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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    • "The EGFR gatekeeper mutant T790M causes drug resistance primarily due to the increased binding affinity to ATP but not the canonical steric hindrance.[25]Several different combination strategies have been explored, such as EGFR monoclonal antibody Cetuximab combination with EGFR inhibitor Afatinib or BIBW2992, allele-specific DNAzyme cDzT with EGFR inhibitor BIBW-2992, and MAPK signaling pathway MEK inhibitor GSK1120212 combination with EGFR inhibitor CO1686.262728Given the fact that both in biochemical assays and cellular colony formation assays ibrutinib and CO-1686 have similar potencies against the EGFR T790M mutation, we then tried to combine MEK kinase inhibitor GSK1120212 with ibrutinib to see if it could potentiate the anti-proliferation efficacy of ibrutinib. The results demonstrated that the combination of Trametinib (used at around the GI 50 of 1.1μM) with 1.1μM ibrutinib is able to effectively block the growth of the cells. "
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    ABSTRACT: Through comprehensive comparison study, we found that ibrutinib, a clinically approved covalent BTK kinase inhibitor, was highly active against EGFR (L858R, del19) mutant driven NSCLC cells, but moderately active to the T790M 'gatekeeper' mutant cells and not active to wild-type EGFR NSCLC cells. Ibrutinib strongly affected EGFR mediated signaling pathways and induced apoptosis and cell cycle arrest (G0/G1) in mutant EGFR but not wt EGFR cells. However, ibrutinib only slowed down tumor progression in PC-9 and H1975 xenograft models. MEK kinase inhibitor, GSK1120212, could potentiate ibrutinib's effect against the EGFR (L858R/T790M) mutation in vitro but not in vivo. These results suggest that special drug administration might be required to achieve best clinical response in the ongoing phase I/II clinical trial with ibrutinib for NSCLC.
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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.
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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.
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