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

Abstract

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.

Conflict of interest statement

Declaration of interests

SA has served on Advisory Boards for MedImmune and AstraZeneca. SG has received research funding from AstraZeneca and Boehringer Ingelheim and has served on Advisory Boards for Clovis. AB has received financial support to run clinical trials from Genentech, Incyte, MedImmune, and Merck; and fees for Speaker Bureau participation from Bristol-Myers Squibb and Merck. JC has received financial clinical trial support from AstraZeneca/MedImmune and has received personal fees from Genentech. AG, KS, YG, JK, and RN are employees of MedImmune; JK, YG, AG, KS, and RN also own stock/stock options in AstraZeneca. YG was previously an employee of Boehringer Ingelheim. JK is also an employee of MedStar Montgomery Medical Center and Fauquier Hospital. KS has a provisional patent application related to this work. NR has received personal fees from AstraZeneca, BMS, Roche, Novartis, and Merck. SA has received an NIH grant. RS declares no competing interests.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Dosing schedule

PD=progressive disease; q=every; w=weeks.

Figure 2. Time to RECIST response (confirmed and unconfirmed) and duration of response

PD=progressive disease; PD-L1=programmed cell death ligand-1; RECIST=Response Evaluation Criteria In Solid Tumors.

Figure 3. Antitumour activity according to PD-L1 status (response evaluable population with ≥24 weeks follow-up)

Change in tumour size from baseline in (A) PD-L1− patients (PD-L1 <25%), (B) PD-L1+ patients (PD-L1 ≥25%), (C) patients with unknown PD-L1 status; (D) Best change in tumour size by PD-L1 status. D=durvalumab; na=status unknown; PD- L1=programmed cell death ligand-1; Q=every; T=tremelimumab; W=weeks.

Figure 3. Antitumour activity according to PD-L1 status (response evaluable population with ≥24 weeks follow-up)

Change in tumour size from baseline in (A) PD-L1− patients (PD-L1 <25%), (B) PD-L1+ patients (PD-L1 ≥25%), (C) patients with unknown PD-L1 status; (D) Best change in tumour size by PD-L1 status. D=durvalumab; na=status unknown; PD- L1=programmed cell death ligand-1; Q=every; T=tremelimumab; W=weeks.