Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial

Our plain-English summary of Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial, by D.A. Fennell, S. Ewings, C. Ottensmeier, et al (The Lancet. Oncology, 2021).

The study

• Authors: D.A. Fennell, S. Ewings, C. Ottensmeier, R. Califano, G.G. Hanna, K. Hill, S. Danson, N. Steele, M. Nye, L. Johnson, J. Lord, C. Middleton, P. Szlosarek, S. Chan, A. Gaba, L. Darlison, P. Wells-Jordan, C. Richards, C. Poile, J.F. Lester, G. Griffiths, CONFIRM trial investigators
• Journal: The Lancet. Oncology
• Published: 2021;22(11):1530-1540
• Type of article: Randomized trial
• Cited by: 226 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients.

Methods: This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450.

Findings: Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2-16·8). Median progression-free survival was 3·0 months (95% CI 2·8-4·1) in the nivolumab group versus 1·8 months (1·4-2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53-0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5-12·1) in the nivolumab group versus 6·9 months (5·0-8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52-0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group.

Interpretation: Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.

Funding: Stand up to Cancer-Cancer Research UK and Bristol Myers Squibb.

Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

In plain English

This was a randomised, double-blind, placebo-controlled phase 3 trial at 24 UK hospitals. Between May 2017 and March 2020, 332 adults with pleural or peritoneal mesothelioma that had progressed after platinum-based chemotherapy were randomly assigned: 221 to nivolumab, an immune checkpoint inhibitor antibody, and 111 to placebo. Treatment was given every 2 weeks for up to 12 months. Most patients had pleural mesothelioma (95%), and 230 (69%) had been exposed to asbestos. In this preliminary analysis, median progression-free survival was 3.0 months with nivolumab versus 1.8 months with placebo (adjusted hazard ratio 0.67, 95% CI 0.53 to 0.85). Median overall survival was 10.2 versus 6.9 months (adjusted hazard ratio 0.69, 95% CI 0.52 to 0.91). Partial responses occurred in 25 of 221 nivolumab patients and 1 of 111 placebo patients. Serious adverse events occurred in 41% and 44% of the two groups, with no treatment-related deaths. The authors found no evidence that tumour PD-L1 levels predicted benefit. The authors concluded that nivolumab might be beneficial for these patients. They noted that scans were not centrally reviewed and that most patients were receiving third-line treatment.

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: Multicentre, placebo-controlled, double-blind, parallel group, randomised phase 3 trial (CONFIRM), with patients assigned 2:1 to nivolumab or placebo; results are from a preliminary analysis
• Who was studied: 332 adults with pleural or peritoneal mesothelioma whose disease had progressed after platinum-based chemotherapy, enrolled at 24 UK hospitals between May 10, 2017 and March 30, 2020. 221 were assigned to the nivolumab group and 111 to the placebo group; 217 and 110, respectively, received at least one dose. 316 (95%) had pleural mesothelioma and 293 (88%) had epithelioid histology.
• Exposure: The study tested a treatment, not an exposure: nivolumab 240 mg or placebo given intravenously every 2 weeks, for up to 12 months or until disease progression. Asbestos exposure was recorded only as a baseline characteristic: 230 (69%) of patients had been exposed to asbestos.
• Main results:
  • Median investigator-reported progression-free survival was 3.0 months (95% CI 2.8 to 4.1) in the nivolumab group versus 1.8 months (1.4 to 2.6) in the placebo group (adjusted HR 0.67, 95% CI 0.53 to 0.85; p=0.0012).
  • Median overall survival was 10.2 months (95% CI 8.5 to 12.1) in the nivolumab group versus 6.9 months (5.0 to 8.0) in the placebo group (adjusted HR 0.69, 95% CI 0.52 to 0.91; p=0.0090).
  • Overall survival at 1 year was 43.4% (95% CI 36.3 to 50.4) in the nivolumab group versus 30.1% (21.0 to 39.6) in the placebo group.
  • A partial response occurred in 25 (11%) of 221 patients in the nivolumab group and in 1 (1%) of 111 patients in the placebo group.
  • Using a 1% positivity threshold, there was no evidence that tumour PD-L1 expression predicted response, for overall survival (HR for interaction 1.16, 95% CI 0.56 to 2.40; p=0.70) or progression-free survival (HR for interaction 1.55, 0.85 to 2.83; p=0.16).
  • Serious adverse events occurred in 90 (41%) of 221 patients in the nivolumab group and 49 (44%) of 111 in the placebo group. There were no treatment-related deaths in either group.
  • Treatment-related adverse events occurred in 163 (74%) of 221 patients in the nivolumab group and 62 (56%) of 111 in the placebo group. Adverse events led to stopping treatment in 30 (14%) of 217 nivolumab patients and 3 (3%) of 110 placebo patients.
  • At the time of this preliminary analysis, a death had been recorded for 210 (63%) of the 332 participants, which was 72% of the 291 deaths required for the final analysis.
• The authors' conclusion: The authors concluded that nivolumab might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.
• Limitations the authors state:
  • CT scans were not centrally reviewed, even though progression-free survival was a co-primary endpoint.
  • Most patients were in the third-line treatment setting. Whether results would differ in a strictly second-line population is unknown.
  • The lack of an observed benefit in non-epithelioid mesothelioma could reflect the small number of such patients and the immature survival data in that subgroup.
  • The PD-L1 findings should be interpreted with caution because the data were immature and PD-L1 expression was low.

Topics

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

Medical terms in this study, explained in our Lexicon: Nivolumab (Opdivo), Mesothelioma, Chemotherapy, Performance Status, Peritoneal Mesothelioma, Disease Progression, Epithelioid, Non-epithelioid.

Related studies

• Constitutive inflammation and epithelial-mesenchymal transition dictate sensitivity to nivolumab in CONFIRM: a placebo-controlled, randomised phase III trial — D.A. Fennell, K. Hill, et al. (2025)
• CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial — D.A. Fennell, E. Kirkpatrick, et al. (2018)
• 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)
• 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)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial — C. Pinto, P.A. Zucali, et al. (2021)

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