Article

Treatment of Non-Small-Cell Lung Cancer with Erlotinib or Gefitinib

Louisiana State University Health Sciences Center and Hematology-Oncology Clinic, Baton Rouge, LA 70805, USA.
New England Journal of Medicine (Impact Factor: 54.42). 03/2011; 364(10):947-55. DOI: 10.1056/NEJMct0807960
Source: PubMed

ABSTRACT A 64-year-old woman receives the diagnosis of metastatic non-small-cell lung cancer (NSCLC), which has progressed during treatment with carboplatin, paclitaxel, and bevacizumab. Erlotinib therapy is recommended.

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    • "Identification of different driver mutations that define new molecular subsets of non-small cell lung cancer (NSCLC) has been critical in defining novel targeted therapeutic approaches [1]. One of the most well-known examples is epidermal growth factor receptor (EGFR), a cell-surface receptor that is activated in more than half of NSCLC patients [2]. The EGFR receptor belongs to the ErbB family of transmembrane tyrosine kinase receptors, which includes EGFR (also known as ErbB1 or HER1), ErbB2 (HER2 or neu), ErbB3 (HER3) and ErbB4 (HER4) [3]. "
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    ABSTRACT: The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50-60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls - afatinib and dacomitinib - covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clinical development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug-drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies.
    Cancer Treatment Reviews 07/2014; 40(8). DOI:10.1016/j.ctrv.2014.06.010 · 6.47 Impact Factor
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    • "However, efficacy is modest with only minimal improvements in clinical outcomes and therapy is often associated with significant toxicity (5). Erlotinib or gefitinib, a small molecule EGFR (HER1) inhibitor, is a standard second line targeted therapy for NSCLC (6,7). However, EGFR protein mutations account for only around 10–15% of all NSCLC (8). "
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    ABSTRACT: Lung cancer is the leading cause of cancer death worldwide. There is an urgent need for early diagnostic tools and novel therapies in order to increase lung cancer survival. Secretory phospholipase A2 group IIa (sPLA2-IIa) is involved in inflammation, tumorigenesis and metastasis. We were the first to uncover that cancer cells secrete sPLA2‑IIa. sPLA2‑IIa is overexpressed in almost all specimens of human lung cancers examined and is significantly elevated in the plasma of lung cancer patients. High levels of plasma sPLA2-IIa are significantly associated with advanced stage and decreased overall cancer survival. In this study, we further showed that elevated HER/HER2‑PI3K-Akt-NF-κB signaling contributes to sPLA2-IIa overexpression in lung cancer cells. sPLA2-IIa in turn phosphorylates and activates HER2 and HER3 in a time- and dose‑dependent manner in lung cancer cells. The structure and sequence‑based docking analysis revealed that sPLA2-IIa β hairpin shares structural similarity with the corresponding EGF hairpin. sPLA2-IIa forms an extensive interface with EGFR and brings the two lobes of EGFR into an active conformation. sPLA2-IIa also enhances the NF-κB promoter activity. Anti-sPLA2-IIa antibody, but not the small molecule sPLA2-IIa inhibitor LY315920, significantly inhibits sPLA2‑IIa-induced activation of NF-κB promoter. Our findings support the notion that sPLA2-IIa functions as a ligand for the EGFR family of receptors leading to an elevated HER/HER2-elicited signaling. Plasma sPLA2-IIa can potentially serve as lung cancer biomarker and sPLA2‑IIa is a potential therapeutic target against lung cancer.
    International Journal of Oncology 06/2014; 45(3). DOI:10.3892/ijo.2014.2486 · 3.03 Impact Factor
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    • "Treatment of non-small cell lung cancer with gefitinib is associated with interstitial lung disease (ILD) in ∼1% of white and 5% of Japanese patients, and is fatal in up to one-third of cases (Cataldo et al., 2011). We have had no occurrences of ILD in any of our participants from this and other studies, cumulatively 70 women treated with ectopic pregnancies and persistent gestational trophoblastic disease from published and unpublished data (Skubisz et al., 2013). "
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    ABSTRACT: Non-tubal ectopic pregnancies are a rare subgroup of ectopic pregnancies implanted at sites other than the Fallopian tube. Mortality from non-tubal ectopic pregnancies is higher compared with that for tubal ectopic pregnancies, and they are becoming more common, partly due to the rising incidence of Caesarean sections and use of assisted reproductive technologies. Non-tubal ectopic pregnancies can be especially difficult to treat. Surgical treatment is complex, and follow-up after medical treatment is usually protracted. There is therefore a need for more effective medical therapies to resolve non-tubal ectopic pregnancies and reduce operative intervention. We have recently reported successful use of combination gefitinib (an orally available epidermal growth factor receptor inhibitor) and methotrexate for treatment of tubal pregnancies. To our knowledge, this combination has not been used to treat non-tubal pregnancies. Here we report the use of combination gefitinib and methotrexate to treat eight women with stable, non-tubal ectopic pregnancies at two tertiary academic teaching hospitals (Edinburgh, UK and Melbourne, Australia); five interstitial and three Caesarean section scar ectopic pregnancies. Pretreatment serum hCG levels ranged from 2458 to 48 550 IU/l, and six women had pretreatment hCG levels >5000 IU/l. The women were co-administered 1-2 doses of i.m. methotrexate (50 mg/m(2) on Day 1, ± Day 4 or Day 7) with seven once daily doses of oral gefitinib (250 mg). The women were monitored until complete resolution of the ectopic pregnancy, defined as a serum hCG <15 IU/l. Time to resolution (days from first methotrexate dose until serum hCG <15 IU/l), safety and tolerability, complication rates and subsequent fertility outcomes were also recorded. All eight women were successfully treated with combination gefitinib and methotrexate. The most common side effects were transient acne/rash and diarrhoea, known side effects of gefitinib. All women promptly resumed menstruation and importantly, three women subsequently conceived spontaneously. Two have delivered a healthy infant at term and the third is currently in her second trimester of pregnancy. Hence, our case series supports a future clinical trial to determine the efficacy of combination gefitinib and methotrexate to treat non-tubal ectopic pregnancies.
    Human Reproduction 05/2014; 29(7). DOI:10.1093/humrep/deu091 · 4.59 Impact Factor
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