Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Mesothelioma

Mesothelioma, Malignant

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Mesothelial

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Pleural Neoplasms

Lung Diseases

Respiratory Tract Diseases

Malignant Mesothelioma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Gemcitabine

Vinorelbine

Pembrolizumab

Immunomodulating Agents

Immunoglobulins

Vinca Alkaloids

Antimetabolites

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Tubulin Modulators

Antimitotic Agents

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.

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.

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.

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").

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.

Sanjay Popat, MD

Alessandra Curioni-Fontecedro, MD

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

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.

PembROlizuMab Immunotherapy Versus Standard Chemotherapy for Advanced prE-treated Malignant Pleural Mesothelioma

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

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.

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.

Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.

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.

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.

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.

Merck Sharp & Dohme LLC

Frontier Science Foundation, Hellas

ETOP IBCSG Partners Foundation

In the 'All Cause Mortality' section, number of at risk patients includes all randomized patients, while in the 'Serious Adverse Events' and 'Other (Not Including Serious) Adverse Events' sections, at risk patients refer to the population who received at least one dose of trial treatment (safety cohort).

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.

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.

Pembrolizumab 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.

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").

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.

Standard Chemotherapy Arm

Total

Age, Continuous

Age category

Age, Customized

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

United Kingdom

Switzerland

Spain

Region of Enrollment

Histologic subtype

Smoking history

0: Fully active, able to carry on all pre-disease performance without restriction; 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2: Ambulatory and capable of all selfcare but unable to carry out any work activities, up and about more than 50% of waking hours.

Of note, although an ECOG performance status (PS) of 0 or 1 was mandatory to be included in the study, one patient was allowed to enter the study with ECOG PS of 2 due to leg braces.

ECOG performance status

EORTC prognostic score (EPS) was calculated based on Fennell et al.(2005) prognostic model. This model takes into account WBC count, ECOG PS, histologic subtype and gender. A value of smaller or equal to 1.27 signifies a "good prognosis" while a value of more than 1.27 a "poor prognosis".

EORTC score

Prior treatment

PD-L1 expression (PD-L1 tumor proportion score) was evaluated by immunohistochemistry (IHC) assay using clone SP263. PD-L1 was quantified as number of positive cells and scored as percentage of PD-L1 positive cells within tumor region. The following classification of PD-L1 scoring was used: 0 to \<1% positive tumor cells; 1 to \<20% positive tumor cells; \>=20% positive tumor cells; Not Evaluable; Not scored.

PD-L1 Tumour proportion score

Heidi Roschitzki

All efficacy evaluations were conducted in the intent-to-treat (ITT) population.

Progression Free Survival (PFS) as Assessed by Independent Radiological Review

Objective Response Rate by Independent Radiological Review

Overall Survival.

Time to Treatment Failure.

Experienced any adverse event

Experienced treatment related adverse event

Experienced treatment related adverse event of grade 3-5

Experienced treatment related adverse event leading to death

Experienced treatment related adverse event leading to treatment discontinuation

Safety evaluation was conducted in the as-treated (AT) population: all randomised patients that received at least one dose of trial treatment, with treatment assignments designed according to actual study treatment received.

Spots Global Cancer Trial Database for pleural mesothelioma malignant advanced