCLC with one or more measurable lesions (based on Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1). Patients had to be immunotherapy-naive (with the exception of previous vaccines) but could have received any number of other

Results

Between Oct 28, 2013, and April 1, 2015, 102 patients from five cancer centres in the USA were recruited into the dose-escalation phase. At data cutoff (June 1, 2015), all patients had received study treatment in the dose-escalation phase and were included in the as-treated population.

Across all dose cohorts, the median duration of follow-up was 18·8 weeks (IQR 11–33) and the median duration of exposure was 11·6 weeks (IQR 7·3–19·0). At data cutoff, four (4%) patients (three with progressive

Discussion

The findings of our phase 1b study show that the maximum tolerated dose was exceeded with a regimen of durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg. In patients who received treatments containing tremelimumab 1 mg/kg, most adverse events were manageable and did not need treatment discontinuation. Relative to the adverse event profile of the tremelimumab 1 mg/kg combination doses, the tremelimumab 3 mg/kg and tremelimumab 10 mg/kg dose-based combinations had a higher frequency of

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