First-line Tyrosine Kinase Inhibitor Treatment Research Articles

Emergence of BCR-ABL kinase domain mutations associated with newly diagnosed chronic myeloid leukemia: a meta-analysis of clinical trials of tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) are a mainstay of treatment for patients suffering from chronic myeloid leukemia (CML). Testing for various mutations in the BCR-ABL gene may help predict lack of response to specific TKIs where resistance has developed. To estimate the emergence of BCR-ABL kinase domain mutations associated with newly diagnosed CML patients exposed to first-line TKI treatment. Published studies were identified using a structured search of online databases. Original research studies were included if they reported the incidence of specific BCR-ABL kinase domain point mutations after first-line TKI treatment failure or baseline mutations for second-line TKI treatment following first-line treatment failure. Meta-analysis of mutation rates across studies was based on DerSimonian and Laird's random-effects model. Of 1,323 citations, 12 studies met the inclusion criteria, involving a total of 1,698 patients. Overall mutation rates (95% CI) were imatinib 9.7% (6.2%-13.3%); dasatanib 1.7% (0.0%-4.3%); and nilotinib 3.3% (0.0%-7.7%). The most common specific mutations were T315I, E255K, and M351T. T315I mutations constituted 58% (7 of 12) of dasatinib-related mutations and 13% (15 of 117) of imatinib-related mutations. Lack of response to TKIs associated with mutation in the BCR-ABL gene was significantly higher in imatinib-treated patients, and all mutations arose after treatment. T315I was a common treatment-emergent mutation. Further research is needed to assess the prognostic value of testing for mutations and the economic implications of treatment-emergent mutations.

Effusion Immunocytochemistry as an Alternative Approach for the Selection of First-Line Targeted Therapy in Advanced Lung Adenocarcinoma

Tumor tissue is often not obtainable or suitable for molecular-based epidermal growth factor receptor (EGFR) mutational analysis in advanced non-small-cell lung cancer (NSCLC). This retrospective and single-institution study was conducted to evaluate the role of effusion immunocytochemistry using two EGFR mutant-specific antibodies for the detection of relevant EGFR mutations in NSCLC, along with the selection of candidates for first-line therapy with EGFR tyrosine kinase inhibitors (TKIs). Immunocytochemistry using two antibodies binding specifically to the major forms of mutant EGFR, L858R, and E746-A750 deletion (delE746-A750), was performed on cell blocks of malignant pleural effusion (MPE) from 78 patients with lung adenocarcinoma, who received first-line EGFR TKIs. The yield of EGFR-mutation detection and prediction of response rate and progression-free survival to TKI treatment by immunocytochemistry were compared with those by clinical characteristics and EGFR sequencing using cell-derived RNA from MPEs. Of the 78 MPE samples, direct sequencing using cell-derived RNA identified L858R mutation in 42 cases, deletions in exon 19 in 12 cases (delE746-A750 in eight cases), other types of mutations in three cases, and wild-type EGFR in 21 cases. Effusion immunocytochemistry with these two mutant-specific antibodies exhibited a sensitivity of 71% and 88% and a specificity of 86% and 96% for identifying predefined L858R and delE746-A750 mutations, respectively. Effusion immunocytochemistry provided a superior prediction of tumor response and progression-free survival to first-line EGFR TKIs than did clinical characteristics like sex and smoking status. Patients whose effusion immunocytochemistry showed a reaction to either of the two antibodies had a comparable TKI response rate (67% versus 72%) to those with EGFR mutations assessed by direct sequencing from cell-derived RNA. Effusion immunocytochemistry could be introduced into clinical practice to identify more NSCLC patients likely to have benefit from first-line TKI treatment, especially for those without adequate tissue for molecular-based EGFR analysis.

Quality of life (QoL) in SAKK 19/03: A multicenter phase II study of first-line gefitinib followed by chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Swiss Group for Clinical Cancer Research (SAKK)

18559 Background: 63 patients (pts) were accrued in this first study testing first-line tyrosine-kinase inhibitor treatment with gefitinib followed by chemotherapy at disease progression (gemcitabine-cisplatin q3w x6, 41 pts) in stage IIIB/IV NSCLC (ASCO 2005 # 7128). We investigated the longitudinal QoL patterns on both subsequent treatment modalities. Methods: FACT-L including TOI (Trial Outcome Index) and LCS (Lung Cancer Subscale) scores were assessed during both treatment phases (gefitinib: baseline, weeks 3,6,12,18 and every 12 weeks thereafter; chemotherapy: baseline and at d1 of cycle 3 and 5). QoL changes from baseline were descriptively analysed. Improvement was defined as a 6 point (FACT-L, TOI) and 2 point (LCS) increase. Results: QoL-scores are shown in the table below. On gefitinib, at week 6 31/18/32% of pts had improvements of FACT-L, TOI and LCS, respectively and 29/15/41% at week 12 (% based on pts with available data). During chemotherapy the respective improvement rates were 60/60/70% of pts at week 6 and 43/29/43% at week 12. At week 12 of gefitinib, 4 of the pts analysed had partial remission (PR, independently confirmed), 31 pts dropped out (none due to toxicity) and QoL submission rate was 84% based on expected forms. Chemotherapy week 12: 5 PR in analysed pts, 18 drop outs (5 due to toxicity), 43% submission rate. Conclusions: QoL was maintained in pts continuing treatment with gefitinib and decreased at disease progression. QoL and tumor symptoms improved in a considerable part of pts during gefitinib therapy despite low remission rates. Declining submission rate during treatment introduces a potential, unquantifiable bias in QoL. [Table: see text] [Table: see text]