A phase I study of the humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody EMD 72000 (matuzumab) in combination with paclitaxel in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC)

Kollmannsberger, Christian; Schittenhelm, Marcus M; Honecker, Friedemann; Tillner, J.; Weber, Dirk; Oechsle, Karin; Kanz, Lothar; Bokemeyer, Carsten

doi:10.1093/annonc/mdl042

Cited by 90 publications

(56 citation statements)

References 20 publications

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“…Phase I trials showed well-tolerated antitumor activity, inhibition of phosphorylated EGFR and effect of receptor-dependent signaling and transduction; effects were seen even in the lowest-dose group (Graeven et al, 2006;Kollmannsberger et al, 2006). HER-2/neu is overexpressed in 25-30% of invasive breast cancer and is associated with poor disease-free survival.…”

Section: Naked Antibodiesmentioning

confidence: 99%

Novel antibodies as anticancer agents

2007

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In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents.

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Section: Naked Antibodiesmentioning

confidence: 99%

Novel antibodies as anticancer agents

2007

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“…The results from the phase I portion of this study, including patients treated with the 200-, 400-, and 800-mg doses of matuzumab, were previously published (13). In our patient cohort, including 23 eligible patients from the phase I/II, clinical activity was seen in 61% (14/23) of patients, including one complete response (CR, 1/23, 4%), three partial responses (PR, 3/23, 13%), and 10 cases with stable diseases (SD, 10/23, 44%) as defined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria for at least two cycles of therapy [as assessed by computed tomography (CT) imaging].…”

Section: Patient Cohortmentioning

confidence: 99%

“…Matuzumab (13), cetuximab (14), and ABX-EGF (15) have proven to be effective in clinical studies enrolling patients with a variety of EGFR-expressing tumors. Recent in vitro data suggest that cetuximab potently targets TKI-sensitive as well as resistant EGFR TK mutant isoforms (16 -18), but substantial differences are observed in clinical response rates (14).…”

Section: Introductionmentioning

confidence: 99%

Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer

Schittenhelm

Kollmannsberger

Oechsle

et al. 2009

Molecular Cancer Therapeutics

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Antibodies targeting epidermal growth factor receptor (EGFR) have proven to be effective in patients with nonsmall cell lung cancer (NSCLC) that express EGFR. We recently published a phase I study of weekly matuzumab plus paclitaxel. This therapy was well tolerated and showed clinical responses in the majority of patients. Although matuzumab displays potent antitumor activity in some patients, not all patients respond well to treatment. Whether dysregulation of EGFR-mediated pathways precludes or sensitizes cells to paclitaxel is unknown. We sought to determine molecular predictive factors for therapy response in a phase

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“…In recent phase I studies of chemotherapy plus matuzumab in lung and pancreatic cancer (at doses ranging from 100 to 800 mg weekly), the MTD was not reached although one DLT of grade 4 neutropaenia was observed at matuzumab 800 mg combined with paclitaxel. Antitumour activity was reported and pharmacodynamic data revealed blockade of the EGFR pathway (Graeven et al, 2006;Kollmannsberger et al, 2006). Preliminary data of the phase I study of PFL (cisplatin, leucovorin and 5FU) and matuzumab (at doses of 400 or 800 mg weekly) in advanced OG cancer indicate good tolerability at the 400 mg dose level (DL) (Trarbach et al, 2005).…”

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confidence: 99%

Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer

Starling

Cunningham

et al. 2008

Br J Cancer

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To evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of the humanised antiepidermal growth factor receptor monoclonal antibody matuzumab combined with epirubicin, cisplatin and capecitabine (ECX) in patients as first-line treatment for advanced oesophagogastric cancer that express epidermal growth factor receptor (EGFR). This was a phase I dose escalation study of matuzumab at 400 and 800 mg weekly and 1200 mg every 3 weeks combined with ECX (epirubicin 50 mg m À2 , cisplatin 60 mg m À2 on day 1 and capecitabine 1000 mg m À2 daily). Patients were treated until disease progression, unacceptable toxicity or for a maximum of eight cycles. Twenty-one patients were treated with matuzumab at three different dose levels (DLs) combined with ECX. The main dose-limiting toxicity (DLT) was grade 3 lethargy at 1200 mg matuzumab every 3 weeks and thus 800 mg matuzumab weekly was the maximum-tolerated dose (MTD). Other common toxicities included rash, nausea, stomatitis and diarrhoea. Pharmacokinetic evaluation demonstrated that the coadministration of ECX did not alter the exposure of matuzumab. Pharmacodynamic studies on skin biopsies demonstrated inhibition of the EGFR pathway. Objective response rates of 65% (95% confidence interval (CI): 43 -82), disease stabilisation of 25% (95% CI: 11 -47) and a disease control rate (CR þ PR þ SD) of 90% were achieved overall. The MTD of matuzumab in combination with ECX was 800 mg weekly, and at this DL it was well-tolerated and showed encouraging antitumour activity. At the doses evaluated in serial skin biopsies, matuzumab decreased phosphorylation of EGFR and MAPK, and increased phosphorylation of STAT-3.

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A phase I study of the humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody EMD 72000 (matuzumab) in combination with paclitaxel in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC)

Abstract: Matuzumab doses up to 800 mg weekly with paclitaxel 175 mg/m(2) every 3 weeks are well tolerated, with no apparent drug interactions and with evidence of antitumor activity.

Cited by 90 publications

References 20 publications

Novel antibodies as anticancer agents

Novel antibodies as anticancer agents

Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer

Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer

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