Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer
Introduction
New effective agents are needed for the treatment of patients with advanced NSCLC. Lung cancer is the leading cause of cancer death in the United States (US). In 2007, an estimated 213,380 new cases and 160,390 deaths are expected in the US [1]. Lung cancer represents 15% of all new cancer cases diagnosed and, 31% and 26% of all cancer deaths in men and women, respectively. In spite of numerous advances in cancer detection and treatment during the past 2 decades, only about 15% of patients diagnosed between 1995 and 2000 are expected to be alive after 5 years. Approximately 80% of all lung cancers are of non-small cell histology, and adenocarcinoma is the most frequently occurring type in the US [2].
Upon initial presentation, less than one-half of patients will have surgically resectable lung cancer. Most patients present with locally advanced disease (Stage IIIB) or metastatic disease (Stage IV). Despite the development of new chemotherapy combinations, a large ECOG trial evaluating 4 of the most commonly used 3rd generation 1st-line NSCLC chemotherapy doublets showed no survival advantage for any regimen over traditional cisplatin/paclitaxel [3]. Many other randomized phase III studies have confirmed a survival benefit for the third generation chemotherapy combinations, but have failed to find a clear cut superior regimen. Recently the addition of the angiogenesis inhibitor bevacizumab to paclitaxel/carboplatin has further improved the survival of patients with advanced NSCLC [4]. In the 2nd-line setting docetaxel, erlotinib and pemetrexed offer improved survival [5], [6], [7]. Further advances in the treatment of NSCLC will rely on the development of other novel therapeutic agents aimed at newly defined molecular targets such as signal transduction inhibitors/cell cycle regulators, angiogenesis inhibitors and gene therapy.
The current study was conducted to assess the anti-tumor activity of an agonistic monoclonal antibody therapy which targets and activates the TRAIL receptor 1 (TRAIL-R1) administered as a single-agent in patients with advanced NSCLC. Preclinical studies have shown that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or agonist antibodies directed to TRAIL receptors induce apoptosis in cancer cell lines and inhibit tumor growth in xenograft models [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24]. Mapatumumab is a recombinant, high affinity, fully human agonist IgG1 monoclonal antibody specific for human TRAIL-R1. Mapatumumab binds TRAIL-R1 with high affinity, displays cytotoxic activity in vitro, and inhibits the growth of human tumor cell lines in xenograft models in vivo.
Little or no TRAIL-R1 expression is detected on most normal human cells. However, TRAIL-R1 is expressed by a broad range of solid tumors, including carcinomas of the lung (NSCLC in particular), colon, pancreas, ovary, cervix, uterus, breast, and stomach, as detected via immunohistochemistry. Although expression of TRAIL-R1 appears to be necessary for mapatumumab-mediated cell death in cell line models, the level of receptor expression does not consistently correlate with activity.
In vitro, mapatumumab is able to decrease the viability of NSCLC cell lines. The efficacy of mapatumumab has also been evaluated in vivo in multiple separate murine xenograft models, including xenografts using NSCLC cell lines [20]. In the H2122 NSCLC xenograft model, weekly IV administration of single-agent mapatumumab resulted in a significant and rapid regression of tumors after the 1st dose, and this effect persisted throughout the duration of the study. Some of the pre-established tumors were completely eliminated after the 3rd weekly administration. In the H460 NSCLC xenograft model with pre-established tumors, single-agent mapatumumab was not effective while a combination of mapatumumab with carboplatin and docetaxel resulted in tumor regression and a sustained reduction in tumor growth, significantly greater than that of any of the agents alone or the carboplatin–docetaxel combination.
The in vitro and in vivo pharmacological properties of mapatumumab suggest that this antibody reduces cell viability and induces in vitro cell death in many types of cancer cell lines. The receptor for mapatumumab, TRAIL-R1, is expressed in NSCLC cell lines. Mapatumumab inhibits or reduces tumor growth in xenograft models of solid tumors and can induce significant tumor regression in some models. This activity may be increased by co-treatment with chemotherapeutic agents, including taxane and platinum-based agents. This pharmacologic profile suggests that mapatumumab may have therapeutic benefit in the treatment of cancer either as a single agent, or in combination with chemotherapeutic agents.
Mapatumumab, administered at doses ranging from 0.01 to 20 mg/kg, has been well tolerated in patients treated in 2 Phase 1 single agent clinical trials [25], [26]. Adverse events have generally been mild to moderate in severity, manageable, and did not appear to be related to dose. Severe events have been uncommon and generally judged not related to mapatumumab. The maximum tolerated dose has not been identified at doses up to 20 mg/kg administered every 28 days. Stable disease was observed in a number of heavily pretreated patients at several dose levels. Therefore, 10 mg/kg was believed to be a safe as well as a potentially effective dose for the treatment of NSCLC.
The study described here was undertaken to evaluate the tumor response, safety and tolerability of mapatumumab at a dose of 10 mg/kg every 21 days in patients with relapsed or refractory advanced NSCLC previously treated with at least 1 platinum-based regimen.
Section snippets
Patient population
Patients were required to have relapsed or refractory histologically or cytologically confirmed Stages IIIB, IV, or recurrent NSCLC. They had to have been previously treated and failed to respond to standard therapy, or progressed after standard therapy, including at least 1 platinum-based therapy in advanced or metastatic disease. Other criteria included: (1) at least 1 non-irradiated measurable target lesion by the RECIST criteria; (2) adequate hematologic function (i.e. absolute neutrophil
Patient population
A total of 32 patients were enrolled in this study. Patient characteristics are listed in Table 1. Fifty-three percent of patients were male; the median age was 61.5 years. The most common histologic subtype was adenocarcinoma (63%). Most patients (26/32, 81%) had an ECOG performance status of 1. At the time of study entry, all patients (32/32) had widely disseminated disease (Stage IV NSCLC). Patients included in this study were heavily pretreated: The median number of prior systemic regimens
Discussion
The primary objective of this Phase 2 clinical study was to assess, in patients with relapsed or refractory NSCLC, the tumor response to mapatumumab administered every 21 days at a dose of 10 mg/kg. Of note, after the initiation of this study, the administration of single-agent mapatumumab at a dose of 20 mg/kg had been shown to be safe [25]. More recently, mapatumumab administered at a dose of 30 mg/kg in combination with chemotherapy was also shown to be tolerable [30]. None of the 32 treated
Conclusion
The administration of mapatumumab in patients with advanced NSCLC was safe and well tolerated. The best response observed was stable disease in a heavily pretreated group of advanced NSCLC patients. Based on preclinical observations and the favorable safety profile, future evaluation of mapatumumab in combination with chemotherapy is warranted.
Conflict of interest
All the authors participated in the conception and the design of the study as well as the writing of the manuscript. The data were collected, assembled, and analyzed by Human Genome Sciences. The final manuscript was approved by all authors. Wendy Halpern, Larry Lo, Gilles Gallant and Jerry Klein are employees of Human Genome Sciences. The authors would like to especially thank Al Corey and Elizabeth Kumm for their important contribution to this study.
Acknowledgements
The authors would like to thank the patients that have participated in this study. The study was supported by Human Genome Sciences.
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