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

Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial
Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial
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.
Aged, Antineoplastic Agents, Immunological/therapeutic use, B7-H1 Antigen/metabolism, Double-Blind Method, Female, Humans, Immune Checkpoint Inhibitors/therapeutic use, Male, Mesothelioma, Malignant/drug therapy, Nivolumab/therapeutic use, Peritoneal Neoplasms/drug therapy, Pleural Neoplasms/drug therapy, Progression-Free Survival, Recurrence, Survival Rate
1470-2045
1530-1540
Fennell, Dean A
e85713c5-cf7d-4d9c-b0de-f4302baa08ab
Ewings, Sean
326656df-c0f0-44a1-b64f-8fe9578ca18a
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Califano, Raffaele
64302730-441a-494f-a1f4-d1a32f40b1cb
Hanna, Gerard G
41388106-e733-4cd7-b7d5-586ed0bd26f3
Hill, Kayleigh
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Danson, Sarah
4812d305-e78a-4484-9462-aa49756006fc
Steele, Nicola
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Nye, Mavis
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Johnson, Lucy
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Lord, Joanne
fd3b2bf0-9403-466a-8184-9303bdc80a9a
Middleton, Calley
bdb03063-7b12-4ca3-a85e-6ca20437f1b0
Szlosarek, Peter
a68a9a12-32ea-40fa-a542-2ea91b6d7699
Chan, Sam
55147597-abc8-44f4-8a99-e500632271b9
Gaba, Aarti
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Darlison, Liz
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Wells-Jordan, Peter
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Richards, Cathy
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Poile, Charlotte
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Lester, Jason F
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Griffiths, Gareth
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CONFIRM trial investigators
Fennell, Dean A
e85713c5-cf7d-4d9c-b0de-f4302baa08ab
Ewings, Sean
326656df-c0f0-44a1-b64f-8fe9578ca18a
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Califano, Raffaele
64302730-441a-494f-a1f4-d1a32f40b1cb
Hanna, Gerard G
41388106-e733-4cd7-b7d5-586ed0bd26f3
Hill, Kayleigh
2c0ee400-2619-495d-81ce-433597a9ba3f
Danson, Sarah
4812d305-e78a-4484-9462-aa49756006fc
Steele, Nicola
c695672a-88b8-492e-8fc8-4afa2f6d356d
Nye, Mavis
ec13c8e7-5c59-4c4e-982e-5d29fbe52aee
Johnson, Lucy
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Lord, Joanne
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Middleton, Calley
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Szlosarek, Peter
a68a9a12-32ea-40fa-a542-2ea91b6d7699
Chan, Sam
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Gaba, Aarti
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Darlison, Liz
1ec51502-bbd1-4776-9c68-c4d2222c66ff
Wells-Jordan, Peter
685e0425-0340-463d-adda-3fd70b28beac
Richards, Cathy
b56f0c2d-1f63-4f79-97ce-7a04cdec7a61
Poile, Charlotte
bac7449a-9fa0-44b0-bfe6-ce8f727d171f
Lester, Jason F
0b74c143-a94b-4c8d-86fe-846f3d074228
Griffiths, Gareth
7fd300c0-d279-4ff6-842d-aa1f2b9b864d

CONFIRM trial investigators (2021) Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncology, 22 (11), 1530-1540. (doi:10.1016/S1470-2045(21)00471-X).

Record type: Article

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.

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Accepted/In Press date: 15 October 2021
Published date: 1 November 2021
Additional Information: Funding Information: DAF reports grants from Astex Therapeutics, Boehringer Ingelheim, Merck Sharp & Dohme, and Bayer; personal fees from Aldeyra, Inventiva, and Paredox; non-financial support from Clovis, Eli Lilly, and Bristol Myers Squibb; and personal fees and non-financial support from Roche, during the study. GG reports grants from Jannsen-Cilag, Novartis, Astex, Roche, Heartflow, Bristol Myers Squibb, BioNtech; grants and personal fees from AstraZeneca; and personal fees from Celldex, outside the submitted work. JL reports grants from Cancer Research UK and non-financial support from Bristol Myers Squibb, during the study. CO reports personal fees from Bristol Myers Squibb, outside the submitted work. RC reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Roche, and AstraZeneca, during the study. All other authors declare no competing interests. Funding Information: This study was funded by Stand up to Cancer?Cancer Research UK (C16728/A21400) and received investigator-initiated support from Bristol Myers Squibb (CA 209?841) for drug, labelling, and distribution. We are most grateful to Stand up to Cancer and Cancer Research UK for funding of this study, the patients who participated in this clinical trial, their families, and the nursing and medical staff at the CONFIRM trial sites. We would also like to thank Mesothelioma UK, the independent blinded clinical trial steering committee, and Bristol Myers Squibb for the provision of nivolumab. This study was sponsored by the University of Southampton. Funding Information: This study was funded by Stand up to Cancer–Cancer Research UK (C16728/A21400) and received investigator-initiated support from Bristol Myers Squibb (CA 209–841) for drug, labelling, and distribution. We are most grateful to Stand up to Cancer and Cancer Research UK for funding of this study, the patients who participated in this clinical trial, their families, and the nursing and medical staff at the CONFIRM trial sites. We would also like to thank Mesothelioma UK, the independent blinded clinical trial steering committee, and Bristol Myers Squibb for the provision of nivolumab. This study was sponsored by the University of Southampton. Publisher Copyright: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
Keywords: Aged, Antineoplastic Agents, Immunological/therapeutic use, B7-H1 Antigen/metabolism, Double-Blind Method, Female, Humans, Immune Checkpoint Inhibitors/therapeutic use, Male, Mesothelioma, Malignant/drug therapy, Nivolumab/therapeutic use, Peritoneal Neoplasms/drug therapy, Pleural Neoplasms/drug therapy, Progression-Free Survival, Recurrence, Survival Rate

Identifiers

Local EPrints ID: 452035
URI: http://eprints.soton.ac.uk/id/eprint/452035
ISSN: 1470-2045
PURE UUID: d776344a-30c7-42ef-917a-4982fc87ac81
ORCID for Sean Ewings: ORCID iD orcid.org/0000-0001-7214-4917
ORCID for Joanne Lord: ORCID iD orcid.org/0000-0003-1086-1624
ORCID for Gareth Griffiths: ORCID iD orcid.org/0000-0002-9579-8021

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Date deposited: 09 Nov 2021 17:32
Last modified: 17 Mar 2024 03:39

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Contributors

Author: Dean A Fennell
Author: Sean Ewings ORCID iD
Author: Raffaele Califano
Author: Gerard G Hanna
Author: Kayleigh Hill
Author: Sarah Danson
Author: Nicola Steele
Author: Mavis Nye
Author: Lucy Johnson
Author: Joanne Lord ORCID iD
Author: Calley Middleton
Author: Peter Szlosarek
Author: Sam Chan
Author: Aarti Gaba
Author: Liz Darlison
Author: Peter Wells-Jordan
Author: Cathy Richards
Author: Charlotte Poile
Author: Jason F Lester
Corporate Author: CONFIRM trial investigators

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