Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study

Summary

Background

CTLA4 blockade by tremelimumab 15 mg/kg every 90 days provided preliminary evidence of activity in patients with pretreated malignant mesothelioma; however, retrospective exposure–response analysis of data from patients with melanoma suggested that this schedule could result in underexposure to tremelimumab. We therefore investigated the efficacy and safety of an intensified schedule of tremelimumab in patients with advanced malignant mesothelioma.

Methods

In this open-label, single-arm, phase 2 study, participants aged 18 years or older with unresectable, advanced malignant mesothelioma (measurable in accordance with the Response Evaluation Criteria in Solid Tumors [RECIST]), a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and who had failed a first-line platinum-based regimen were enrolled at the University Hospital of Siena, Siena, Italy. Participants received tremelimumab 10 mg/kg once every 4 weeks for six doses, then every 12 weeks until disease progression, unacceptable toxic effects, or refusal to continue treatment. The primary endpoint was the proportion of patients achieving an immune-related objective response (complete or partial), assessed in all patients who received at least one dose of the study drug. This study is registered with the European Union Clinical Trials Register, number 2012-002762-12, and ClinicalTrials.gov, number NCT01655888.

Findings

Between July 30, 2012, and July 15, 2013, we enrolled 29 patients with a median age of 65 years (range 42–78), stage III (n=11) or IV (n=18) disease, and an Eastern Cooperative Oncology Group performance status of 0–1 (n=23) or 2 (n=6). Malignant mesothelioma histology was epithelioid (n=21, including one peritoneal), biphasic (n=6), sarcomatoid (n=1), or undefined (n=1). Patients received a median of six doses of tremelimumab (range 1–13). After a median follow-up of 21·3 months (IQR 18·7–25·9), four immune-related-partial responses were recorded, one at the first tumour assessment (after about 12 weeks) and three at the second tumour assessment (about 24 weeks), with two responses occurring after initial progressive disease and one response after initial stable disease. 15 (52%) of patients achieved disease control, with a median duration of 10·9 months (95% CI 8·2–13·6). According to modified RECIST, one patient (3%) achieved a partial response and 11 (38%) patients achieved disease control rate. Grade 1–2 treatment-related adverse events occurred in 26 (90%) patients and grade 3–4 adverse events in two (7%) patients. The most common treatment-related adverse events were gastrointestinal, dermatological, and fever.

Interpretation

Our results suggest that the intensified schedule of tremelimumab investigated seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile. The same intensified schedule is now being investigated in an ongoing randomised, double-blind, placebo-controlled, phase 2b study.

Funding

Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, and MedImmune.

Introduction

The incidence of malignant mesothelioma is increasing worldwide, mainly because of exposure to asbestos.¹ Despite the unquestionable improvement in its diagnosis, the prognosis for malignant mesothelioma remains dismal and most patients present with surgically unresectable disease that requires medical intervention.² Pemetrexed-platinum therapy is currently the standard of care as first-line treatment for pleural malignant mesothelioma; however, the outcome of patients remains poor, with a median overall survival of 12·1 months.³ Patients with progressive disease after first-line treatment have a high unmet medical need in view of their poor survival and the absence of a clinically meaningful overall survival benefit with existing salvage regimens (vinorelbine and gemcitabine).4, 5

So far, the various immunotherapeutic approaches investigated in malignant mesothelioma have yielded disappointing results.6, 7 Targeting immune checkpoints with immunomodulatory monoclonal antibodies is a novel and rapidly evolving strategy for the treatment of cancer. The prototype of this approach relies on blocking inhibitory signals delivered by cytotoxic T lymphocyte-associated protein 4 (CTLA4) expressed on T lymphocytes. The first-in-class anti-CTLA4 monoclonal antibody ipilimumab has profoundly changed the therapeutic landscape for metastatic melanoma, significantly prolonging long-term survival for a sizeable proportion of patients, and is currently under active development for other tumour types.8, 9, 10, 11 Tremelimumab, another human anti-CTLA4 monoclonal antibody, was developed as a G2 isotype immunoglobulin to minimise complement activation and reduce the risk of cytokine storm. Initial studies with tremelimumab showed durable tumour regression in some patients with metastatic melanoma.10, 12 However, first-line tremelimumab did not improve survival when given to patients with metastatic melanoma compared with dacarbazine or temozolomide in a phase 3 trial.¹³ One possible explanation for this finding is that patients were underexposed to tremelimumab with the regimen used (15 mg/kg every 90 days); in support of this hypothesis, retrospective exposure–response analysis showed longer median overall survival (16 months vs 10 months) in patients with greater exposure to tremelimumab as measured by the area under the concentration–time curve from time 0 to 90 days (AUC90). Indeed, the survival analysis for patients in the tremelimumab group analysed by AUC90 above or below the median AUC showed a more favourable and prolonged median overall survival for patients who had an AUC higher than the median than for those with an AUC lower than the median.¹⁴

Research in context

Evidence before this study

We searched PubMed for reports published in English and Italian with the terms “mesothelioma”, “anti-CTLA4 antibody treatment”, and “immunotherapy in mesothelioma” from 2000, to 2014. Most of the reports identified were from the past 10 years. Patients with malignant mesothelioma progressing after first-line therapy have a high unmet medical need, in view of the absence of meaningful clinical effectiveness of existing salvage regimens. Anti-CTLA4 monoclonal antibody therapy has shown activity in several different types of tumour. CTLA4 blockade by tremelimumab (15 mg/kg every 90 days) provided initial signs of activity in patients with pretreated malignant mesothelioma; however, retrospective data from patients with melanoma suggested that this schedule could result in underexposure to tremelimumab. Therefore, we investigated an intensified schedule of tremelimumab (10 mg/kg once every 4 weeks for six doses, then every 12 weeks) in patients with advanced malignant mesothelioma.

Added value of this study

The clinical and immunological findings of this study provide evidence that this intensified schedule of tremelimumab seems to be active and safe in patients with previously treated malignant mesothelioma and suggest that it could eventually represent an effective second-line regimen for this group of patients with very poor prognosis.

Implications of all the available evidence

The same intensified schedule of tremelimumab is now being investigated in an ongoing randomised, double-blind, placebo-controlled, phase 2b study. Tremelimumab might also merit further exploration in malignant mesothelioma, both in the first-line setting and in combination or sequence with other immune checkpoint inhibitor monoclonal antibodies, such as those directed against programmed cell death protein-1 and its ligand, programmed death ligand-1.

We previously reported encouraging data for the activity of tremelimumab given at 15mg/kg every 90 days for the second-line treatment of malignant mesothelioma, with two partial responses out of 29 patients (one lasting 6 months and the other longer than 18 months), seven (24%) patients with stable disease of 12·4 months median duration, a median overall survival of 10·7 months (IQR 6·1–28·5, a 1-year survival of 48%, and 2-year survival of 37%.¹⁵ These initial findings, together with our pharmacokinetic data from patients with melanoma, prompted us to explore the activity of tremelimumab given in an intensified schedule for patients with malignant mesothelioma.