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

Our plain-English summary of 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, by L. Calabrò, G. Rossi, A. Morra, et al (The Lancet. Respiratory Medicine, 2021).

The study

• Authors: L. Calabrò, G. Rossi, A. Morra, C. Rosati, O. Cutaia, M.G. Daffinà, M. Altomonte, A.M. Di Giacomo, M. Casula, C. Fazio, G. Palmieri, D. Giannarelli, A. Covre, M. Maio
• Journal: The Lancet. Respiratory Medicine
• Published: 2021;9(9):969-976
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [IQR 49-53]. Here, we report 4-year survival and outcomes after retreatment, and the role of tumour mutational burden (TMB) in identifying patients who might have a better outcome in response to combined therapy.

Methods: NIBIT-MESO-1 was an open-label, non-randomised, phase 2 trial of patients with unresectable pleural or peritoneal mesothelioma who 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. In this follow-up study, patients with disease progression following initial clinical benefit-ie, a partial repsonse or stable disease-were eligible for retreatment and with the same doses and schedules for tremelimumab and durvalumab as used in the NIBIT-MESO-1 trial. The primary endpoint, immune-related objective response rate, was evaluated per immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST 1.1 criteria for patients with pleural or peritoneal malignant mesothelioma, respectively. Key secondary endpoints were overall survival and safety, and TMB was also evaluated post hoc in patients who had tumour tissue available before treatment. The intention-to-treat population was used for analysis of all efficacy endpoints. This study is registered with ClinicalTrials.gov, number NCT02588131.

Findings: 40 patients were enrolled in the NIBIT-MESO-1 study between Oct 30, 2015, and Oct 12, 2016. At data cut-off, April 30, 2020, five (13%) of 40 patients were alive, and 35 (88%) patients had died of progressive disease. At a median follow-up of 52 months (IQR 49-53), median overall survival was 16·5 months (95% CI 13·7-19·2). Survival was 20% (eight of 40 patients) at 36 months and 15% (six of 40 patients) and 48 months. 17 (43%) of 40 patients met the criteria for enrolment in the retreatment study and were retreated with at least one dose of tremelimumab and durvalumab. No immune-related objective responses were observed in the 17 retreated patients. Seven (41%) of 17 patients achieved immune-related stable disease. From the start of retreatment to a median follow-up of 24 months (22·0-25·0), median overall survival was 12·5 months (95% CI 0·0-25·8), and survival at 12 months was 52·9%, at 18 months was 35·3%, and at 24 months was 23·5%. There were no grade 3-4 immune-related adverse events in the retreatment cohort. In a post-hoc analysis of 28 patients for whom tumour tissue before treatment was available, patients with a TMB higher than the median value of 8·3 mutations per Mb had a higher median overall survival compared with patients with TMB below the median value, but this difference was non-significant. Moreover, when patients were additionally stratified for ICI retreatment (n=13), there was a significant difference in survival between those with a TMB higher than the median of 8·3 mutations per Mb and those with TMB lower than the median in the retreated cohort (41·3 months vs 17·4 months; p=0·02).

Interpretation: Tremelimumab combined with durvalumab was associated with long-term survival in patients with mesothelioma. Retreatment was safe and resulted in clinically meaningful outcomes, thus suggesting its potential application in the clinical practice of mesothalioma patients.

Funding: NIBIT Foundation, Fondazione AIRC, AstraZeneca.

Copyright © 2021 Elsevier Ltd. All rights reserved.

In plain English

This follow-up of NIBIT-MESO-1, an open-label, single-arm phase 2 trial, covered 40 patients with unresectable pleural or peritoneal mesothelioma given tremelimumab and durvalumab. The study examined treatment, not asbestos exposure. By April 30, 2020, 5 were alive. Median overall survival was 16.5 months (95% CI 13.7 to 19.2), and 8 of 40 (20%) were alive at 36 months and 6 of 40 (15%) at 48 months. Seventeen patients whose disease was controlled and then worsened received the same drugs again. None had an objective response by the study's criteria, and 7 had stable disease. Their median survival from retreatment was 12.5 months (95% CI 0.0 to 25.8), with no grade 3–4 immune-related side effects. A post-hoc comparison measured survival from the original study's start. Retreated patients had a median of 25.6 months (95% CI 9.6 to 41.6), against 11.0 months (9.4 to 12.6) for 15 chemotherapy patients who had not qualified for retreatment. In 13 retreated patients with tumour tissue, higher tumour mutational burden was linked to longer survival (41.3 vs 17.4 months), which the authors called preliminary. The authors concluded retreatment was safe and merits study. They cited the small, selected, non-randomised group.

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: Follow-up analysis of an open-label, single-arm, non-randomised phase 2 trial, including a retreatment phase and post-hoc analyses
• Who was studied: 40 patients with unresectable pleural or peritoneal mesothelioma enrolled in NIBIT-MESO-1 between Oct 30, 2015, and Oct 12, 2016. Of these, 17 were retreated (16 pleural, 1 peritoneal; 14 epithelioid, 3 biphasic). Retreatment was approved by the University Hospital of Siena's ethics committee in Italy.
• Exposure: Drug treatment, not asbestos. Patients received intravenous tremelimumab 1 mg/kg plus durvalumab 20 mg/kg every 4 weeks for four doses, then durvalumab alone for nine doses. Eligible patients were retreated on the same schedule. The article does not report the patients' asbestos exposure.
• Main results:
  • At the April 30, 2020 data cut-off, 5 (13%) of the 40 original patients were alive and 35 (88%) had died of progressive disease.
  • In all 40 patients, median overall survival was 16.5 months (95% CI 13.7 to 19.2).
  • In all 40 patients, survival was 20% (8 of 40) at 36 months and 15% (6 of 40) at 48 months.
  • 17 (43%) of the 40 patients met the criteria for retreatment.
  • Among the 17 retreated patients, none had an immune-related objective response. Seven (41%) had immune-related stable disease, which lasted over 11 months in three of them.
  • In the 17 retreated patients, median overall survival from the start of retreatment was 12.5 months (95% CI 0.0 to 25.8).
  • In the 17 retreated patients, survival was 52.9% (9 of 17) at 12 months, 35.3% (6 of 17) at 18 months and 23.5% (4 of 17) at 24 months.
  • Six (35%) of the 17 retreated patients had grade 1 to 2 immune-related adverse events, most commonly skin-related. No grade 3 to 4 immune-related adverse events occurred.
  • In a post-hoc comparison, survival was measured from the start of the original study. Median overall survival was 25.6 months (95% CI 9.6 to 41.6) for the 17 retreated patients and 11.0 months (9.4 to 12.6) for 15 patients who did not qualify for retreatment but received chemotherapy (p=0.009).
  • Post-hoc comparison figures: 25.6 months (95% CI 9.6 to 41.6) for retreated patients versus 11.0 months (9.4 to 12.6) for the chemotherapy patients, p=0.009.
  • In a post-hoc analysis of 28 patients with tumour tissue available, median survival was 30.9 months for those with tumour mutational burden above the median of 8.3 mutations per Mb and 14.9 months for those below it (p=0.06). This difference was not statistically significant.
  • Among the 13 retreated patients with tumour tissue, median survival was 41.3 months for those above the median tumour mutational burden (n=5) and 17.4 months for those below it (n=8) (p=0.02). This was a post-hoc analysis.
• The authors' conclusion: The authors concluded that tremelimumab plus durvalumab was associated with long-term survival in patients with mesothelioma. They also concluded that the results support the efficacy and safety of retreatment in patients who become refractory to initial treatment, and that further investigation is warranted.
• Limitations the authors state:
  • The authors stated that the small number of retreated patients and the non-randomised design prevent firm conclusions.
  • Only patients who had benefited from the first course of treatment were eligible for retreatment.
  • The authors said the tumour mutational burden findings are preliminary, come from a post-hoc analysis of few patients, and need to be interpreted with caution.

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, Durvalumab (Imfinzi), Mesothelioma, Unresectable, Peritoneal Mesothelioma, Disease Progression, Modified RECIST (mRECIST), Malignant Mesothelioma.

Related studies

• 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 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)
• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial — A. Scherpereel, J. Mazieres, et al. (2019)

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