Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial

Our plain-English summary of Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial, by L. Calabrò, A. Morra, E. Fonsatti, et al (The Lancet. Oncology, 2013).

The study

• Authors: L. Calabrò, A. Morra, E. Fonsatti, O. Cutaia, G. Amato, D. Giannarelli, A.M. Di Giacomo, R. Danielli, M. Altomonte, L. Mutti, M. Maio
• Journal: The Lancet. Oncology
• Published: 2013;14(11):1104-1111
• Cited by: 277 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Monoclonal antibodies to cytotoxic T-lymphocyte antigen 4 (CTLA4) have therapeutic activity in different tumour types. We aimed to investigate the efficacy, safety, and immunological activity of the anti-CTLA4 monoclonal antibody, tremelimumab, in advanced malignant mesothelioma.

Methods: In our open-label, single-arm, phase 2 study, we enrolled patients aged 18 years or older with measurable, unresectable malignant mesothelioma and progressive disease after a first-line platinum-based regimen. Eligible patients had to have a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and no history of autoimmune disease. Patients received tremelimumab 15 mg/kg intravenously once every 90 days until progressive disease or severe toxicity. The primary endpoint was the proportion of patients who achieved an objective response (complete or partial response), with a target response rate of 17% according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) for pleural malignant mesothelioma or standard RECIST 1.0 for peritoneal malignant mesothelioma. Analyses were done according to intention to treat. This trial is registered with EudraCT, number 2008-005171-95, and ClinicalTrials.gov, number NCT01649024.

Findings: Between May 27, 2009, and Jan 10, 2012, we enrolled 29 patients. All patients received at least one dose of tremelimumab (median two doses, range one to nine). No patients had a complete response and two patients (7%) had a durable partial response (one lasting 6 months and one lasting 18 months); one partial response occurred after initial progressive disease. Thus, the study did not reach its primary endpoint. However, we noted disease control in nine (31%) patients and a median progression-free survival of 6·2 months (95% CI 1·3-11·1) and a median overall survival of 10·7 months (0·0-21·9). 27 patients (93%) had at least one grade 1-2 treatment-emergent adverse event (mainly cutaneous rash, pruritus, colitis, or diarrhoea), and four patients (14%) had at least one grade 3-4 treatment-emergent adverse event (two gastrointestinal, one neurological, two hepatic, and one pancreatic).

Interpretation: Although the effect size was small in our phase 2 trial, tremelimumab seemed to have encouraging clinical activity and an acceptable safety and tolerability profile in previously treated patients with advanced malignant mesothelioma.

Funding: Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, Pfizer, and Fondazione Buzzi Unicem.

Copyright © 2013 Elsevier Ltd. All rights reserved.

In plain English

This single-arm phase 2 trial in Siena, Italy, enrolled patients from May 2009 to January 2012. It tested the antibody drug tremelimumab in 29 adults with advanced malignant mesothelioma (28 pleural, one peritoneal) that had progressed after platinum-based chemotherapy. Patients received 15 mg/kg intravenously every 90 days. No patient had a complete response and two of 29 (6.9%, 95% CI 0.0 to 16.1) had a partial response. Four were needed, so the main goal was not met. Nine patients (31.0%, 95% CI 14.2 to 47.9) had disease control. Median overall survival was 10.7 months (95% CI 0 to 21.9) and median progression-free survival 6.2 months (1.3 to 11.1). Estimated survival was 48.3% at 1 year (30.1 to 66.5) and 36.7% at 2 years (18.7 to 54.7). No deaths were attributed to treatment; four patients (14%) had grade 3 or 4 side effects. Higher day-30 counts of activated CD4-positive, ICOS-positive T cells were associated with longer survival. The authors concluded tremelimumab had promising activity, but said results should be interpreted with caution given the small, non-randomised study.

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-arm phase 2 clinical trial of a drug treatment, using a two-stage design with an interim analysis. There was no comparison group.
• Who was studied: 29 adults aged 18 or older with unresectable stage III or stage IV (advanced) malignant mesothelioma whose disease had progressed after one platinum-based chemotherapy. They were enrolled at the University Hospital of Siena, Italy, between May 27, 2009, and Jan 10, 2012, and followed for a median of 27 months. The group was 21 men and 8 women, with a median age of 64. Patients with autoimmune disease or brain metastases were excluded. Asbestos exposure of the patients was not studied.
• Exposure: Treatment with tremelimumab, an anti-CTLA4 monoclonal antibody, at 15 mg/kg by slow intravenous infusion once every 90 days until disease progression or excessive toxicity. Patients received a median of two doses (range one to nine). Asbestos exposure was not studied.
• Main results:
  • Tumour types: of 25 epithelioid tumours, 24 were pleural and one was peritoneal. The 3 sarcomatoid tumours and the 1 biphasic tumour were all pleural.
  • Of 29 patients, none had a complete response and 2 (6.9%; 95% CI 0.0 to 16.1) had a partial response. The primary endpoint, which required four objective responses, was not reached.
  • One partial response lasted 6 months. The other came after initial disease progression and had lasted 18 months at the end of follow-up.
  • 9 of 29 patients (31.0%; 95% CI 14.2 to 47.9) achieved disease control: two partial responses and seven with stable disease. Stable disease lasted a median of 12.4 months (range 6 to 30).
  • In the whole group, median overall survival was 10.7 months (95% CI 0 to 21.9) and median progression-free survival was 6.2 months (1.3 to 11.1).
  • Kaplan-Meier estimated survival was 48.3% at 1 year (95% CI 30.1 to 66.5) and 36.7% at 2 years (18.7 to 54.7).
  • Disease control was significantly associated with stage: 60.0% of patients with stage III disease versus 17.7% with stage IV disease (p=0.03).
  • No patient died from treatment-related causes. Four patients (14%) had at least one grade 3 to 4 adverse event: two with grade 3 colitis or diarrhoea, one with grade 3 Guillain-Barré-like peripheral neuropathy, and one with grade 4 rises in liver and pancreatic enzymes.
  • Patients whose CD4-positive, ICOS-positive T-cell counts at day 30 were above the median of 54 cells per microlitre had significantly better survival (hazard ratio 0.21, 95% CI 0.07 to 0.61; p=0.007).
• The authors' conclusion: The authors concluded that tremelimumab has promising clinical activity in previously treated malignant mesothelioma, with long-lasting tumour regression and disease stability, and that the findings warrant further investigation.
• Limitations the authors state:
  • The authors stated that the small number of patients and the non-randomised design mean the results should be interpreted with caution.
  • The authors stated that objective response, the primary endpoint they chose, has since been recognised as an inappropriate measure for this type of drug, and that overall survival would be more appropriate.
  • The immunological measurements were exploratory and hypothesis-generating.

Topics

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

Medical terms in this study, explained in our Lexicon: Tremelimumab, Chemotherapy, Malignant Mesothelioma, Monoclonal, Monoclonal Antibody, Unresectable, Life Expectancy, Performance Status.

Related studies

• 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 combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study — L. Calabrò, A. Morra, et al. (2018)
• Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial — B. Geoerger, H.J. Kang, et al. (2020)
• 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 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)
• Immunological checkpoint inhibitors enter adolescence — A.K. Nowak (2013)

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