Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study

Our plain-English summary of Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study, by L. Calabrò, A. Morra, E. Fonsatti, et al (The Lancet. Respiratory Medicine, 2015).

The study

• Authors: L. Calabrò, A. Morra, E. Fonsatti, O. Cutaia, C. Fazio, D. Annesi, M. Lenoci, G. Amato, R. Danielli, M. Altomonte, D. Giannarelli, A.M. Di Giacomo, M. Maio
• Journal: The Lancet. Respiratory Medicine
• Published: 2015;3(4):301-9
• Cited by: 162 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: CTLA4 blockade by tremelimumab 15 mg/kg every 90 days provided preliminary evidence of activity in patients with pretreated malignant mesothelioma; however, retrospective exposure-response analysis of data from patients with melanoma suggested that this schedule could result in underexposure to tremelimumab. We therefore investigated the efficacy and safety of an intensified schedule of tremelimumab in patients with advanced malignant mesothelioma.

Methods: In this open-label, single-arm, phase 2 study, participants aged 18 years or older with unresectable, advanced malignant mesothelioma (measurable in accordance with the Response Evaluation Criteria in Solid Tumors [RECIST]), a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and who had failed a first-line platinum-based regimen were enrolled at the University Hospital of Siena, Siena, Italy. Participants received tremelimumab 10 mg/kg once every 4 weeks for six doses, then every 12 weeks until disease progression, unacceptable toxic effects, or refusal to continue treatment. The primary endpoint was the proportion of patients achieving an immune-related objective response (complete or partial), assessed in all patients who received at least one dose of the study drug. This study is registered with the European Union Clinical Trials Register, number 2012-002762-12, and ClinicalTrials.gov, number NCT01655888.

Findings: Between July 30, 2012, and July 15, 2013, we enrolled 29 patients with a median age of 65 years (range 42-78), stage III (n=11) or IV (n=18) disease, and an Eastern Cooperative Oncology Group performance status of 0-1 (n=23) or 2 (n=6). Malignant mesothelioma histology was epithelioid (n=21, including one peritoneal), biphasic (n=6), sarcomatoid (n=1), or undefined (n=1). Patients received a median of six doses of tremelimumab (range 1-13). After a median follow-up of 21·3 months (IQR 18·7-25·9), four immune-related-partial responses were recorded, one at the first tumour assessment (after about 12 weeks) and three at the second tumour assessment (about 24 weeks), with two responses occurring after initial progressive disease and one response after initial stable disease. 15 (52%) of patients achieved disease control, with a median duration of 10·9 months (95% CI 8·2-13·6). According to modified RECIST, one patient (3%) achieved a partial response and 11 (38%) patients achieved disease control rate. Grade 1-2 treatment-related adverse events occurred in 26 (90%) patients and grade 3-4 adverse events in two (7%) patients. The most common treatment-related adverse events were gastrointestinal, dermatological, and fever.

Interpretation: Our results suggest that the intensified schedule of tremelimumab investigated seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile. The same intensified schedule is now being investigated in an ongoing randomised, double-blind, placebo-controlled, phase 2b study.

Funding: Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, and MedImmune.

Copyright © 2015 Elsevier Ltd. All rights reserved.

In plain English

This single-arm, phase 2 drug trial in Italy did not study asbestos. From July 2012 to July 2013 it enrolled 29 adults with advanced malignant mesothelioma (28 pleural, one peritoneal) that had progressed after platinum-based chemotherapy. Patients were to receive tremelimumab, a CTLA4-blocking antibody, at 10 mg/kg every 4 weeks for six doses (induction), then every 12 weeks (maintenance); 19 completed induction and 12 entered maintenance. Four patients (13.8%; 95% CI 3.9 to 31.7) had an immune-related partial response, meeting the primary goal. Disease was controlled in 15 (51.7%; 95% CI 32.5 to 70.6), for a median 10.9 months (95% CI 8.2 to 13.6). Under modified RECIST, one (3.4%; 95% CI 0 to 10.0) had a partial response and 11 (37.9%; 95% CI 20.2 to 55.6) had disease control. Median overall survival was 11.3 months (95% CI 3.4 to 19.2). Treatment-related side effects were grade 1 or 2 in 26 patients (90%) and grade 3 in two (7%); no death was attributed to treatment. The authors concluded the schedule seems to have clinical and immunological activity and a good safety profile.

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 (no comparison group), phase 2 clinical trial of a drug treatment
• Who was studied: 29 adults with unresectable, advanced malignant mesothelioma (28 pleural, one peritoneal) whose disease had progressed after one platinum-based chemotherapy regimen. They were enrolled at the University Hospital of Siena, Italy, between July 30, 2012, and July 15, 2013. Median age was 65 years (range 42 to 78), and 20 (69%) were men.
• Exposure: The study treatment was tremelimumab, an anti-CTLA4 monoclonal antibody. The planned schedule was 10 mg/kg every 4 weeks for six doses, then every 12 weeks until disease progression, unacceptable side effects, or refusal. Asbestos exposure was not studied.
• Main results:
  • All 29 patients received at least one dose, with a median of six doses (range 1 to 13). 19 patients completed the induction phase and 12 entered the maintenance phase. The remaining seven had disease progression and were discontinued from the study. Twelve patients missed one dose because of persisting grade 2 side effects; 11 of these missed doses were during the induction phase.
  • Four of the 29 patients had an immune-related partial response (13.8%; 95% CI 3.9 to 31.7), and none had a complete response. Under modified RECIST, one patient had a partial response (3.4%; 95% CI 0 to 10.0).
  • The four immune-related partial responses meant the study reached its primary endpoint.
  • Of the four responses, two occurred after initial progressive disease and one after initial stable disease.
  • Disease control rates differed by method:
• Immune-related criteria: 15 of 29 (51.7%; 95% CI 32.5 to 70.6).
• Modified RECIST: 11 of 29 (37.9%; 95% CI 20.2 to 55.6).
  • Under immune-related criteria, the median duration of disease control was 10.9 months (95% CI 8.2 to 13.6).
  • Across all 29 patients:
• Median immune-related progression-free survival was 6.2 months (95% CI 5.7 to 6.7).
• Median overall survival was 11.3 months (95% CI 3.4 to 19.2).
• 1-year survival was 48.3%.
  • Patients with a performance status of 0 or 1 did significantly better than patients with a performance status of 2:
• Overall survival: p less than 0.0001.
• Immune-related progression-free survival: p less than 0.0001.
• Disease control: p=0.04.
  • 26 patients (90%) had at least one grade 1 or 2 treatment-related adverse event, and two patients (7%) had a grade 3 treatment-related adverse event. The most common were gastrointestinal, skin, and fever.
  • No deaths were treatment-related. There were 23 deaths not related to treatment: 22 from disease progression and one from infection.
  • Compared with baseline, circulating CD4-positive, ICOS-positive T cells were significantly increased at every timepoint tested (p less than 0.0001).
• The authors' conclusion: The authors concluded that the intensified tremelimumab schedule seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile.
• Limitations the authors state:
  • The authors said the finding in the seven patients with biphasic or sarcomatoid histology (median overall survival 15.8 months) should be interpreted with caution because the number of patients was very small.
  • The authors said the possibility of long-lasting disease control needs to be assessed in a randomised, controlled study.
  • The authors called the link between the neutrophil to CD4-positive, ICOS-positive T-cell ratio and survival preliminary and hypothesis-generating.
  • Results of the planned anti-mesothelin antibody analyses were not available when the report was written.

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, Chemotherapy, Mesothelioma, Unresectable, Life Expectancy, Performance Status, Disease Progression, Clinical Trial.

Related studies

• Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial — L. Calabrò, A. Morra, et al. (2013)
• 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)
• 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)
• Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study — T.A. Yap, K. Nakagawa, 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)
• 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)

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