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

Greco, F. Anthony; Bonomi, Philip; Crawford, Jeffrey; Kelly, Karen; Oh, Yun; Halpern, Wendy; Lo, Larry; Gallant, Gilles; Klein, Jerry L.

doi:10.1016/j.lungcan.2007.12.011

Cited by 147 publications

(86 citation statements)

References 28 publications

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“…Mapatumumab did not seem to markedly affect haematological parameters other than lymphocyte counts. In this study, 42% of patients experienced lymphopaenia, consistent with other previously published single-agent mapatumumab studies (Tolcher et al, 2007;Greco et al, 2008;Hotte et al, 2008). None of these transient lymphocytopaenias were associated with clinically relevant infections, but subsequent studies of mapatumumab should evaluate this further, for example, by characterising lymphocyte subsets in patients who experience lymphocytopaenia, especially as TRAIL targets certain lymphocyte subsets (Janssen et al, 2005).…”

Section: Discussionsupporting

confidence: 88%

“…Hence, when administered as a single agent, mapatumumab did not demonstrate the ability to shrink tumours or generate a clinically meaningful response in this population of heavily pretreated refractory colorectal cancer patients. Similar results were also reported with mapatumumab in patients with pre-treated advanced non-small-cell lung cancer (Greco et al, 2008). However, two complete and one partial responses were reported in patients with relapsed or refractory follicular lymphoma receiving mapatumumab (Younes et al, 2005), demonstrating that single-agent mapatumumab has activity at these doses.…”

Section: Discussionsupporting

confidence: 63%

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Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer

et al. 2010

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BACKGROUND: Recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour-selective apoptosis in various pre-clinical models by binding its specific receptors expressed on cancer cells. Mapatumumab is a fully human monoclonal antibody that is agonistic to the TRAIL Receptor 1 (TRAIL-R1). METHODS: This phase II multicentre study was designed to evaluate the efficacy and safety of mapatumumab in patients with colorectal cancer (CRC) who had failed to respond to, were intolerant to, or not candidates for fluoropyrimidine, oxaliplatin, and irinotecanbased regimens. All patients received two loading doses of mapatumumab (20 mg kg À1 every 14 days), followed by maintenance therapy with 10 mg kg À1 infused every 14 days. RESULTS: A total of 38 patients, who had progressive disease after a median of three earlier chemotherapy lines, were enrolled. No response according to the Response Evaluation Criteria in Solid Tumors was observed. A total of 12 patients (32%) achieved stable disease for a median of 2.6 months. The median progression-free survival was 1.2 months. The most common adverse events reported, regardless of relationship, were fatigue, nausea, anorexia, and abdominal pain. Plasma mapatumumab concentrations were within the range of exposures predicted by the results of phase I studies of mapatumumab. CONCLUSION: No clinical activity of single-agent mapatumumab was observed in patients with advanced refractory CRC. However, on the basis of its favourable safety profile and pre-clinical evidence of potential synergy in combination with agents commonly used in the treatment of colorectal cancer, further evaluation of mapatumumab in combination with chemotherapy is warranted.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 63%

Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer

et al. 2010

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“…A recent phase 2 trial of mapatumumab in NSCLC patients indicates that the antibody is safe and well tolerated, although no objective single-agent activity was shown (12). Preclinical studies indicate that the maximal activity of mapatumumab occurs when used in combination with chemotherapeutic agents that sensitize tumor cells to proapoptotic stimuli (13).…”

Section: Discussionmentioning

confidence: 99%

“…A separate study of stage I and II NSCLC patients found high TRAIL-R2 expression in 67% of tumor biopsies (11). Thus, many NSCLC patients may be good candidates for TRAIL-R1 and TRAIL-R2 agonist-mediated therapy, although recent single-agent phase 2 data with mapatumumab suggest that combination with sensitizing agents may be required for maximum efficacy (12).…”

Section: Introductionmentioning

confidence: 99%

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

Luster¹,

Carrell

McCormick³

et al. 2009

Molecular Cancer Therapeutics

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Mapatumumab and lexatumumab are fully human monoclonal antibodies that bind and activate human tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2, respectively. These antibodies induce apoptosis in various tumor cell types, although the degree of sensitivity can vary from highly sensitive to completely resistant. Importantly, tumor cells that are partially or completely resistant to mapatumumab or lexatumumab can often be sensitized when treated in combination with chemotherapeutic drugs. In this regard, the proteasome inhibitor bortezomib has recently shown synergistic activity against established lymphoma cell lines and primary lymphomas when combined with mapatumumab and lexatumumab. Here, we report similar findings using a panel of human non-small cell lung cancer (NSCLC) cell lines. Specifically, we show that bortezomib rapidly induces sensitivity to mapatumumab and lexatumumab in NSCLC cell lines that are completely resistant to antibody alone and that bortezomib concentrations as low as 25 nmol/L sensitize NSCLC cells to the antibodies. Furthermore, bortezomib at the tested concentration has minimal effect on its own, indicating the combination generates synergistic cytotoxicity. Combination treatment induces activation of the caspase cascade and the effect of the combination is caspase dependent. Bortezomib treatment increases the intracellular levels of several important apoptosis regulators that may mediate enhanced sensitivity to mapatumumab and lexatumumab. These results suggest future evaluation of mapatumumab or lexatumumab in combination with bortezomib is warranted in NSCLC patients.

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“…Furthermore, no immunogenicity against mapatumumab or lexatumumab has been observed. Clinical responses ranging from stable disease, partial responses and even a complete response have been reported after administering either untagged versions of recombinant human TRAIL or antibodies targeting death receptors as monotherapy (Plummer et al, 2007;Tolcher et al, 2007;Greco et al, 2008;Hotte et al, 2008;Leong et al, 2009;Mom et al, 2009;Trarbach et al, 2010;Wakelee et al, 2010). Taken together, safety results and clinical responses encourage further diseasedirected assays of these agents.…”

Section: Novel Paradigms For Cancer Therapy V Pavet Et Almentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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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

Cited by 147 publications

References 28 publications

Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer

Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

Towards novel paradigms for cancer therapy

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