China
Africa
Explore chapters and articles related to this topic
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
As with other antibodies of this class, zalutumumab works by binding to the extracellular component of EGFR and inhibiting the intracellular signaling pathway. It binds to the EGFR Domain III on the cell surface, locking the receptor into an inactive conformation. Thus, zalutumumab is a competitive antagonist for the EGF ligand. In the inactive conformation, the distance between intracellular tyrosine kinase residues is larger, thus inhibiting dimerization. Therefore, subsequent phosphorylation and resultant signaling are inhibited. In addition, zalutumumab causes cell death at low concentrations through the ADCC mechanism.
Biologically Targeted Agents in Head and Neck Cancers
Published in John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford, Head & Neck Surgery Plastic Surgery, 2018
Kevin J. Harrington, Magnus T. Dillon
Similar findings have been reported with a human MAB, zalutumumab, from the DAHANCA-19 study in which 619 patients were enrolled to receive modestly accelerated radiotherapy, the hypoxic cell sensitizer nimorazole and cisplatin (if indicated), with or without zalutumumab.29 The majority of patients had stage III/IV disease and 70% received concomitant cisplatin. Treatment was well tolerated, but almost all (94%) patients in the zalutumumab arm reported a skin rash (grade 3–4 in 29%). No difference was seen between the study arms in terms of locoregional control at 3 years (78% in the zalutumumab arm and 79% in the control arm, (hazard ratio 0.8; 95% confidence interval 0.6–1.2). The data for disease-free and overall survival rates also failed to show a difference between the zalutumumab and control arms.
Immunotherapy
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Sowmiya Renjith, Sathya Chandran
Cetuximab is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody that has been approved by the U.S. Food and Drug Administration (FDA) in combination with chemotherapy as the standard first-line treatment for R/M HNSCC. It is also used along with radiation for locally advanced HNSCC (Bonner et al. 2006; Vermorken et al. 2008). Cetuximab efficacy is controlled by antibody-dependent cell-mediated cytotoxicity (ADCC), a mechanism of cell-mediated immune defense where NK cells actively destroy a target cell, whose membrane-surface antigen has been bound by cetuximab. NK cells are initiated upon binding to surface receptor FCγRIIIa (Seidel et al. 2013). Moreover, cetuximab triggers a CTL antitumor response through cross-priming of DCs and NKs (Gildener-Leapman et al. 2013). Other anti-EGFR monoclonal antibodies currently increased in HNSCC include panitumumab, nimotuzumab, and zalutumumab. Among them, panitumumab has produced merge results when added to platinum-based chemotherapy in patients with R/M HNSCC (Ermorken et al. 2013). Zalutumumab has demonstrated an OS of 5.3 months and a PFS of 2.1 when administered as monotherapy in individuals with platinum refractory R/M HNSCC (Saloura et al. 2014). Finally, nimotuzumab in combination with (chemo) radiation in locally advanced HNSCC has shown a survival benefit in tumors overexpressing EGFR (Basavaraj et al. 2010).
Genomic-based treatment of patients with head and neck cancer
Published in Expert Review of Precision Medicine and Drug Development, 2020
Arpan Patel, Seyed Mohammad Abedi, Manidhar Lekkala, Megan Baumgart
Panitumumab, a fully human IgG2 monoclonal antibody targeting EGFR, was given in combination with paclitaxel for first-line treatment of recurrent or metastatic HNSCC. While there was signal of clinical benefit (median PFS: 7.5 months; 95% CI, 4.9–8.3; and median OS: 9.9 months; 95% CI, 7.9–16.3), it was associated with an unacceptable safety profile (15% fatal adverse events) [45]. A phase III study of Panitumumab in which patients with recurrent or metastatic head and neck cancer were randomized to treatment with cisplatin and 5FU every 3 weeks with or without panitumumab (9 mg/kg on day 1) prolonged median PFS by 1.2 months (P = 0.004); however, there was no difference in primary endpoint of median OS, the primary end point [46]. Grade ≥ 3 toxicities were more frequent with panitumumab, and there were more treatment-related deaths compared to chemotherapy alone (4% v 2%, respectively). Zalutumumab, a humanized IgG1 monoclonal antibody targeting also showed disappointing results with suspension of further clinical development of this monoclonal antibody [47].
Optimizing treatments for recurrent or metastatic head and neck squamous cell carcinoma
Published in Expert Review of Anticancer Therapy, 2018
Pol Specenier, Jan B Vermorken
Zalutumumab is a human IgG1 monoclonal antibody targeting EGFR. In an open-label phase III trial, Machiels et al. randomly allocated 286 patients progressing within 6 months of platinum-based therapy in a 2:1 ratio to receive zalutumumab plus best BSC (zalutumumab group) or BSC with optional methotrexate (control group). Seventy-two percent of the patients in the control group received methotrexate from the initiation of the trial and a further 6% methotrexate during the trial. Zalutumumab was given weekly by individual dose titration on the basis of skin rash. There was no difference in OS (primary endpoint) but PFS was significantly longer in the zalutumumab group [77]. Gefitinib was compared to methotrexate in a phase III trial conducted by Stewart et al. who randomly assigned 486 patients to gefitinib 250 mg/day, gefitinib 500 mg/day, or methotrexate 40 mg/m2 intravenously weekly. Neither gefitinib 250 nor 500 mg/day improved OS (primary endpoint) compared with methotrexate. In patients with platinum-resistant disease, there appeared to be an advantage for methotrexate over both doses of gefitinib (HR 1.62 for gefitinib 250 mg vs. methotrexate; 95% CI, 1.13–2.32; p = .01; HR = 1.50 for gefitinib 500 mg vs. methotrexate; 95% CI 1.06–2.13; p = .02). ORRs were 2.7%, 7.6% and 3.9%, respectively, with no statistically significant difference between treatment arms [78].
Associations between skin rash, treatment outcome, and single nucleotide polymorphisms in head and neck cancer patients receiving the EGFR-inhibitor zalutumumab: results from the DAHANCA 19 trial
Published in Acta Oncologica, 2018
Line Brøndum, Jan Alsner, Brita Singers Sørensen, Christian Maare, Jørgen Johansen, Hanne Primdahl, Jan Folkvard Evensen, Claus Andrup Kristensen, Lisbeth Juhler Andersen, Jens Overgaard, Jesper Grau Eriksen
The main modus of action of zalutumumab is inhibition of the ligand activation of the EGFR resulting in reduced angiogenesis, reduced cell proliferation, and reduced cell survival [11,12]. An alternative mode of action is antibody-dependent cell-mediated cytotoxicity (ADCC). The monoclonal antibodies against EGFR can mediate antigen-specific immune responses through direct killing of tumor cells by natural killer cells, monocyte lysis, or phagocytosis leading to antigen processing [13]. The efficacy of ADCC depends on the activation of effector cells after engagement of the IgG fragment C receptors FCGR2A and FCGR3A [14]. This immunotherapeutic approach has demonstrated clinical efficacy in several types of cancer diseases and has been proposed to be important in preventing metastasis [15,16]. Several single nucleotide polymorphisms (SNPs) have previously been associated with toxicity and survival in cancer patients [3,4,6,17–21]. We analyzed the influence of nine candidate SNPs assumed to be related to EGFR signaling, or ADCC, on skin toxicity and outcome in HNSCC patients treated with zalutumumab. We aimed to test the hypotheses that severe skin toxicity is associated with outcome in HNSCC patients from the phase III DAHANCA 19 trial receiving zalutumumab and whether nine previously evaluated SNPs in or near candidate genes potentially related to EGFR signaling (EGFR (rs2227983 and rs2293347), EGF (rs4444903), AREG (rs13104811, rs9996584, rs11942466), CCND1 (rs9344)) or ADCC (FCGR2A (rs1801274), FCGR3A (rs396991)) are associated with skin toxicity, loco-regional failure (LRF), disease-specific survival (DSS), and OS.