Combination effects of gefitinib plus cisplatin in non-small cell lung cancer (NSCLC): Why have phase III trials failed?

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11022-11022
Author(s):  
C. Tsai ◽  
T. Chen ◽  
K. Chang ◽  
S. Hsiao
Keyword(s):  
Drug Combination ◽  
Large Scale ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Cell Entry ◽  
Phase Iii ◽  
Wild Type ◽  
Response Curves ◽  
Mutant Cells

11022 Background: Four phase III large scale randomized controlled trials combining standard chemotherapeutics and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced NSCLC have failed to show benefit. The mechanism for the failure is still yet not clear. Methods: Seventeen NSCLC cell lines were tested; two had induced P-glycoprotein (Pgp) over-expression. Three of the 4 EGFR mutants exhibited activating mutations. All lines were simultaneously treated with gefitinib plus cisplatin (GC). Selected 4 lines were tested with paclitaxel plus cisplatin (PC) or gefitinib (PG) and three-drug combination (PCG). The MTT assay with application of classical isobole method and statistical analysis was used and dose-log response curves (DRCs) were examined for evaluating the possible resistance mechanisms. Results: We found that combined GC regimen had significant antagonism at the IC50 level (13/15 lines; mean CI=1.184±0.037, P=0.001). The mean CI values of PCG were higher than or comparable with those of PC or PG in either EGFR wild type or mutant cells. DRC analysis mainly showed non-saturable passive resistance, suggesting that gefitinib 0.001–0.3 μM could interfere with cisplatin cell entry in a dose dependent fashion when cisplatin concentrations over 1–3μM, thus leaded to antagonism. Giving gefitinib 24 hours after administration of cisplatin could abolish the antagonism. Conclusions: In NSCLC cells, combination of GC showed antagonistic interaction likely because gefitinib interfered with cisplatin cell entry. Three-drug combination PCG was not better than two-drug combination PC or PG in either EGFR wild type or mutant cells. Clinically, simultaneously combined EGFR TKI with platinum in NSCLC should be avoided regardless of EGFR mutation status. [Table: see text]

scholarly journals KRASoncogene in lung cancer: focus on molecularly driven clinical trials

2016 ◽  
Vol 25 (139) ◽  
pp. 71-76 ◽  
Author(s):  
Emmanuelle Kempf ◽  
Benoît Rousseau ◽  
Benjamin Besse ◽  
Luis Paz-Ares
Keyword(s):  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Lung Cancers ◽  
Molecular Abnormalities ◽  
Mitogen Activated Protein ◽  
Pathway Inhibition

KRASmutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically forKRAS-mutated NSCLC patients. Direct inhibition ofRASactivation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients’ clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step inKRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens.

scholarly journals Targeting Oncogenic BRAF: Past, Present, and Future

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1197 ◽  
Author(s):  
Zaman ◽  
Wu ◽  
Bivona
Keyword(s):  
Kinase Inhibitors ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Wild Type ◽  
Braf Mutations ◽  
Molecular Alterations ◽  
Mutant Braf

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.

Targeted Therapy in Combination with Chemotherapy in Recurrent and/or Metastatic Head and Neck Cancer

2010 ◽  
Vol 06 (01) ◽  
pp. 43
Author(s):  
Pol Specenier ◽  
Jan B Vermorken ◽  
◽  
Keyword(s):  
Monoclonal Antibodies ◽  
Tyrosine Kinase ◽  
Head And Neck ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Cell Cancer ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Platinum Based Chemotherapy ◽  
Pathway Inhibition

Two epidermal growth factor receptor (EGFR)-targeting strategies are used in recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN): monoclonal antibodies and small-molecule tyrosine kinase inhibitors. Thus far, the monoclonal antibody cetuximab has been studied in most detail. Based on the results of two randomised phase III trials, cetuximab in combination with platinum-based chemotherapy should be considered the new standard first-line regimen for patients with recurrent and/or metastatic disease for whom a platinum-based regimen regimen is considered the best treatment option. Other EGFR-directed monoclonal antibodies are under investigation. The role of EGFR tyrosine kinase inhibitors (TKIs) in SCCHN is less well established and early data on other targeted agents have also been disappointing thus far. Dual pathway inhibition may overcome resistance to single pathway inhibition.

Clustered Genomic Alterations in Chromosome 7p Dictate Outcomes and Targeted Treatment Responses of Lung Adenocarcinoma With EGFR-Activating Mutations

2011 ◽  
Vol 29 (25) ◽  
pp. 3435-3442 ◽  
Author(s):  
Shinsheng Yuan ◽  
Sung-Liang Yu ◽  
Hsuan-Yu Chen ◽  
Yi-Chiung Hsu ◽  
Kang-Yi Su ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Comparative Genomic ◽  
Wild Type ◽  
Free Survival ◽  
Activating Mutation ◽  
Disease Free ◽  
Egfr Tkis

Purpose Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been proven more effective for patients with lung adenocarcinoma with EGFR-activating mutation rather than wild type, the former group still includes approximately 30% nonresponders. The molecular basis of this substantial response heterogeneity is unknown. Our purpose was to seek molecular aberrations contributing to disease progression at the genome-wide level and identify the prognostic signature unique to patients with EGFR-activating mutation. Patients and Methods We first investigated the molecular differences between tumors with EGFR-activating mutation and wild-type tumors by conducting high-density array comparative genomic hybridization on a collection of 138 adenocarcinoma tissues. We then used an independent group of 114 patients to validate the clinical relevance of copy-number alterations (CNAs) in predicting overall and disease-free survival. Finally, focusing on 23 patients with EGFR mutation receiving EGFR-TKI treatment, we investigated the association between CNAs and response to EGFR-TKIs. Results We identified chromosome regions with differential CNAs between tumors with EGFR-activating mutation and wild-type tumors and found the aberration sites to cluster highly on chromosome 7p. A cluster of six representative chromosome 7p genes predicted overall and disease-free survival for patients with EGFR-activating mutation but not for those with wild type. Importantly, simultaneous presence of more genes with increased CNAs in this cluster correlated with less favorable response to EGFR-TKIs in patients with EGFR-activating mutation. Conclusion Our results shed light on why responses to EGFR-TKIs are heterogeneous among patients with EGFR-activating mutation. They may lead to better patient management in this population.

scholarly journals Landscape of drug-resistance mutations in kinase regulatory hotspots

2020 ◽  
Author(s):  
Pora Kim ◽  
Hanyang Li ◽  
Junmei Wang ◽  
Zhongming Zhao
Keyword(s):  
Drug Resistance ◽  
Large Scale ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Systematic Investigation ◽  
Drug Binding ◽  
Data Sets ◽  
Resistance Mutations ◽  
Cancer Data

Abstract More than 48 kinase inhibitors (KIs) have been approved by Food and Drug Administration. However, drug-resistance (DR) eventually occurs, and secondary mutations have been found in the previously targeted primary-mutated cancer cells. Cancer and drug research communities recognize the importance of the kinase domain (KD) mutations for kinasopathies. So far, a systematic investigation of kinase mutations on DR hotspots has not been done yet. In this study, we systematically investigated four types of representative mutation hotspots (gatekeeper, G-loop, αC-helix and A-loop) associated with DR in 538 human protein kinases using large-scale cancer data sets (TCGA, ICGC, COSMIC and GDSC). Our results revealed 358 kinases harboring 3318 mutations that covered 702 drug resistance hotspot residues. Among them, 197 kinases had multiple genetic variants on each residue. We further computationally assessed and validated the epidermal growth factor receptor mutations on protein structure and drug-binding efficacy. This is the first study to provide a landscape view of DR-associated mutation hotspots in kinase’s secondary structures, and its knowledge will help the development of effective next-generation KIs for better precision medicine.

Is there a benefit on survival of tyrosine-kinase inhibitors versus chemotherapy in first line in mutated EGFR patients with advanced non-small cell cancer (NSCLC)? A meta-analysis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18020-e18020
Author(s):  
Gaetan Des Guetz ◽  
Bernard Uzzan ◽  
Kader Chouahnia ◽  
Patrick Nicolas ◽  
Jean F. Morere
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Cell Cancer ◽  
Random Effect Model ◽  
Lung Neoplasm ◽  
Phase Iii ◽  
Wild Type ◽  
Effect Model

e18020 Background: Tyrosine-Kinase Inhibitors (TKIs) markedly improve Progression Free Survival (PFS) of advanced NSCLC patients mutated for Epidermal Growth Factor Receptor (EGFR). Results on Overall Survival (OS) are more questionable. Therefore, we performed a publication-based meta-analysis to further assess this issue. Methods: We did a PubMed query using keywords simultaneously (lung neoplasm, TKI, EGFR mutation, survival). We also searched for relevant abstracts in proceedings of ASCO, ESMO, WCLC annual meetings. We cross-checked all references from all articles. Only phase III randomized controlled trials comparing TKI and chemotherapy were included. We used EasyMA software. Results: The 6 eligible studies included 2223 patients (516 males, 1688 females, mostly Asian, median age 60 years, 2155 adenocarcinomas (97 %), 996 mutated tumors, 389 stage IIIB, 1572 Stage IV (71 %), 1989 never smokers (89.5 %). Four studies assessed gefitinib, 2 erlotinib. Chemotherapies were doublets including a platinum salt. Four studies included only mutated patients. Compared to chemotherapy, EGFR TKIs significantly improved PFS (HR=0.39, 95 % CI 0.28-0.53, random effect model). Conversely, OS was similar among patients who first received TKI or chemotherapy (HR=1.00, CI 0.83-1.22, fixed effect model). PFS was significantly worse among non mutated patients in the 2 studies including both mutated and wild-type EGFR patients, whereas OS was unchanged. Concerning side-effects, rash, diarrhoea and interstitial lung disease were significantly more frequent after TKI (RRs 5.00; 2.40 and 6.07). As expected, fatigue (RR 0.41), nausea/vomiting (0.19) and haematological disorders were all significantly more frequent after chemotherapy (RRs for neutropenia, thrombocytopenia and anaemia 0.08; 0.18 and 0.26). Conclusions: The major discrepancy between a markedly improved PFS and a similar OS after TKI compared with chemotherapy could be related to the high level of crossing-over between the 2 groups. We found no detrimental effect on OS of TKIs among wild-type patients.

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