Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study

Our plain-English summary of Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study, by L. Calabrò, A. Morra, D. Giannarelli, et al (The Lancet. Respiratory Medicine, 2018).

The study

• Authors: L. Calabrò, A. Morra, D. Giannarelli, G. Amato, A. D'Incecco, A. Covre, A. Lewis, M.C. Rebelatto, R. Danielli, M. Altomonte, A.M. Di Giacomo, M. Maio
• Journal: The Lancet. Respiratory Medicine
• Published: 2018;6(6):451-460
• Cited by: 180 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma.

Methods: In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients.

Findings: From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16·1 months (IQR 11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8·0 months (95% CI 6·7-9·3), median progression-free survival was 5·7 months (1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines.

Interpretation: The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration.

Funding: Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.

Copyright © 2018 Elsevier Ltd. All rights reserved.

In plain English

This small phase 2 drug trial did not study asbestos exposure. At one hospital in Siena, Italy, 40 adults with inoperable mesothelioma (38 pleural, 2 peritoneal) enrolled in 2015 and 2016. Twelve had refused first-line chemotherapy; 28 had worsened during or after platinum-based chemotherapy. Planned treatment was tremelimumab plus durvalumab every 4 weeks for four doses, then durvalumab alone for nine; 35 finished the first phase and 31 started the second. There was no comparison group. On scan criteria adapted for immunotherapy, 11 of 40 (28%, 95% CI 15 to 44) had partial tumour shrinkage, confirmed in ten. On the same criteria, disease was controlled in 26 (65%, 95% CI 48 to 79). Median overall survival was 16.6 months (95% CI 13.1 to 20.1); 25 (62%, 95% CI 46 to 77) were alive at 1 year. Tumour PD-L1 levels were not significantly linked to outcomes. Treatment-related side effects affected 30 patients (75%); 7 (18%) had grade 3 to 4, the more severe grades. There were no treatment-related deaths. The authors concluded the combination appeared active and safe.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Open-label, single-group, single-centre, non-randomised phase 2 drug trial
• Who was studied: 40 adults with unresectable pleural (38) or peritoneal (2) mesothelioma, enrolled at the University Hospital of Siena, Italy, from Oct 30, 2015, to Oct 12, 2016. 12 were treated first-line because they had refused chemotherapy. 28 were treated second-line, after disease progression during or after one platinum-based chemotherapy regimen.
• Exposure: No asbestos exposure was studied. The planned treatment was intravenous tremelimumab (1 mg/kg) plus durvalumab (20 mg/kg) every 4 weeks for four doses, followed by durvalumab 20 mg/kg every 4 weeks for nine doses. Treatment stopped earlier on confirmed progression, unacceptable toxicity, investigator's decision or withdrawal of consent.
• Main results:
  • All 40 patients received at least one dose of each drug. 35 completed the four-dose combination phase, and 31 started durvalumab maintenance. 11 of these 31 completed maintenance.
  • 11 of 40 patients (28%, 95% CI 15 to 44) had an immune-related objective response. All were partial responses, and 10 were confirmed by a later CT scan.
  • In the 10 patients with a confirmed partial response, the median duration of response was 16.1 months (IQR 11.5 to 20.5).
  • 26 of 40 patients (65%, 95% CI 48 to 79) had immune-related disease control, with a median duration of 10.6 months. By conventional criteria, 25 of 40 (63%) had disease control.
  • Median immune-related progression-free survival was 8 months (95% CI 6.7 to 9.3). Median progression-free survival by standard criteria was 5.7 months (95% CI 1.7 to 9.7).
  • Median overall survival for all 40 patients was 16.6 months (95% CI 13.1 to 20.1). 25 of 40 (62%, 95% CI 46 to 77) were alive at 1 year.
  • PD-L1 was measured in the 38 patients with enough tumour tissue. In them, baseline tumour PD-L1 expression at any level was not significantly associated with objective response or with survival.
  • 30 of 40 patients (75%) had treatment-related adverse events of any grade, and 7 (18%) had grade 3 to 4 treatment-related adverse events. There were no treatment-related deaths. Three patients (8%) stopped treatment because of treatment-related adverse events.
  • In a post-hoc analysis, 4 of 12 first-line patients (33%) and 7 of 28 second-line patients (25%) had an immune-related objective response.
• The authors' conclusion: The authors concluded that the results provide preliminary evidence that tremelimumab plus durvalumab is active and safe in patients with mesothelioma, regardless of tumour PD-L1 expression. They said further studies in more homogeneous patient groups are needed.
• Limitations the authors state:
  • The study was small, open-label, single-group and non-randomised.
  • The population was heterogeneous. It included first-line and second-line patients, pleural and peritoneal mesothelioma, and patients who were and were not re-treated.
  • The post-hoc analyses were exploratory and either descriptive or not powered to compare groups. The analysis of possible selection bias in second-line patients was not conclusive.
  • The study was not powered to detect differences of less than 40% between groups defined by PD-L1 expression cutoffs.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Tremelimumab, Durvalumab (Imfinzi), Mesothelioma, Monoclonal Antibody, Overall Survival, Chemotherapy, PD-L1, Malignant Mesothelioma.

Related studies

• Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study — L. Calabrò, G. Rossi, et al. (2021)
• Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial — L. Calabrò, A. Morra, et al. (2013)
• Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study — L. Calabrò, A. Morra, et al. (2015)
• Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial — M. Maio, A. Scherpereel, et al. (2017)
• Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial — E.W. Alley, J. Lopez, et al. (2017)
• NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma — V.D. Haakensen, A.K. Nowak, et al. (2021)

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