Phase II Trial of Dasatinib for Patients with Acquired Resistance to Treatment with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Erlotinib or Gefitinib

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer (Impact Factor: 5.28). 06/2011; 6(6):1128-31. DOI: 10.1097/JTO.0b013e3182161508
Source: PubMed


Dual inhibition of SRC- and EGFR-dependent pathways may overcome acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for patients with lung adenocarcinoma with EGFR mutations. The SRC inhibitor dasatinib demonstrates antitumor activity in gefitinib-resistant cells lines and xenografts. Dasatinib is tolerable for patients with advanced non-small cell lung cancer, and in combination with erlotinib.
We conducted this phase II study of dasatinib 70 mg twice daily in patients with EGFR-mutant lung adenocarcinoma and acquired resistance to EGFR-TKIs. After a protocol amendment based on evolving data about both drugs, patients received dasatinib at a dose of 100 mg daily with continued erlotinib after developing acquired resistance. Enrolled patients either harbored an activating mutation in EGFR or experienced clinical benefit with single-agent erlotinib or gefitinib, followed by RECIST documented progression while being treated with an EGFR-TKI.
Twenty-one patients were enrolled, 9 under the original trial design and 12 after the protocol amendments. We observed no complete or partial responses (0% observed rate, 95% confidence interval: 0-18%). The median time to progression was 0.5 months (range, 0.2-1.8 months) in patients treated with dasatinib and 0.9 months (range, 0.4-5 months) for patients treated with dasatinib and erlotinib in combination. Pleural effusions and dyspnea were frequent toxicities.
Dasatinib has no activity in patients with EGFR-mutant lung adenocarcinoma with acquired resistance to erlotinib and gefitinib.

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    • "Preliminary studies also indicate that the T790M mutation may play a crucial role in primary resistance to first-generation EGFR inhibitors because of clonal evolution in tumor cells with preexisting T790M mutations.20 Different strategies have been pursued in the management of progressive disease after treatment with first-generation EGFR TKIs, including monotherapies such as dasatinib21 and neratinib,22 as well as the rational combinations of cetuximab plus erlotinib23 and of erlotinib/gefitinib plus everolimus.24 To date, the results of these clinical trials have, however, been generally disappointing. "
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    ABSTRACT: The use of genomics to discover novel targets and biomarkers has placed the field of oncology at the forefront of precision medicine. First-generation epidermal growth factor receptor (EGFR) inhibitors have transformed the therapeutic landscape of EGFR mutant non-small-cell lung carcinoma through the genetic stratification of tumors from patients with this disease. Somatic EGFR mutations in lung adenocarcinoma are now well established as predictive biomarkers of response and resistance to small-molecule EGFR inhibitors. Despite early patient benefit, primary resistance and subsequent tumor progression to first-generation EGFR inhibitors are seen in 10%-30% of patients with EGFR mutant non-small-cell lung carcinoma. Acquired drug resistance is also inevitable, with patients developing disease progression after only 10-13 months of antitumor therapy. This review details strategies pursued in circumventing T790M-mediated drug resistance to EGFR inhibitors, which is the most common mechanism of acquired resistance, and focuses on the clinical development of second-generation EGFR inhibitors, exemplified by afatinib (BIBW2992). We discuss the rationale, mechanism of action, clinical efficacy, and toxicity profile of afatinib, including the LUX-Lung studies. We also discuss the emergence of third-generation irreversible mutant-selective inhibitors of EGFR and envision the future management of EGFR mutant lung adenocarcinoma.
    Pharmacogenomics and Personalized Medicine 09/2014; 7:285-95. DOI:10.2147/PGPM.S55339
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    • "The majority of resistance to EGFR-TKIs are seen with: 1) the second-site exon 20 EGFR gatekeeper mutation plasmid T790M that reduces drug binding in ~50% of all cases of EGFR mutation;21 2) the plasmid T790M mutation plus EGFR amplification in ~8% of cases;22 3) tyrosine kinase switching or receptor dimerization through MET (proto-oncogene that encodes a protein known as hepatocyte growth factor receptor) amplification in ~5%–19% of cases;23 4) overexpression of AXL (encodes tyrosine-protein kinase receptor UFO in human) and its ligand GAS6 in 20% and 25% of cases, respectively;24 and 5) activating mutation of the phosphatidylinositol 3-kinase (PI3K) p110α-encoding gene PIK3CA in ~5% of cases.25–27 There is also evidence of nuclear factor-κB(NF-κB) signaling being implicated as a resistance mechanism to avoid TKI-induced apoptosis, possibly through the low expression of the NF-κB inhibitory protein IκB.25 "
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    ABSTRACT: Lung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies. With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies.
    Drug Design, Development and Therapy 06/2014; 8:735-744. DOI:10.2147/DDDT.S60672 · 3.03 Impact Factor
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    • "Many drugs have been studied in patients who progressed after treatment with a reversible EGFR-TKI, including XL-647,45 dasatinib,46 and neratinib,47 with little success. Combinations of therapy such as cetuximab plus erlotinib48 and gefitinib plus everolimus42 have also been tried. "
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    ABSTRACT: The discovery of epidermal growth-factor receptor (EGFR)-activating mutations and the introduction of oral EGFR tyrosine kinase inhibitors (EGFR-TKIs) have expanded the treatment options for patients with non-small cell lung cancer. The first two reversible EGFR-TKIs, erlotinib and gefitinib, are approved for use in the first-line setting in patients with known EGFR-activating mutations and in the second- and third-line settings for all NSCLC patients. These first-generation EGFR-TKIs improve progression-free survival when compared to chemotherapy in patients with EGFR-activating mutations in the first-line setting. However, nearly all patients develop resistance to EGFR-directed agents. There is a need for further therapy options for patients with disease progression after treatment with reversible EGFR-TKIs. Afatinib is an irreversible ErbB family blocker that inhibits EGFR, HER2, and HER4. In vitro and in vivo, afatinib have shown increased inhibition of the common EGFR-activating mutations as well as the T790M resistance mutation when compared to erlotinib and gefitinib. Clinically, afatinib has been evaluated in the LUX-Lung series of trials, with improvement in progression-free survival reported in patients with EGFR-activating mutations in both first- and second-/third-line settings when compared to chemotherapy. Further investigation is needed to determine the precise role that afatinib will play in the treatment of patients with non-small cell lung cancer and EGFR-activating mutations.
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