Malignant Mesothelioma Clinical Trial Combines Immunotherapy Drugs


3Malignant mesothelioma clinical trial combines immunotherapy drugs

Studies utilizing single-agent PD-1 or PD-L1 inhibitor for mesothelioma have reported tumor response rates in approximately 10–20% of patients treated. Given the success of combining these agents with CTLA-4 inhibitor in melanoma, there is a strong rationale to study it in mesothelioma. Recently results from clinical trials investigating this approach have been released. Though limited by small sample size, the studies conclusively demonstrated feasibility and suggested a modestly higher tumor response rate than one would expect from treatment with single-agent PD-1 or PD-L1 inhibitor. Nevertheless, toxicity was also increased. Immunotherapy-related deaths due to encephalitis, renal failure and hepatitis were observed. Further studies are warranted.

Malignant mesothelioma is an uncommon thoracic malignancy diagnosed in approximately 3000 cases each year in the USA [1]. Typically associated with asbestos exposure, mesothelioma disproportionately affects older patients, who often have significant comorbidity and advanced stage of the disease, making treatment challenging. Improvement in systemic therapy, the mainstay of treatment, has been slow, with pemetrexed being the last agent to gain regulatory approval by the US FDA, in 2004 [2]. Today, the first-line systemic therapy remains pemetrexed-based chemotherapy. Typical median overall survival with this treatment as reported from clinical trials using pemetrexed cisplatin with or without bevacizumab typically ranges from 1 to 1.5 years [3]. For patients with recurrent or refractory disease, subsequent therapeutic options are limited. There is a clear need for additional treatment options beyond chemotherapy.

During the past decade, there has been a rapid advance in anti-cancer immunotherapy, specifically through blockade of the immune checkpoints, PD-1 or PD-L1 and CTLA-4 [4]. Immune checkpoint inhibitors have already gained regulatory approval for treatment of many cancers. For mesothelioma, there has been much enthusiasm for these agents, given the inflammatory phenotype and reported 20 to 40% PD-L1 expression of the mesothelioma and stromal cells [5]. To date, several studies have documented the efficacy of single-agent immunotherapy in mesothelioma. For example, pembrolizumab, an anti-PD-1, produced a response rate of approximately 20% [6,7]. Nivolumab, another anti-PD-1 agent, produced a response rate of 15% in a small cohort of pretreated patients [8]. Avelumab, an anti-PD-L1 with antibody-dependent cell mediated cytotoxicity, yielded 9.4% partial response rate [9]. Given that combining anti-PD-1 or anti-PD-L1 therapy with CTLA-4 agent may produce synergism, thus further enhancing the efficacy of treatment, there has been an interest investigating the use of combined checkpoint inhibitors as a treatment for mesothelioma.