PembROlizuMab Immunotherapy Versus Standard Chemotherapy for Advanced prE-treated Malignant Pleural Mesothelioma (PROMISE-meso)

A Multicentre Randomised Phase III Trial Comparing Pembrolizumab Versus Standard Chemotherapy for Advanced Pre-treated Malignant Pleural Mesothelioma

Trial comparing standard treatment (chemotherapy) with pembrolizumab treatment in patients with advanced pretreated malignant mesothelioma.

Study Overview

• Status: Completed
• Conditions: Pleural Mesothelioma Malignant Advanced
• Intervention / Treatment: Drug: Pembrolizumab; Drug: Gemcitabine; Drug: Vinorelbine

Detailed Description

Mesothelioma is an aggressive malignancy usually affecting the surfaces of body coelomic cavities. It most commonly originates from the pleura with a propensity to the lower parietal pleura and costo-diaphragmatic recess, and is almost always caused by asbestos exposure, with a usual lag time of 30 years between exposure and presentation. Outcomes for most patients are invariably fatal, with median survival from presentation around 9-12 months in most series due to difficulties in achieving a complete microscopic surgical resection and tumour relative chemo-refractoriness. Whilst initially considered rare, due to the demand of asbestos of all varieties associated with industrialization following the Second World War, the background incidence of mesothelioma of 1/million has risen to 40/million in some countries. In the UK, where substantial asbestos exposure continued until the 1970s, the death rate is the highest in the world with a current epidemic of new cases, predicted to continue for another 5-10 years. Two main histological subtypes of mesothelioma are identified. The epitheliod subtype is the commonest, accounting for around 40% of cases, whilst the sarcomatoid subtype is observed in 20% of cases; the latter being typically aggressive and chemorefractory. Around 35% cases have features of both epitheliod and sarcomatoid subtypes and are termed biphasic subtype.

For patients with pleural mesothelioma, in whom surgery is not considered appropriate, systemic chemotherapy (platinum combined with pemetrexed) remains the international standard of care. Cisplatin/pemetrexed is associated with a response rate of 41% and confers an OS advantage of 3 months over cisplatin alone, and is the only licensed systemic therapy for mesothelioma in Europe. Despite this, the median survival is 9-12 months from most series in unresectable cases. At relapse, after platinum-based chemotherapy, no anti-cancer systemic therapies are licensed. Whilst several small phase II studies and retrospective series have suggested potential efficacy for chemotherapy with agents including carboplatin/gemcitabine, or vinorelbine, none thus far have demonstrated efficacy benefit in a randomised study, with median PFS rates reported of about 3 months for both gemcitabine and vinorelbine. There is therefore a huge unmet need for effective therapy for patients with relapsed pleural mesothelioma. The largest trial ever performed of systemic therapy in relapsed pleural mesothelioma in 661 patients documented the natural outcome of this group of relapsed mesothelioma patients, reporting a median OS of 27.1 weeks (6 months) and median PFS for 6.1 weeks (1.5 months) for placebo.

Programmed cell death-1 (PD-1) is a co-inhibitory molecule at the immunological synapse that acts as a major regulator of adaptive immunity, and is exploited by tumour cells to result in adaptive immune resistance (tolerance). This occurs when PD-1 binds to the ligands PD-L1 (B7H1) or PD-L2, which are expressed on many tumour types. High PD-L1 expression on tumours is associated with poorer outcomes. Mesothelioma has been shown to express PD-L1, with a small study identifying PDL1 expression in up to 40% of mesotheliomas. Moreover, immunologically-mediated inflammation is known to be a key driver for mesothelioma development via the Nalp3 imflammasome.

Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

There is a need to identify new ways for the systemic therapy of malignant mesothelioma and immune checkpoint inhibition is a promising way forward. Results from the proposed trial will contribute to overcoming tumour-specific immune suppression with immune checkpoint inhibition.

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain
    • ICO Hospitalet
  • La Coruña, Spain
    • Hospital Teresa Herrera
  • Valladolid, Spain
    • Hospital Clinico Universitario de Valladolid
• Switzerland
  • Aarau, Switzerland
    • Kantonsspital Aarau
  • Lausanne, Switzerland
    • Centre Hospitalier Universitaire Vaudois
  • Luzern, Switzerland
    • Kantonsspital Luzern
  • Winterthur, Switzerland
    • Kantonsspital Winterthur
  • Zurich, Switzerland
    • University Hospital Zürich
• United Kingdom
  • Cambridge, United Kingdom
    • Addenbrooke's Hospital
  • Liverpool, United Kingdom
    • Clatterbridge Cancer Centre
  • London, United Kingdom, SW3 6JJ
    • Royal Marsden Hospital
  • London, United Kingdom
    • Guy's and St Thomas' Hospital
  • Plymouth, United Kingdom, PL6 8DH
    • Plymouth Hospitals Nhs Trust
  • Sheffield, United Kingdom, UK S10 2SJ
    • Weston Park Hospital
  • Kent
    • Maidstone, Kent, United Kingdom, ME16 9QQ
      • Maidstone and Tunbridge Wells NHS Trust, Kent Oncology Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed malignant pleural mesothelioma (all subtypes are eligible)
• Progressing after or on previous platinum based chemotherapy.
• Availability of tumour tissue for translational research.
• Female and male patients aged 18 years or over.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Life expectancy of at least 3 months.
• Measurable or evaluable disease according to RECIST 1.1 criteria.
• Adequate renal function
• Creatinine 1.5 × Upper Limit of Normal (ULN) OR Calculated creatinine clearance 40 mL/min (using the Cockroft-Gault formula).
• Adequate haematological function
• Haemoglobin 90 g/L or 5.6 mmol/L
• White Blood Cell (WBC) 1.0 × 109/L
• Lymphocytes 0.5 g/L
• Absolute neutrophils count (ANC) 1.5 × 109/L
• Platelet count 100 × 109/L.
• Adequate liver function
• ALT and AST 2.5 × ULN. If the patient has liver metastases, ALT and AST must be ≤5 × ULN.
• Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 35 days before randomisation (the test has to be repeated 72 hours before pembrolizumab treatment start).
• Written informed consent must be signed and dated by the patient and the investigator prior to any trial-related intervention including the submission of mandatory biomaterial.

Exclusion Criteria:

• Prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), anti-programmed cell death ligand 2 (anti-PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Prior therapy with gemcitabine or vinorelbine.
• Known active central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to randomisation and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to randomisation. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
• Known or suspected hypersensitivity to pembrolizumab or any of its excipients.
• Known unstable or unresolved surgical or chemotherapy-related toxicity that would compromise the patient's capacity to participate in the trial.
• Previous allogeneic tissue/solid organ transplant.
• Live vaccines within 30 days prior to first dose of pembrolizumab.
• Regular intake of immune-modulating drugs (such as interferon, methotrexate).
• History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) or topical therapy (e.g., steroids) for psoriasis or eczema is not considered a form of systemic treatment.
• Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, or antifungal therapy.
• Human immunodeficiency virus (HIV) infection.
• Known active hepatitis B or hepatitis C.
• Known history of active tuberculosis.
• Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomisation.
• Patients with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical condition that could affect the patient's capacity to participate in the trial.
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial results.
• Women who are pregnant or in the period of lactation.
• Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the trial and up to 120 days following cessation of trial treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab arm; Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.	Drug: Pembrolizumab; Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.; Other Names: KEYTRUDA; MK-3475; SCH 900475
Active Comparator: Standard chemotherapy arm; Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated. Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.	Drug: Gemcitabine; Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide").; Other Names: Gemzar; Drug: Vinorelbine; Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.; Other Names: Navelbine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) as Assessed by Independent Radiological Review	To investigate whether treatment with pembrolizumab improves PFS, compared to standard, institutional choice chemotherapy, assessed according to RECIST 1.1 criteria based on independent radiological review; using Kaplan-Meier method and compared between the two treatment arms by a stratified log rank test.	Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate by Independent Radiological Review	Defined as the best overall response (complete or partial response) across all assessment time-points from randomisation to end of trial treatment, determined by RECIST 1.1 criteria.	Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
Overall Survival.	Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.	Time from randomization of the first patient until database cutoff date for the OS analysis (Sep 2017 - Aug 2019; approximately 2 years).
Time to Treatment Failure.	Time from from randomisation to discontinuation of treatment for any reason, including progression of disease, treatment toxicity, refusal and death, by Kaplan Meier method. Censoring will occur at the last follow-up date.	Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
Percentage of Patients Experienced AEs/SAEs	The safety and tolerability of pembrolizumab treatment will be assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period. Adverse events are collected from study treatment initiation to 30 days after treatment is ceased for any reason. Serious adverse events and events of clinical interest are collected within 90 days after last dose of trial treatment.	Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
Progression Free Survival (PFS) Assessed by Investigator	Investigator assessed PFS, from the date of randomisation until documented progression or death, if progression is not documented. Censoring occurs at the last tumor assessment.	Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

Collaborators and Investigators

• Sponsor: ETOP IBCSG Partners Foundation
• Collaborators: Merck Sharp & Dohme LLC; Frontier Science Foundation, Hellas
• Investigators: Study Chair: Sanjay Popat, MD, Royal Marsden NHS Foundation Trust; Study Chair: Alessandra Curioni-Fontecedro, MD, University Hospital, Zürich

Publications and helpful links

General Publications

• Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19.
• Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003 Jul 15;21(14):2636-44. doi: 10.1200/JCO.2003.11.136.
• Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005 Jul 30-Aug 5;366(9483):397-408. doi: 10.1016/S0140-6736(05)67025-0.
• Fennell DA, Gaudino G, O'Byrne KJ, Mutti L, van Meerbeeck J. Advances in the systemic therapy of malignant pleural mesothelioma. Nat Clin Pract Oncol. 2008 Mar;5(3):136-47. doi: 10.1038/ncponc1039.
• Rake C, Gilham C, Hatch J, Darnton A, Hodgson J, Peto J. Occupational, domestic and environmental mesothelioma risks in the British population: a case-control study. Br J Cancer. 2009 Apr 7;100(7):1175-83. doi: 10.1038/sj.bjc.6604879. Epub 2009 Mar 3.
• Tsiouris A, Walesby RK. Malignant pleural mesothelioma: current concepts in treatment. Nat Clin Pract Oncol. 2007 Jun;4(6):344-52. doi: 10.1038/ncponc0839.
• Krug LM, Kindler HL, Calvert H, Manegold C, Tsao AS, Fennell D, Ohman R, Plummer R, Eberhardt WE, Fukuoka K, Gaafar RM, Lafitte JJ, Hillerdal G, Chu Q, Buikhuisen WA, Lubiniecki GM, Sun X, Smith M, Baas P. Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 2015 Apr;16(4):447-56. doi: 10.1016/S1470-2045(15)70056-2. Epub 2015 Mar 20. Erratum In: Lancet Oncol. 2015 May;16(5):e199.

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2017
• Primary Completion (Actual): February 20, 2019
• Study Completion (Actual): November 30, 2021

Study Registration Dates

• First Submitted: December 9, 2016
• First Submitted That Met QC Criteria: December 9, 2016
• First Posted (Estimate): December 13, 2016

Study Record Updates

• Last Update Posted (Actual): August 24, 2022
• Last Update Submitted That Met QC Criteria: August 23, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: MPM
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Mesothelioma; Mesothelioma, Malignant; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Gemcitabine; Pembrolizumab; Vinorelbine
• Other Study ID Numbers: ETOP 9-15; 2016-002062-31 (EudraCT Number); 3475-594 (Other Identifier: Merck Sharp Dohme)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No