Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial

Our plain-English summary of Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial, by M. Maio, A. Scherpereel, L. Calabrò, et al (The Lancet. Oncology, 2017).

The study

• Authors: M. Maio, A. Scherpereel, L. Calabrò, J. Aerts, S.C. Perez, A. Bearz, K. Nackaerts, D.A. Fennell, D. Kowalski, A.S. Tsao, P. Taylor, F. Grosso, S.J. Antonia, A.K. Nowak, M. Taboada, M. Puglisi, P.K. Stockman, H.L. Kindler
• Journal: The Lancet. Oncology
• Published: 2017;18(9):1261-1273
• Type of article: Randomized trial
• Cited by: 338 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma.

Methods: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374.

Findings: Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7·7 months (95% CI 6·8-8·9) in the tremelimumab group and 7·3 months (5·9-8·7) in the placebo group (hazard ratio 0·92 [95% CI 0·76-1·12], p=0·41). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient.

Interpretation: Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing.

Funding: AstraZeneca.

Copyright © 2017 Elsevier Ltd. All rights reserved.

In plain English

DETERMINE was a randomised, double-blind, placebo-controlled phase 2b trial of tremelimumab, an antibody against CTLA-4, in people whose unresectable pleural or peritoneal malignant mesothelioma had progressed after one or two previous systemic treatments for advanced disease. Asbestos exposure was not studied. In 19 countries, 571 patients were randomly assigned to tremelimumab (382) or placebo (189); 545 had pleural disease. Median overall survival was 7.7 months (95% CI 6.8 to 8.9) with tremelimumab and 7.3 months (5.9 to 8.7) with placebo. The difference was not statistically significant (hazard ratio 0.92, 95% CI 0.76 to 1.12, p=0.41). Estimated survival at 18 months was 17.4% (95% CI 13.4 to 21.8) with tremelimumab and 18.2% (12.7 to 24.5) with placebo. Grade 3 or worse adverse events of any cause occurred in 246 of 380 treated tremelimumab patients (65%) and 91 of 189 placebo patients (48%); those judged treatment-related, in 110 (29%) and 12 (6%). Five tremelimumab patients died of treatment-related adverse events. The authors concluded that tremelimumab did not significantly prolong survival and that its safety profile was consistent with other CTLA-4 inhibitors.

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: International, multicentre, randomised (2:1), double-blind, placebo-controlled phase 2b drug trial
• Who was studied: 571 adults with unresectable pleural or peritoneal malignant mesothelioma that had progressed after one or two previous systemic treatments for advanced disease. They were treated at 105 centres in 19 countries and randomised from May 17, 2013 to Dec 4, 2014. 382 were assigned to tremelimumab and 189 to placebo; 545 (95%) had pleural mesothelioma.
• Exposure: Not an asbestos exposure study. The intervention was intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses, then every 12 weeks.
• Main results:
  • Median overall survival (intention-to-treat): 7.7 months (95% CI 6.8 to 8.9) in the tremelimumab group and 7.3 months (5.9 to 8.7) in the placebo group. Hazard ratio 0.92 (95% CI 0.76 to 1.12), p=0.41; not significantly different.
  • At data cutoff (Jan 24, 2016), 307 (80%) of 382 tremelimumab patients and 154 (82%) of 189 placebo patients had died.
  • Overall survival at 18 months, estimated with the Kaplan-Meier method, was 17.4% (95% CI 13.4 to 21.8) with tremelimumab and 18.2% (12.7 to 24.5) with placebo. Because the primary endpoint was not met, statistical significance could not be assessed for secondary endpoints.
  • Objective responses, all partial, occurred in 17 (4.5%) of 382 tremelimumab patients and 2 (1.1%) of 189 placebo patients.
  • Treatment-emergent adverse events of grade 3 or worse, regardless of attributed cause, occurred in 246 (65%) of 380 treated tremelimumab patients and 91 (48%) of 189 placebo patients. The most common were dyspnoea (9% vs 14%), diarrhoea (15% vs less than 1%) and colitis (7% vs none).
  • Grade 3 or worse treatment-related adverse events occurred in 110 (29%) tremelimumab patients and 12 (6%) placebo patients.
  • Adverse events led to stopping treatment in 104 (27%) of 380 tremelimumab patients and 10 (5%) of 189 placebo patients.
  • Treatment-related adverse events led to death in five (1%) tremelimumab patients and none in the placebo group.
• The authors' conclusion: The authors concluded that tremelimumab did not significantly prolong overall survival compared with placebo in previously treated malignant mesothelioma. They also concluded that its safety profile was consistent with the known profile of CTLA-4 inhibitors.
• Limitations the authors state:
  • Patients had limited exposure to study treatment (median of three doses).
  • Because fewer than 5% of patients had peritoneal disease, overall survival could not be reviewed by anatomic site.
  • Patient-reported outcome data were not collected beyond the end of treatment or discontinuation, which limited their interpretation.

Topics

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

Medical terms in this study, explained in our Lexicon: Tremelimumab, Malignant Mesothelioma, CTLA-4, Monoclonal Antibody, Unresectable, Performance Status, Modified RECIST (mRECIST), Pleural Mesothelioma.

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