Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial

Pirker, Robert; Pereira, José Rodrígues; Szczęsna, Aleksandra; Pawel, Joachim von; Krzakowski, Maciej; Ramlau, Rodryg; Vynnychenko, I.; Park, Keunchil; Yu, Chih Teng; Ganul, Valentyn; Roh, Jae Kyung; Bajetta, Emilio; O’Byrne, Kenneth J.; Marinis, Filippo de; Eberhardt, Wilfried; Goddemeier, Thomas; Emig, Michael; Gatzemeier, U.

doi:10.1016/s0140-6736(09)60569-9

Cited by 1,209 publications

(803 citation statements)

References 22 publications

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“…Also, in phase 3 clinical trials, adding cetuximab to first-line chemotherapy or RT improves outcomes in various types of cancers. [9][10][11] Because of encouraging results of clinical trials with cetuximab in different tumors, the need for more effective therapies, particularly in locally advanced anal canal carcinoma (LAACC), 12 and the high expression of EGFR in anal carcinoma, we set out to develop a regimen to evaluate the safety and activity of cetuximab combined with 5-fluorouracil (5-FU)/CP concurrent with radiation for LAACC.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Olivatto

Vieira

Pereira

et al. 2013

Cancer

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BACKGROUND: This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5-fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma. METHODS: Cetuximab was administered on days 1,8,15, 29, 36, 43, and 50 (400 mg/m 2 initial dose, then 250 mg/m 2 /week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96-hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP 5 800/60 mg/m 2 /day and up to dose level (12) 5-FU/CP 5 1000/80 mg/m 2 /day. RESULTS: Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (12). The RP2D was 5-FU/CP 5 800/80 mg/m 2 /day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%. CONCLUSIONS: Cetuximab could not be integrated with chemoradiotherapy-cisplatin-based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor-targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued. Cancer 2013;119:2973-80.

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Section: Introductionmentioning

confidence: 99%

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Olivatto

Vieira

Pereira

et al. 2013

Cancer

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“…4 Moreover, they can be as effective as conventional therapies or induce synergistic effects. [5][6][7][8][9] Recently, we described fibroblast growth factor receptor 1 (FGFR1) as the first actionable target in squamous cell lung cancer. FGFR1 is a receptor tyrosine kinase located on chromosome 8p12.…”

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Fibroblast growth factor receptor 1 amplification is a common event in squamous cell carcinoma of the head and neck

et al. 2013

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“…15 In addition, molecularly targeted therapeutics such as erlotinib, gefitinib and cetuximab, as well as conventional chemotherapeutics such as pemetrexed are poorly active in squamous-cell lung cancer patients. 11,16 Drugs such as bevacizumab or sorafenib that primarily inhibit vascular endothelial growth factor receptor (VEGFR) signaling are also not registered for the treatment of squamous-cell lung cancer patients due to increased risk of fatal hemorrhage. 17,18 Thus, the therapeutic repertoire for squamouscell lung cancer patients is rather limited.…”

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confidence: 99%

Genetic insight and therapeutic targets in squamous-cell lung cancer

Sos

Thomas

2012

Oncogene

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Squamous-cell lung cancer is one of the most prevalent subtypes of lung cancer worldwide and its pathogenesis is closely linked with tobacco exposure. Unfortunately, squamous-cell lung cancer patients do not benefit from major advances in the development of targeted therapeutics such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors that show exquisite activity in lung adenocarcinomas with EGFR mutations or echinoderm microtubule associated protein like-4 (EML4)-ALK fusions, respectively. Major efforts have been launched to characterize the genomes of squamous-cell lung cancers. Among the new results emanating from these efforts are amplifications of the fibroblast growth factor receptor 1 gene and mutations of the discoidin domain receptor 2 gene as potential novel targets for the treatment of squamous-cell lung cancer patients. Here, we provide a review on these discoveries and their implications for clinical trials in squamous-cell lung cancer assessing the value of novel therapeutics addressing these targets.Oncogene ( Keywords: squamous-cell lung cancer; FGFR1; DDR2 Major advances in molecular biology and high-throughput sequencing techniques have boosted cancer drug treatment strategies over the past decades. 1 --6 The envisioned paradigm is the identification of genetic aberrations that are unique for defined subgroups of patients, and the development of drugs that specifically aim at oncogenic targets and their signaling pathways of these patients. In lung cancer, this development has led to the identification of oncogenic EGFR mutations that are present in up to 20% of adenocarcinoma patients 7 --9 and confer exquisite sensitivity to EGFR inhibitors (for example, gefitinib, erlotinib). 10 --12 Another example is the identification of EML4-ALK, the first fusion gene that is causally linked with the development of lung cancer. 13 Encouraging first clinical studies show that in patients with EML4 --ALK fusions overall response rates of up to 57% can be observed when treated with crizotinib. 14 However, the known 'druggable' targets are primarily enriched in the subgroup of adenocarcinomas of never smokers. 15 In addition, molecularly targeted therapeutics such as erlotinib, gefitinib and cetuximab, as well as conventional chemotherapeutics such as pemetrexed are poorly active in squamous-cell lung cancer patients. 11,16 Drugs such as bevacizumab or sorafenib that primarily inhibit vascular endothelial growth factor receptor (VEGFR) signaling are also not registered for the treatment of squamous-cell lung cancer patients due to increased risk of fatal hemorrhage. 17,18 Thus, the therapeutic repertoire for squamouscell lung cancer patients is rather limited.Several genomic studies tackled this unmet medical need by systematically characterizing the landscape of genetic lesions of squamous-cell lung cancer patients in order to define new therapeutically amenable targets. The first large-scale analysis of significant copy-number changes in squamous-cell lun...

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Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial

Cited by 1,209 publications

References 22 publications

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Fibroblast growth factor receptor 1 amplification is a common event in squamous cell carcinoma of the head and neck

Genetic insight and therapeutic targets in squamous-cell lung cancer

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