ArticlesTremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial
Introduction
Malignant mesothelioma is a rapidly progressing tumour with a high mortality and steadily increasing incidence worldwide.1 The close association between exposure to asbestos fibres and development of malignant mesothelioma is well documented.1 Histologically, three main variants of malignant mesothelioma exist: epithelioid, which has a relatively favourable course, and sarcomatoid and biphasic variants, which are both characteristically aggressive.1
Despite improvements made in accuracy and speed of diagnosis in the past few years, more than 85–90% of patients with malignant mesothelioma present with unresectable disease at diagnosis and rely on palliative treatment.2 Pemetrexed-platinum therapy is regarded as the standard of care for first-line treatment of unresectable pleural malignant mesothelioma;3 however, the outcome of patients with malignant mesothelioma remains dismal, with a median overall survival from diagnosis of about 12 months.3 No effective therapeutic options exist after failure of first-line systemic treatment,4 and no treatment has shown superiority compared with supportive care alone.5
In the view of evidence suggesting that patients with malignant mesothelioma can spontaneously mount a tumour-specific immune response, different immunotherapeutic approaches have been investigated, although with disappointing results.6, 7 A new immunotherapeutic strategy involves targeting of regulatory molecules expressed on immune cells to enhance the anti-tumour activity of T cells. The anti-cytotoxic T lymphocyte antigen 4 (CTLA4) specific monoclonal antibodies ipilimumab and tremelimumab are prototypes of this new class of immunomodulatory monoclonal antibody, and both agents are under clinical development for different tumour types.8, 9, 10 Despite showing few objective responses, ipilimumab significantly prolonged the survival of patients with metastatic melanoma and has received marketing authorisation in Europe and the USA.11, 12 Moreover, continued follow-up of patients enrolled in clinical trials and in expanded-access programmes with ipilimumab, have recently identified a substantial proportion of patients who achieve a long-term benefit from treatment.13, 14
The fully humanised monoclonal antibody tremelimumab (CP-675,206) was developed as a G2 isotype immunoglobulin to reduce complement activation and the risk of cytokine storm. Single-agent tremelimumab induced durable tumour regression (up to 8 years) in 7–10% of patients with advanced melanoma.15 In a randomised phase 3 study,16 tremelimumab alone did not improve the overall survival of advanced stage melanoma compared with standard treatment with dacarbazine or temozolomide; nevertheless, tremelimumab led to a significantly longer duration of response. Tremelimumab has also yielded promising results in phase 1–2 trials, alone or in combination with other drugs.8, 15, 17
The identification of markers of T-cell activation, which could indicate treatment with anti-CTLA4 monoclonal antibody could be appropriate, is an unsolved issue. Inducible costimulatory (ICOS) molecule, a third member of the CD28/CTLA-4 family expressed at low levels on naive T cells, and upregulated rapidly after T-cell activation is an interesting candidate.18 We aimed to assess safety and therapeutic and immunological activity of tremelimumab in patients with unresectable malignant mesothelioma.
Section snippets
Study design and participants
Between May 27, 2009, and Jan 10, 2012, we undertook an open-label, single-arm phase 2 trial (MESOT-TREM-2008) at the University Hospital of Siena, Siena, Italy. We enrolled adults (aged ≥18 years) with unresectable stage III or stage IV (advanced) malignant mesothelioma for whom their disease had progressed after one platinum-based chemotherapy and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 for peritoneal malignant mesothelioma or
Results
The aim of the prespecified interim efficacy analysis was successfully met because one patient had an objective response; thus, enrolment continued to reach the 29 patients planned (table 1). 23 (79%) of 29 patients had documented disease progression within 6 months from first-line platinum-based chemotherapy, of whom 15 (68%) progressed during chemotherapy; 25 (86%) of 29 patients received platinum combined with pemetrexed as first-line chemotherapy. The median time from diagnosis to
Discussion
We report clinical and immunological activity of the anti-CTLA4 monoclonal antibody tremelimumab in patients with previously treated malignant mesothelioma. To our knowledge, this study is the first to investigate the efficacy of CTLA4 blockade in this hard-to-treat indication (panel).
Two of 29 (6·9%; 95% CI 0·0–16·1) patients enrolled in the study achieved a partial response; therefore, our primary endpoint was not reached. This limited objective response rate is consistent with that reported
References (31)
- et al.
Second-line treatment for malignant pleural mesothelioma
Cancer Treat Rev
(2010) - et al.
Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications
Semin Oncol
(2010) Clinical development of the anti-CTLA-4 antibody tremelimumab
Semin Oncol
(2010)- et al.
Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy
Semin Oncol
(2010) - et al.
Modified RECIST criteria for assessment of response in malignant pleural mesothelioma
Ann Oncol
(2004) - et al.
Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey
Lung Cancer
(2012) - et al.
The emerging toxicity profiles of anti-CTLA4 antibodies across clinical indications
Semin Oncol
(2010) - et al.
Advances in malignant mesothelioma
N Engl J Med
(2005) - et al.
Multidisciplinary treatment of malignant pleural mesothelioma
Oncologist
(2007) - et al.
Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma
J Clin Oncol
(2003)