Final results of DIADEM, a phase II study to investigate the efficacy and safety of durvalumab in advanced pretreated malignant pleural mesothelioma

Our plain-English summary of Final results of DIADEM, a phase II study to investigate the efficacy and safety of durvalumab in advanced pretreated malignant pleural mesothelioma, by S. Canova, G.L. Ceresoli, F. Grosso, et al (ESMO Open, 2022).

The study

• Authors: S. Canova, G.L. Ceresoli, F. Grosso, P.A. Zucali, F. Gelsomino, G. Pasello, M. Mencoboni, E. Rulli, F. Galli, I. De Simone, L. Carlucci, A. De Angelis, M. Belletti, M. Bonomi, A. D'Aveni, M. Perrino, F. Bono, D.L. Cortinovis, DIADEM groupD
• Journal: ESMO Open
• Published: 2022;7(6):100644
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a cancer with a high mortality rate and few therapeutic options. After platinum-pemetrexed combination, no further promising drug seems to be effective. Immune checkpoint inhibitors may have some activity in pretreated patients and no data are available in this population about durvalumab.

Materials And Methods: DIADEM was a multicenter, open-label, single-arm, phase II trial aimed at evaluating the efficacy and safety of durvalumab. Patients with locally advanced/metastatic MPM who progressed after platinum-pemetrexed chemotherapy were enrolled to receive durvalumab (1500 mg, intravenously Q4W) for 12 months or until evidence of disease progression or unacceptable toxicity. The primary endpoint was the proportion of patients alive and free from progression at 16 weeks (PFS16wks) calculated from treatment initiation. Secondary endpoints were progression-free survival, overall survival, overall response rate, and safety.

Results: Sixty-nine patients with a median age of 69 years (range 44-82 years) were enrolled; 62 patients (89.9%) had epithelioid histotype. As first-line treatment, all patients received platinum derivatives-pemetrexed combination (60.9% with carboplatin and 39.1% with cisplatin). As of March 2021, the median follow-up was 9.2 months (interquartile range 5.2-11.1 months). Six patients (8.7%) completed the 12-month treatment; 60 patients discontinued, of whom 42 for progressive disease, and 4 died. Seventeen patients (28.3%; 95% confidence interval 17.5% to 41.4%) were alive or free from progression at 16 weeks. Eleven patients (18.6%) had a grade 3 or 4 treatment-related adverse event (AE), and one (1.4%) had a grade ≥3 immune-related, treatment-related AE. There was one drug-related death.

Conclusion: Durvalumab alone in pretreated non-selected MPM did not reach a meaningful clinical activity, showing any new major safety issue signals.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

In plain English

This phase II trial, without a comparison group, tested the immunotherapy durvalumab in malignant pleural mesothelioma progressing after platinum-pemetrexed chemotherapy. Sixty-nine patients were enrolled at seven Italian centers from November 2018 to May 2019; 39 of 68 with recorded data (57.4%) had asbestos exposure. Seventeen of 61 assessable patients (27.9%; 95% confidence interval, CI, 17.1% to 40.8%) were alive without progression at 16 weeks; the main goal was not met. Six of 58 evaluated patients (10.3%; 95% CI 3.9% to 21.2%) had partial tumor shrinkage. Median progression-free survival was 1.9 months (95% CI 1.8 to 3.6) and median overall survival 7.3 months (95% CI 5.4 to not estimable). Non-epithelioid tumors were linked to shorter survival in the authors' multivariable analysis; asbestos exposure was not significant. Treatment-related side effects affected 27 patients (39.1%). One sudden death was judged possibly related to both durvalumab and the disease; without an autopsy, its cause could not be established. The authors concluded durvalumab alone failed to demonstrate promising activity, with no new safety signal, and noted the lack of a control arm as a limitation.

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: Phase II, single-arm (no control group), multicenter, open-label drug trial
• Who was studied: 69 adults with advanced unresectable malignant pleural mesothelioma previously treated with pemetrexed plus a platinum drug, enrolled at seven Italian centers from November 2018 to May 2019. Median age was 69.9 years, 25 were female, and 62 (89.9%) had epithelioid histotype. Asbestos exposure was recorded in 39 (57.4%) of the 68 patients with available data; data were missing for 1 patient.
• Exposure: The studied exposure was a treatment, not asbestos: durvalumab 1500 mg intravenously on day 1 every 4 weeks for a maximum of 12 months. Asbestos exposure was recorded only as a patient characteristic.
• Main results:
  • The primary endpoint was not met. 27.9% of the 61 assessable patients (17 patients) were alive and progression-free at 16 weeks (95% CI 17.1% to 40.8%). Among the first 47 assessable patients the rate was 23.4% (11 patients). In both cases the confidence interval included the 20% null rate.
  • Of 58 patients with at least one disease evaluation, 6 had a partial response (ORR 10.3%, 95% CI 3.9% to 21.2%) and 27 (46.6%) had stable disease, giving a disease control rate of 56.9%.
  • In all 69 enrolled patients, median progression-free survival was 1.9 months (95% CI 1.8 to 3.6 months, Figure 1A), at a median follow-up of 9.2 months.
  • In all 69 enrolled patients, median overall survival was 7.3 months (95% CI 5.4 months to not estimable, Figure 1B). During the study, 60 patients (87.0%) progressed and 33 (47.8%) died.
  • Response rates did not differ by PD-L1 expression: 3 of 27 PD-L1-negative patients (11.1%) versus 2 of 21 patients with PD-L1 above 1% (9.5%).
  • In the multivariable analysis (all enrolled patients), the text reports that non-epithelioid mesothelioma had worse progression-free survival (HR 4.43, 95% CI 1.60-12.2) and worse overall survival (HR 5.24, 95% CI 1.38-19.9) than epithelioid mesothelioma.
  • In Table 2, asbestos exposure had a hazard ratio of 1.42 (95% CI 0.75-2.69, P 0.281) for progression-free survival and 1.65 (95% CI 0.74-3.68, P 0.223) for overall survival.
  • Treatment-related adverse reactions occurred in 27 of 69 patients (39.1%). Immune-related adverse events occurred in 15 patients (21.7%), and only one of these (an infusion-related reaction) was grade 3.
  • One sudden death was assessed as possibly related to both durvalumab and the disease under study. No autopsy was done, so its cause could not be established.
• The authors' conclusion: The authors concluded that the study did not reach its primary endpoint and that durvalumab alone failed to demonstrate promising activity in patients pretreated with platinum-pemetrexed. They stated that no new safety signal emerged. They suggested durvalumab may deserve a role combined with chemotherapy in untreated patients.
• Limitations the authors state:
  • There was no control arm, which reduces the robustness of the results.
  • Central review of CT scans showed a moderate discrepancy with the local site evaluations (concordance in 53 of 71 assessments). Because the primary endpoint used investigator assessments, this could limit the validity of the results.
  • The choice of primary endpoint (progression-free rate at 16 weeks) depends on how reproducible and how consistently timed the CT evaluations are, especially in a single-arm trial.
  • The authors considered the longer progression-free survival in smokers to be possible speculation, given the small number of patients and the lack of an effect on overall survival.

Topics

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

Medical terms in this study, explained in our Lexicon: Durvalumab (Imfinzi), Pleural Mesothelioma, Platinum-Pemetrexed, checkpoint inhibitors, Chemotherapy, Disease Progression, Progression-Free Survival, Overall Survival.

Related studies

• Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in — A.K. Nowak, W.J. Lesterhuis, et al. (2020)
• Protocol of DREAM3R: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma-a phase 3 randomised trial — P.S. Kok, P.M. Forde, et al. (2022)
• Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial — P.M. Forde, V. Anagnostou, 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 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)
• A phase II study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with malignant pleural mesothelioma — P.A. Zucali, M. Perrino, et al. (2020)

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