scholarly journals Clinical activity of the EGFR tyrosine kinase inhibitor osimertinib in EGFR-mutant glioblastoma

CNS Oncology ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. CNS43 ◽  
Author(s):  
Igor Makhlin ◽  
Ryan D Salinas ◽  
Daniel Zhang ◽  
Fadi Jacob ◽  
Gou-li Ming ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Young Female ◽  
Egfr Mutations ◽  
Clinical Activity ◽  
Molecular Heterogeneity ◽  
Dismal Prognosis ◽  
Egfr Mutant

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. The EGFR gene is among the most commonly deranged genes in GBM and thus an important therapeutic target. We report the case of a young female with heavily pretreated EGFR-mutated GBM, for whom we initiated osimertinib, an oral, third-generation tyrosine kinase inhibitor that irreversibly inhibits EGFR and has significant brain penetration. We then review some of the main challenges in targeting EGFR, including lack of central nervous system penetration with most tyrosine kinase inhibitors, molecular heterogeneity of GBM and the need for enhanced specificity for the EGFR mutations relevant in GBM.

First-line dacomitinib (PF-00299804), an irreversible pan-HER tyrosine kinase inhibitor, for patients with EGFR-mutant lung cancers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7530-7530 ◽  
Author(s):  
Mark G. Kris ◽  
Tony Mok ◽  
Sai-Hong Ignatius Ou ◽  
Renato Martins ◽  
Dong-Wan Kim ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Open Label ◽  
Lung Cancers ◽  
Egfr Mutant ◽  
Exon 19

7530 Background: Dacomitinib irreversibly inhibits EGFR, HER2 and HER4, and showed superior activity vs. reversible EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer models, including resistant forms. This open-label Phase II study evaluates dacomitinib as 1st-line treatment (tx) for patients (pts) with lung cancers. Pts with sensitizing EGFR deletions/mutations in exons 19 or 21 are reported here. Methods: Pts had stage IIIB/IV adenocarcinoma, no prior systemic tx, had smoked <10 pack years (none within 15 years of enrollment) or had known EGFR mutation. Pts received dacomitinib orally once daily continuously at 45 mg, or 30 mg with the option to escalate to 45 mg; evaluation was every 28 days. Endpoints included progression-free survival rate at 4 months (PFS at 4M, primary); PFS, and partial response (PR) rate. Results: 92 pts enrolled; 47 had EGFR mutation in exons 19 (n=25) or 21 (n=22), 33 were female and 27 Asian. 34/46 evaluable pts with EGFR exon 19 or 21 mutations had a PR (PR rate = 74%; 95% CI: 59–86; exon 19 = 72%; exon 21 = 76%). PR rates and preliminary PFS were not significantly different for exons 19 and 21. Preliminary PFS at 4M was 96% (95% CI: 84–99), preliminary PFS rate at 1 year was 77% (95% CI: 61–87) and preliminary median PFS was 17 months (95% CI: 13–24). Median tx duration was 13.1 months. For pts with EGFR wild-type lung cancers, PR and PFS at 4M rates were 7% (n=14; 95% CI: 0–34) and 33% (n=14; 95% CI: 11–58), respectively, and for pts with EGFR unknown lung cancers, 46% (n=22; 95% CI: 24–68) and 68% (n=24; 95% CI: 45– 83), respectively. 7 pts had lung cancers with non-sensitizing EGFR mutations; 2 had a PR and 3 SD. For all 92 pts, common side effects included dermatitis acneiform (grade 3/4 = 17%/0) and diarrhea (14%/0). 3/46 pts with EGFR exon 19 or 21 mutations discontinued tx due to drug-related toxicity. Conclusions: 74% of pts in this cohort with EGFR exon 19 or 21 mutant lung cancers experienced PRs with 1st-line dacomitinib; preliminary PFS rate was 77% at 1 year; preliminary median PFS was 17 months; further research is planned in this pt population. As dacomitinib is well tolerated, with preclinical activity against HER2, a cohort of pts with HER2 mutant lung cancers is recruiting.

scholarly journals Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

2019 ◽  
Vol 4 (1-2) ◽  
pp. 41-45 ◽  
Author(s):  
Takeo Koshida ◽  
Sylvia Wu ◽  
Hitoshi Suzuki ◽  
Rimda Wanchoo ◽  
Vanesa Bijol ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Thrombotic Microangiopathy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kidney Biopsy ◽  
Kinase Inhibitor ◽  
Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

scholarly journals Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

2019 ◽  
Vol 20 (24) ◽  
pp. 6141 ◽  
Author(s):  
Luana Bavaro ◽  
Margherita Martelli ◽  
Michele Cavo ◽  
Simona Soverini
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Dismal Prognosis

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence.

Sign in / Sign up

Export Citation Format

Share Document