Dual Inhibition of the Epidermal Growth Factor Receptor with Cetuximab, an IgG1 Monoclonal Antibody, and Gefitinib, A Tyrosine Kinase Inhibitor, in Patients with Refractory Non-small Cell Lung Cancer (NSCLC): A Phase I Study

Ramalingam, Suresh S.; Forster, Judy; Naret, C. L.; Evans, Terry; Sulecki, M.; Lu, Haolan; Teegarden, Paola; Weber, Martin R.; Belani, Chandra P.

doi:10.1097/jto.0b013e3181653d1b

Cited by 48 publications

(39 citation statements)

References 34 publications

(33 reference statements)

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“…Moreover, cetuximab, alone or with chemotherapy, has shown limited efficacy in EGFR-driven lung cancer (30,31). Phase I studies have shown that various combinations of EGFR-TKI and EGFR monoclonal antibodies are safe and tolerable in patients with non-small cell lung carcinoma (32)(33)(34)(35)(36). However, combined EGFR inhibition has not been prospectively studied in patients with acquired resistance to EGFR-TKIs.…”

Section: Introductionmentioning

confidence: 99%

Phase I/II Trial of Cetuximab and Erlotinib in Patients with Lung Adenocarcinoma and Acquired Resistance to Erlotinib

Janjigian

Azzoli

Krug

et al. 2011

Clinical Cancer Research

108

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Purpose: In patients with epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma, treatment with erlotinib or gefitinib is associated with a 75% radiographic response rate and progressionfree survival of approximately 12 months. The most common mechanism of acquired resistance to erlotinib is development of a secondary mutation in EGFR, suggesting that these tumors continue to depend on EGFR signaling. We hypothesized that combined EGFR blockade would overcome acquired resistance to erlotinib in patients with lung adenocarcinoma. To evaluate the toxicity and efficacy of cetuximab and erlotinib in patients with acquired resistance to erlotinib, we conducted this phase I/II clinical trial.Experimental Design: Patients with lung adenocarcinoma and clinically defined acquired resistance to erlotinib were treated with erlotinib 100 mg daily, along with cetuximab every 2 weeks in three escalating dose cohorts (250 mg/m 2 , 375 mg/m 2 , and 500 mg/m 2 ). The recommended phase II dose was then evaluated in a two-stage trial, with a primary end point of objective response rate.Results: A total of 19 patients were enrolled. The most common toxicities for the combination of cetuximab and erlotinib were rash, fatigue, and hypomagnesemia. The recommended phase II dose identified was cetuximab 500 mg/m 2 every 2 weeks and erlotinib 100 mg daily. At this dose and schedule, no radiographic responses were seen (0 of 13, 0%, 95% CI, 0-25).

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Section: Introductionmentioning

confidence: 99%

Phase I/II Trial of Cetuximab and Erlotinib in Patients with Lung Adenocarcinoma and Acquired Resistance to Erlotinib

Janjigian

Azzoli

Krug

et al. 2011

Clinical Cancer Research

108

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“…Dual EGFR inhibition has been shown to be feasible in phase 1 studies with a combination of cetuximab and erlotinib in patients with advanced solid malignancies or cetuximab and gefitinib in patients with refractory NSCLC [30,31]. Conventional doses of each agent (250 mg/m 2 cetuximab intravenously weekly; 150 mg erlotinib orally daily; 250 mg gefitinib orally daily) were achieved but cutaneous toxicity, generally grade 1/2, seemed to be more frequent.…”

Section: Dual Her1/egfr Inhibitionmentioning

confidence: 97%

“…The triple combination of cetuximab/erlotinib/bevacizumab has been investigated in a phase 1 study of patients with advanced solid tumors, but toxicity did not allow the administration of usual erlotinib doses [31]. The triple combination of imatinib (400 mg daily), erlotinib (150 mg daily), and bevacizumab (10 mg/kg every 2 weeks) was found to be a tolerable therapy in a phase 1/2 trial of patients with advanced renal cell cancer, and there were early indications of activity.…”

Section: Combination Of Egfr Tkis and Anti-vegf Monoclonal Antibodiesmentioning

confidence: 99%

Combining molecular targeted therapies

Pivot¹,

Bedairia²,

Thiery-Vuillemin³

et al. 2011

Anti-Cancer Drugs

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Approximately 20 molecular targeted therapies, mainly monoclonal antibodies and tyrosine kinase inhibitors, have been approved for the treatment of various cancers. They are being increasingly investigated in combination in clinical trials. We review the rationale for combining molecular targeted therapies and the results of clinical trials to date. There have been some exciting clinical results with some combinations, for example, lapatinib/trastuzumab or bevacizumab/trastuzumab in HER2-positive metastatic breast cancer, whereas other potential combinations have provided disappointment, for example, cetuximab or panitumumab in combination with bevacizumab/chemotherapy in first-line treatment of metastatic/advanced colorectal cancer. Therefore, at this point no general guidance to study such combinations can be derived.

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“…Bortezomib which is the first drug of a new class of targeted drugs that are proteasome inhibitors may be also synergistic with cetuximab [88]. Despite the benefit in preclinical studies, association of cetuximab with TKI or bortezomid did not lead to objective response in phase II trials [88][89][90][91][92][93]. To the best of our knowledge, no phase III has yet started.…”

Section: Cetuximab and Other Targeted Therapiesmentioning

confidence: 99%

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

Guilleminault¹,

Lemarié²,

Heuzé-Vourc’h³

2012

JCT

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Lung cancer is the leading cause of cancer-related deaths in industrialized countries and non small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Cisplatin doublet based chemotherapy, which is the recommended regimen in first line therapy in advanced or metastatic NSCLC, improves survival but in low proportion. Monoclonal antibodies (mAbs) are a novel promising therapeutic class used with great results in inflammatory diseases such as rheumatoid arthritis. Antibodies are natural proteins with modular structure, specific pharmacodynamics and pharmacokinetics and possibly produced against any antigens, thus giving them several advantages over small drug therapeutics. In solid tumors, therapeutic mAbs improved progression free survival (PFS) and overall survival (OS) of patients with breast and colon cancers and had considerably changed the treatment in clinical practice. In NSCLC, bevacizumab, an anti-VEGF mAb, and cetuximab, an anti-EGFR mAb, are the most studied antibodies. Bevacizumab acts on angiognenesis and improved PFS of non squamous NSCLC but in low proportion as shown in two large phase III trials. It was approved by European Medicines Agency (EMEA) and Food and Drug administration (FDA) as a first line therapy in combination with cisplatin doublet chemotherapy. Cetuximab slightly enhanced OS but did not improve PFS in two large phase III trials. These results added to high adverse effect lead to cetuximab refusal by EMEA and FDA in NSCLC. At first glance, the results of mAbs in NSCLC are somewhat disappointing, in contrast to the benefits obtained with mAb treatments in other solid tumors. However, many other mAbs directed against novel targets, such as IGF1-R or CTLA-4, and new mAbs targeting VEGFR and EGFR pathways with different pharmacodymamical and pharmacokinetic properties are under evaluation and may change our vision of taking care of patients with NSCLC. In conclusion, it seems that mAbs therapy in NSCLC clearly marks the start of a new era in NSCLC treatment, with promises in improving patient survival and quality of life.

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Dual Inhibition of the Epidermal Growth Factor Receptor with Cetuximab, an IgG1 Monoclonal Antibody, and Gefitinib, A Tyrosine Kinase Inhibitor, in Patients with Refractory Non-small Cell Lung Cancer (NSCLC): A Phase I Study

Cited by 48 publications

References 34 publications

Phase I/II Trial of Cetuximab and Erlotinib in Patients with Lung Adenocarcinoma and Acquired Resistance to Erlotinib

Phase I/II Trial of Cetuximab and Erlotinib in Patients with Lung Adenocarcinoma and Acquired Resistance to Erlotinib

Combining molecular targeted therapies

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

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