Phase I Study of Lapatinib in Combination With Chemoradiation in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Harrington, Kevin; El‐Hariry, Iman; Holford, C.; Lusinchi, A.; Nutting, Christopher M.; Rosine, Dominique; Tanay, Mary Anne; Deutsch, Éric; Matthews, Jennifer; D'Ambrosio, Consuelo; Turner, Simon; Pandeshwara, Jagannatha S.; Bourhis, Jean

doi:10.1200/jco.2008.17.5349

Cited by 71 publications

(30 citation statements)

References 27 publications

(12 reference statements)

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“…These chemotherapeutic agents which are available for HNSCC, are good candidates for the combination treatment with lapatinib. A phase I study of lapatinib in combination with chemoradiation in patients with locally advanced HNSCC was reported (12). In that report, cisplatin was used as a chemotherapeutic agent and the overall response rate was 81%.…”

Section: -------------------------------------------------mentioning

confidence: 99%

Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma

et al. 2010

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Abstract. The epidermal growth factor receptor (EGFR) and a related family member, HER-2, are often overexpressed simultaneously in patients with a variety of malignant tumors, and the combination may cooperatively promote cancer cell growth and survival. Heterodimerization of EGFR and HER-2 has been known to create intense proliferative signals. Lapatinib (GW572016) is a small molecule that is administrated orally and functions as a reversible inhibitor of both EGFR and HER-2 tyrosine kinases. In the present study, we evaluated the antitumor effect of lapatinib on head and neck squamous cell carcinoma (HNSCC) cell lines in vitro and in vivo. In vivo we examined the antitumor effects of combined treatment with lapatinib and either cisplatin or paclitaxel. In vitro lapatinib displayed antiproliferative effects on HNSCC cells. The IC 50 of lapatinib ranged between 13.6 and 60.2 μM after 24-h exposure to lapatinib. A correlation was not observed between results of in vitro proliferation assays for lapatinib and the expression of EGFR or HER-2. In vivo lapatinib displayed antitumor activity, and induced apoptosis in nude mice bearing an established xenograft of YCU-H891 cells. Lapatinib did not significantly inhibit angiogenesis. Combination treatment of lapatinib with cisplatin or paclitaxel enhanced antitumor activity mainly by inducing apoptosis. Inhibition of antiangiogenesis was observed only for combination treatment of lapatinib with paclitaxel (compared to vehicle control). These results suggest that: i) lapatinib has antitumor effects in vitro and in vivo; ii) lapatinib may be more effective in combination with cisplatin or paclitaxel; and iii) lapatinib might provide useful clinical benefits to HNSCC patients.

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confidence: 99%

Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma

et al. 2010

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“…In preclinical models, lapatinib has synergistic activity with chemotherapy and RT (Montemurro et al, 2007). Harrington et al have reported results of a phase I trial of the combination of lapatinib (500 mg, 1000 mg, 1500 mg), cisplatin (100 mg/m2 every 3 weeks x 3 cycles), and RT (66-70 Gy) in 31 patients (Harrington et al, 2009). No DLT's w e r e o b s e r v e d i n t h i s e v a l u a t i o n a n d t h e recommended lapatinib dose of for phase II evaluation was determined as 1500 mg daily.…”

Section: Lapatinibmentioning

confidence: 99%

Novel Chemoradiotherapy Regimens Incorporating Targeted Therapies in Locally Advanced Head and Neck Cancers

Rathore¹

2012

Head and Neck Cancer

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A forest plot analysis was done to assess whether certain patient groups benefitted with the addition of cetuximab to RT. In this analysis, factors which were associated with a potential increased benefit included presence of oropharyngeal tumors, concomitant boost RT, early T stage (T1-T3), high Karnofsky performance score (90%-100%), male sex, and age < 65 years. These results are provocative but given that the trial was not powered for this subgroup analysis, they should be interpreted with caution.Patients who received cetuximab commonly developed an acneiform rash (83.7%); the severity of the rash was grade 3-4 in 16.8% patients. Infusion-related reactions were also seen in 15.4% patients; in 3.9% patients these were of grade 3/4 severity. However, in-field toxicities, such as mucositis, dermatitis, and dysphagia did not significantly increase with the addition of cetuximab to RT. Quality-of-life parameters were not adversely affected by the addition of cetuximab. This study allowed different RT fractionation regimens which may have impacted results and survival outcomes.

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“…A randomized trial of cetuximab, a monoclonal antibody against EGFR has demonstrated a survival benefit compared with RT alone [36]. Lapatinib, a small-molecule inhibitor of tyrosine kinases associated with EGFR and human EGFR type 2 (HER2) has demonstrated activity in head and neck cancer and is undergoing Phase III trials in combination with CRT [37]. The antitumor effect of the EGFR inhibitors is due to the effect on the signal transduction pathways, which leads to inhibition of cell proliferation.…”

Section: Newer Targeted Agentsmentioning

confidence: 99%

Combined chemotherapy and intensity-modulated radiotherapy for the treatment of head and neck cancers

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Harrington

et al. 2010

Expert Review of Anticancer Therapy

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Phase I Study of Lapatinib in Combination With Chemoradiation in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Abstract: The recommended phase II dose is lapatinib 1,500 mg/d with chemoradiotherapy in patients with LA SCCHN; this regimen is associated with an acceptable tolerability profile. Given these findings, randomized phase II and III studies of lapatinib plus chemoradiotherapy have been initiated.

Cited by 71 publications

References 27 publications

Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma

Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma

Novel Chemoradiotherapy Regimens Incorporating Targeted Therapies in Locally Advanced Head and Neck Cancers

Combined chemotherapy and intensity-modulated radiotherapy for the treatment of head and neck cancers

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