Recent Tyrosine Kinase Inhibitors Research Articles

Incidence, Interpretation and Management of Liver Function Abnormalities in Patients with Chronic Myeloid Leukemia (CML) Treated with Tyrosine Kinase Inhibitors (TKI)

Background: Hepatotoxicity is a well-recognised side effect of tyrosine kinase inhibitors (TKI) and in some patients it can be a challenge to find a well-tolerated and effective drug. Isolated hyperbilirubinemia is common but, particularly in the case of nilotinib, is generally attributed to concomitant Gilbert's syndrome, characterized by the reduced expression of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We have previously reported hyperbilirubinemia in association with the homozygous Gilbert genotype in patients treated with imatinib, dasatinib and nilotinib and have now extended our studies to more recent TKI. In addition we have analysed the incidence of TKI-associated transaminitis and attempted to identify safer alternative TKI. Methods: From our database of >900 patients presenting with CML CP1 from 2000-2022 and treated with a TKI, we identified 467 individuals who had received only TKI (prior interferon, combination experimental therapy, auto- and allografted patients all excluded), had normal liver function tests (LFT) at TKI start and for whom serial consecutive LFT were available. Variations in dinucleotide repeats in the UGT1A1 promoter region were analyzed by PCR with genotypes: 6/6 (homozygous for (TA) 6 allele; wild-type), 7/7 (homozygous for (TA) 7 allele) and 6/7 (heterozygous). Because individual patients could receive more than one TKI, we defined the period on treatment with each TKI as an ‘episode’ so as to attribute abnormal LFT to a specific drug. Abnormal LFT were graded according to the CTCAE version 4.0 and any occurrence of abnormalities was cross-checked to exclude a confounding reason (e.g. antibiotics, cholecystitis). Patients were censored at last LFT. Results: 229 females and 238 males (median age at diagnosis 47 yrs (range 11-90) had 955 separate TKI episodes: imatinib 406, dasatinib 222, nilotinib 189, bosutinib 87, ponatinib 28 and asciminib 23. The median number of LFT per patient was 47 (range 3-264). 7 UGT1A1 genotypes were identified, of which 45%, 41% and 13% were wild type 6/6, heterozygous 6/7 and homozygous 7/7 respectively (6 patients with other genotypes excluded). With the exception of asciminib, hyperbilirubinemia was more frequent in homozygous patients for all TKI. It was also common in all patients treated with nilotinib but in wild type and heterozygous patients, was frequently associated with concomitant transaminitis. A close temporal relationship between start of TKI and raised bilirubin suggests causality (Fig 1a-d). The incidences of transaminitis of any grade were 44%, 47%, 65%, 66%, 43% and 39%, and of >grade 1 were 7%, 8%, 17%, 32%, 18% and 13% for imatinib, dasatinib, nilotinib, bosutinib, ponatinib and asciminib respectively. Of 202 patients with a transaminitis on first line TKI, 94 were subsequently switched to a 2 nd line TKI, and 27 of those to a 3 rd line TKI. Irrespective of the TKI used, recurrent transaminitis of any grade was common occurring in 60/94 (64%) on 2 nd line and 19/27 (71%) on 3 rd line, although abnormalities >grade 2 were unusual (<1% on 2 nd line, <5% on 3 rd line). 179 patients developed transaminitis on imatinib, 46 and 29 switched (rarely for transaminitis) to dasatinib and nilotinib respectively. 28 (61%) on dasatinib and 23 (79%) on nilotinib had a second transaminitis (dasatinib - 14% >grade 1, nilotinib - 22% >grade 1)). Of 227 patients without transaminitis on imatinib, 63 and 67 switched to dasatinib or nilotinib. 28 (44%) on dasatinib and 38 (57%) on nilotinib developed further transaminitis (dasatinib - 0% >grade 1, nilotinib 19% >grade1). With respect to identifying a ‘safer’ drug we studied in detail 15 patients with grades 3-4 transaminitis on 1 st line therapy; imatininb-10, dasatinib-1, nilotinib-3, bosutinib -1. Four settled on dose reduction, and of the remaining 11, 7 returned to normal or maximum grade 1 on dasatinib. Conclusion: With the exception of asciminib the previous association of TKI, homozygous Gilbert and hyperbilirubinemia was confirmed. Grade 1 transaminitis is common on all TKIs, with higher grades of severity most frequent on bosutinib. Patients experiencing abnormal transaminases on 1 st line TKI are likely to have similar problems on 2 nd and 3 rd line agents, with a trend to higher incidence/severity on nilotinib compared to dasatinib.

Characterization and survival benefit of drugs approved for advanced renal cell carcinoma.

633 Background: The treatment landscape of advanced renal cell carcinoma (RCC) drastically changed with the approval of tyrosine kinase inhibitors (TKIs). Since then, immunotherapy (IO) and now TKI plus IO combination therapies is considered standard-of-care. Despite multiple drug approvals, it remains unclear how much improvement in survival these therapies have provided. Methods: We reviewed the US Food and Drug Administration (FDA) website to evaluate all approvals for RCC from 2005 to 2022. We collected progression-free survival (PFS) and overall survival (OS) from the approval notification or from the corresponding clinical trial cited for drug approval. Results: Between 2005 and 2022, there were 16 drug (single or combination) approvals for advanced RCC. Most therapy approvals (93.75%) were granted through accelerated approval. Eight approvals were TKIs, 6 approvals were TKI plus IO combination therapies, and 1 approval each were for immunotherapy and a VEGF inhibitor. Average PFS benefit for 1st line approvals was 5.63 months (range 1.9-14.7) and average PFS benefit for 2nd or later line approvals was 2.95 months (range 0.2-9.1). Average OS benefit in the 1st line setting was 3.6 months and average OS benefit in the 2nd or later line setting was 5.4 months. Conclusions: Despite 16 drug (single or combination) approvals for advanced RCC since 2005, the improvements in average PFS and OS were modest. As OS data matures from recent TKI plus IO combination therapies, OS benefit may improve. Nonetheless, continued drug development is urgently warranted in advanced RCC. [Table: see text]

ASC4OPT: A Phase 3b Open-Label Optimization Study of Oral Asciminib in Chronic Myelogenous Leukemia in Chronic Phase Previously Treated with 2 or More Tyrosine Kinase Inhibitors

Introduction Tyrosine kinase inhibitors (TKIs) are the standard of care in the treatment of chronic myeloid leukemia (CML). However, patients (pts) may experience resistance or intolerance to successive lines of TKI therapy. Asciminib is the first BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). It is approved in the United States for the treatment of adults with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP) previously treated with ≥2 TKIs (at 40 mg twice daily [BID] or 80 mg once daily [QD]), and also Ph+ CML-CP with the T315I mutation (at 200 mg BID). This was based on the Phase 3 ASCEMBL trial (Rea et al. Blood 2021) and a Phase 1 study (Cortes et al. ASH 2020). The ASC4OPT (NCT04948333) trial was initiated to investigate the potential optimization of treatment with asciminib in adult pts with CML-CP previously treated with ≥2 TKIs (≥3rd-line). ASC4OPT will explore 3 aspects of treatment optimization: 1. Pt population, ASCEMBL inclusion criteria were based on the European LeukemiaNet (ELN) treatment recommendations from 2013. ASC4OPT will re-evaluate asciminib in an expanded ≥3rd-line population using the ELN 2020 treatment recommendations for warning and failure criteria. 2. Simplified posology, asciminib dosing in ASCEMBL was 40 mg BID. BID dosing may affect optimal compliance for pts and ASC4OPT will investigate both asciminib 40 mg BID and 80 mg QD. 3. Dose escalation, with limited treatment options in the ≥3rd-line setting, ASC4OPT will explore whether pts not in major molecular response (MMR) at ≥48 weeks (wks) could benefit from a potential dose escalation to 200 mg QD. Methods ASC4OPT is an international, multi-center, non-comparative, Phase 3b study in pts aged ≥18 years with CML-CP previously treated with ≥2 TKIs. The trial will enroll approximately 156 pts who are in treatment failure or warning (ELN 2020) or intolerant to the last prior TKI and not in MMR at baseline. Up to 30 additional pts in MMR at baseline and intolerant to their most recent TKI treatment will also be enrolled; these pts will not be included in the primary endpoint analysis, however all assessments will be performed. Pts are excluded if they have had previous or planned hematopoietic stem cell transplantation, second CP after previous progression to accelerated phase/blast crisis, or known presence of the BCR::ABL1 T315I mutation at any time prior to study entry. Pts will be randomized 1:1 to receive asciminib 40 mg BID or 80 mg QD. In pts not achieving MMR at 48 wks or losing response after wk 48 and up to wk 108, asciminib dose may be escalated to 200 mg QD if in the investigator's opinion the pt may benefit from the escalation. In addition, for dose escalation there must not be any grade 3 or 4 toxicity while on therapy, or persistent grade 2 toxicity, possibly related to asciminib and unresponsive to optimal management (Figure). The primary endpoint is MMR rate (BCR::ABL1IS ≤0.1%) at wk 48 in pts not in MMR at baseline. Secondary endpoints include MMR rate at wks 12, 24, 36, 72, 96 and 144 in pts not in MMR at baseline, MMR rate at wk 48 for pts in MMR at baseline, time to MMR, rate of early responses of BCR::ABL1IS ≤10% and ≤1% at wks 12, 24, 36 and 48, deep molecular responses (rates of MR4.0 [BCR::ABL1IS ≤0.01%] and MR4.5 [BCR::ABL1IS ≤0.0032%] at wks 12, 24, 36, 48, 72, 96 and 144), rate of cytogenetic response at wk 48 and at end of treatment (up to 144 wks), and patient-reported outcomes and quality of life. Current status As of July 2022, 77 patients have been enrolled in the study. This study is sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety Results from Ascembl, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, Vs Bosutinib in Patients with Chronic Myeloid Leukemia in Chronic Phase after ≥2 Prior Tyrosine Kinase Inhibitors: Update after 48 Weeks

Efficacy and Safety Results from Ascembl, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, Vs Bosutinib in Patients with Chronic Myeloid Leukemia in Chronic Phase after ≥2 Prior Tyrosine Kinase Inhibitors: Update after 48 Weeks

Trial in Progress: Asciminib in Monotherapy 4 CML (AIM4CML), a Phase IIIb Study of Asciminib Monotherapy in Patients with Chronic Myeloid Leukemia in Chronic Phase without or with T315I Mutations

Trial in Progress: Asciminib in Monotherapy 4 CML (AIM4CML), a Phase IIIb Study of Asciminib Monotherapy in Patients with Chronic Myeloid Leukemia in Chronic Phase without or with T315I Mutations

P59.01 Clinical Characteristics of Patients With MET Amplification-Positive NSCLC After EGFR-TKI Therapy

Patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) ultimately acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) during treatment. In 5–22% of these patients, resistance is mediated by aberrant mesenchymal epithelial transition factor (MET) gene amplification. Here, we evaluated the emergence of MET amplification after EGFR-TKI treatment failure based on clinical parameters. We retrospectively analyzed 186 patients with advanced EGFR-mutant NSCLC for MET amplification status by in situ hybridization (ISH) assay after EGFR-TKI failure. We collected information including baseline patient characteristics, metastatic locations and generation, line, and progression free survival (PFS) of EGFR-TKI used before MET evaluation. Multivariate logistic regression analysis was conducted to evaluate associations between MET amplification status and clinical variables. View Large Image Figure ViewerDownload Hi-res image Download (PPT) Regarding baseline EGFR mutations, exon 19 deletion was predominant (57.5%), followed by exon 21 mutation (39.2%). The proportions of MET ISH assays performed after first/second-generation and third-generation TKI failure were 66.7% and 33.1%, respectively. The median PFS for the most recent EGFR-TKI treatment was shorter in MET amplification-positive patients than in MET amplification-negative patients (mPFS of 1st/2nd generation TKI cohort, 7.0 vs. 10.4 months, p = 0.003, PFS of 3rd generation TKI cohort, 7.2 vs. 11.0 months, p=0.163). Multivariate logistic regression demonstrated that a history of smoking, short PFS on the most recent TKI, and less intracranial progression were associated with a high probability of MET amplification (all p < 0.05). Our results demonstrated the distinct clinical characteristics of patients with MET amplification-positive NSCLC after EGFR-TKI therapy. Our clinical prediction can aid physicians in selecting patients eligible for MET amplification screening and therapeutic targeting.

Distinct Characteristics and Clinical Outcomes to Predict the Emergence of MET Amplification in Patients with Non-Small Cell Lung Cancer Who Developed Resistance after Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

Simple SummaryMET amplification is one of the resistance determinants after EGFR-TKI therapy in EGFR mutant NSCLC. In this study, we evaluated the emergence of MET amplification after EGFR-TKI treatment failure. The median progression-free survival associated with the most recent EGFR-TKI treatment was shorter in MET amplification-positive patients than in negative patients. Smoking history and less intracranial progression are associated with MET amplification. Suboptimal responses with previous EGFR-TKI are associated with MET amplification. Proper MET amplification screening for therapeutic targeting is needed.Objectives: Patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) ultimately acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) during treatment. In 5–22% of these patients, resistance is mediated by aberrant mesenchymal epithelial transition factor (MET) gene amplification. Here, we evaluated the emergence of MET amplification after EGFR-TKI treatment failure based on clinical parameters. Materials and Methods: We retrospectively analyzed 186 patients with advanced EGFR-mutant NSCLC for MET amplification status by in situ hybridization (ISH) assay after EGFR-TKI failure. We collected information including baseline patient characteristics, metastatic locations and generation, line, and progression-free survival (PFS) of EGFR-TKI used before MET evaluation. Multivariate logistic regression analysis was conducted to evaluate associations between MET amplification status and clinical variables. Results: Regarding baseline EGFR mutations, exon 19 deletion was predominant (57.5%), followed by L858R mutation (37.1%). The proportions of MET ISH assays performed after first/second-generation and third-generation TKI failure were 66.7% and 33.1%, respectively. The median PFS for the most recent EGFR-TKI treatment was shorter in MET amplification-positive patients than in MET amplification-negative patients (median PFS 7.0 vs. 10.4 months, p = 0.004). Multivariate logistic regression demonstrated that a history of smoking, short PFS on the most recent TKI, and less intracranial progression were associated with a high probability of MET amplification (all p < 0.05). Conclusions: Our results demonstrated the distinct clinical characteristics of patients with MET amplification-positive NSCLC after EGFR-TKI therapy. Our clinical prediction can aid physicians in selecting patients eligible for MET amplification screening and therapeutic targeting.

A Phase I Trial of Incorporating Natural Killer (K-NK) Cells for Patients with Chronic Myeloid Leukemia (CML) and Molecular Residual Disease after Tyrosine Kinase Inhibitor (TKI) Therapy

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML) ushering in an era where, in select patient populations, treatment planning goals have shifted towards the achievement of treatment free remission (TFR) after TKI cessation. Both duration and depth of response to TKI therapy are predictors of future success in achieving a lasting TFR and with improved outcomes independent of TKI cessation. Unfortunately, molecular residual disease (MRD) persists in many patients despite optimal therapy and predicts for worse outcomes over time and decreased ability to maintain a TFR after TKI cessation. Achievement of a major molecular response (MMR) and probability of TFR have been associated with increased numbers of NK cells, particularly mature cytolytic NK cells. Kiadis K-NK003 cells are off-the-shelf NK cells from a universal donor expanded using PM21, proprietary membrane particles modified to express membrane bound IL-21 and 4-1bb ligand. The resulting expanded K-NK003 cells have a hyperfunctional phenotype that are simultaneously highly cytotoxic with high release of perforin and Granzyme B, and potent producers of the cytokines IFN-γ, TNF-α and IL-2. This is an open label, non-randomized, prospective phase I pilot study designed to evaluate safety and to examine whether the addition of K-NK003 to ongoing TKI therapy for CML patients with persistent MRD will allow patients to achieve MRD negative status. Patients will be treated with K-NK003 on day 1 of each 14 day cycle, for a total of 6 cycles, in conjunction with their ongoing TKI therapy. The primary endpoint is safety. The efficacy objective is to estimate the rate of optimal molecular responses (negative to at least MR4.5). Secondary and exploratory endpoints include the proportion of patients with a reduction in BCR-ABL transcripts and NK cell number and function. Adult patients with chronic phase CML who have been on TKI therapy for at least 1 year prior to enrollment in the study will be eligible. Patients must have been on their most recent TKI consistently for at least 6 months prior to enrollment on study and must be expected to remain on current TKI for the duration of the study. Patients with current accelerated or blast crisis phase disease will be excluded. Disclosures Rein: Celgene: Consultancy; Blueprint Medicine: Consultancy; Novartis: Consultancy; Clinical Care Options: Consultancy, Other: Speaker. Rizzieri:Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; abbvie: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

A multicenter, randomized phase III study of asciminib (ABL001) versus bosutinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs).

TPS7070 Background: There is a need for new treatment options for pts with CML who are intolerant/resistant to currently available BCR-ABL1 ATP-binding site targeted TKIs. Asciminib is a potent and specific BCR-ABL1 inhibitor with a novel allosteric mechanism of action targeting the ABL1 myristoyl pocket. This results in a mutation-driven resistance profile different from that of ATP binding-site TKIs, providing potential for both monotherapy and combination therapy with ATP-binding-site TKIs. In a phase 1 study (NCT02081378), asciminib showed clinical activity and good safety/tolerability in CML pts with resistance/intolerance to ≥2 TKIs and in pts with the T315I mutation. The recommended dose for asciminib monotherapy in CML pts without the T315I mutation was established as 40 mg BID. An ongoing phase 3 study (NCT03106779) is evaluating asciminib monotherapy vs bosutinib in pts with CML who have been treated with ≥2 prior ATP-binding-site TKIs. Methods: Eligible pts are adults with CML-CP who previously received ≥2 TKIs, with intolerance or failure to the most recent TKI. Treatment failure is defined per 2013 European LeukemiaNet (ELN) recommendations. Pts harboring T315I or V299L mutations are excluded. Pts are randomized 2:1 – stratified by baseline cytogenetic response status – to receive asciminib 40 mg BID or bosutinib 500 mg QD (planned enrollment: N = 222). Primary and key secondary objectives are to compare the rate of major molecular response ( BCR-ABL1IS≤0.1%) with asciminib vs bosutinib at 24 and 96 weeks, respectively. In a recent protocol amendment, the baseline BCR-ABL1IS threshold for enrollment was lowered from ≥1% to &gt; 0.1% for pts with intolerance to the most recent TKI. This change was implemented to align with clinical practice and satisfy the treatment need to avoid waiting for an increase in BCR-ABL1IS levels to ≥1%. In addition, pts with documented bosutinib treatment failure as per ELN recommendations may switch to receive asciminib therapy at any time, as such pts may have limited treatment options outside of this study. This study is ongoing with 149 participating study sites in 30 countries. Clinical trial information: NCT03106779.

Asciminib, a Specific Allosteric BCR-ABL1 Inhibitor, in Patients with Chronic Myeloid Leukemia Carrying the T315I Mutation in a Phase 1 Trial

Asciminib, a Specific Allosteric BCR-ABL1 Inhibitor, in Patients with Chronic Myeloid Leukemia Carrying the T315I Mutation in a Phase 1 Trial

Predictors of Ponatinib Therapy Duration Among Real-World Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients in the US

Background: Ponatinib is a potent oral tyrosine kinase inhibitor (TKI) active against native and mutant forms of BCR-ABL. It is approved for patients with resistant or intolerant CML or Ph+ ALL, or with the T315I mutation, which renders other TKIs ineffective. The USPI recommends a starting dose of 45 mg/day, with consideration of lower starting doses in patients with selected comorbidities. In the US, ponatinib is available exclusively through a specialty pharmacy that maintains prescribing data for all US ponatinib-treated patients. Analyses of dispensed ponatinib prescriptions for CP-CML patients show that median therapy duration exceeds 1.5 years but is variable across groups; examination of demographic, clinical and physician characteristics may reveal predictors of therapy duration.Methods: We performed a retrospective analysis of patients starting treatment with ponatinib over the 2.5-year period from 01 January 2014 and 30 June 2016 using data from referring physicians, patient intake forms and pharmacy dispensing records. Gender (M/F), age (</≥65 years), reported T315I status (Y/N), line of therapy (2nd-5th), most recent prior TKI (imatinib, nilotinib, dasatinib, or bosutinib), starting dose (15, 30 or 45 mg/day), prescribing physician practice type (academic/community), and number of ponatinib patients treated by physician (1, 2, 3 or more) were examined as predictors of therapy duration using Kaplan-Meier (K-M) techniques and log-rank tests; multivariable, stepwise, proportional-hazard regression was used to generate adjusted hazard ratios and identify primary drivers of therapy duration.Results: 475 US patients identified with CP-CML initiated treatment with ponatinib over this 2.5-year period; K-M median time on therapy was 20.7 months. About one-half of patients were male (Table) and most were aged <65 years. Only 10% were reported to have the T315I mutation, most were in their 3rd or 4th line of therapy, and had most commonly switched from dasatinib; nearly one-half had a starting dose of 45 mg/day. Slightly more than one-half of prescribing physicians were in academic settings, and more than three-quarters had only one ponatinib patient. When examining each predictor individually, only gender was a significant predictor of time on therapy (Table), with women having significantly shorter duration than men. There was also a trend for T315I patients to have longer duration than non-T315I. In analyses adjusted for other covariates, non-T315I patients had significantly shorter duration (hazard ratio [HR]: 2.09; p=0.033), as did those whose most recent TKI was not imatinib (HR nilotinib v imatinib: 3.61; dasatinib v imatinib 4.72; bosutinib v imatinib 1.85; overall p=0.001). Women had a borderline significantly shorter duration than men (HR: 1.40; p= 0.085) and versus 2nd line, patients in 3rd (HR: 0.67) and 4th (HR: 0.68) line had longer duration, while 5th line had shorter (HR: 1.45; overall p=0.054).Conclusions: Real-world US data for CP-CML patients receiving ponatinib show that a number of subgroups have median duration on ponatinib exceeding 2 years, but suggest drivers of therapy duration may be complex including both disease (e.g. T315I, prior line of tx) and patient (e.g. sex) related factors.Study sponsor: ARIAD Pharmaceuticals, Inc. [Display omitted] DisclosuresMauro:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. McGarry:ARIAD: Employment, Equity Ownership. Lustgarten:ARIAD: Employment, Equity Ownership. Huang:ARIAD: Employment, Equity Ownership.

Pooled analysis of clinical outcome for EGFR TKI-treated patients with EGFR mutation-positive NSCLC.

Patients with non-small-cell lung cancer (NSCLC) appear to gain particular benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKI) if their disease tests positive for EGFR activating mutations. Recently, several large, controlled, phase III studies have been published in NSCLC patients with EGFR mutation-positive tumours. Given the increased patient dataset now available, a comprehensive literature search for EGFR TKIs or chemotherapy in EGFR mutation-positive NSCLC was undertaken to update the results of a previously published pooled analysis. Pooling eligible progression-free survival (PFS) data from 27 erlotinib studies (n = 731), 54 gefitinib studies (n = 1802) and 20 chemotherapy studies (n = 984) provided median PFS values for each treatment. The pooled median PFS was: 12.4 months (95% accuracy intervals [AI] 11.6–13.4) for erlotinib-treated patients; 9.4 months (95% AI 9.0–9.8) for gefitinib-treated patients; and 5.6 months (95% AI 5.3–6.0) for chemotherapy. Both erlotinib and gefitinib resulted in significantly longer PFS than chemotherapy (permutation testing; P = 0.000 and P = 0.000, respectively). Data on more recent TKIs (afatinib, dacomitinib and icotinib) were insufficient at this time-point to carry out a pooled PFS analysis on these compounds. The results of this updated pooled analysis suggest a substantial clear PFS benefit of treating patients with EGFR mutation-positive NSCLC with erlotinib or gefitinib compared with chemotherapy.

Is a cure for CML without allogeneic stem cell transplantation around the corner?

Is a cure for CML without allogeneic stem cell transplantation around the corner?

Recent Advances in Small Molecule Inhibitors of VEGFR and EGFR Signaling Pathways

Aberrant angiogenesis has been observed in many solid tumors. The formation and metastases of tumors such as non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) are very complex, often regulated by proangiogenic factors such as the vascular endothelial growth factor (VEGF) and other tyrosine kinases. The VEGFR, EGFR and mTOR pathways have played critical roles in controlling cell proliferation and angiogenesis. This paper reviews the mechanism and binding modes of recently approved tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, nilotinib, dasatinib, sunitinib, sorafenib, pazopanib, lapatinib, afinitor, and temsirolimus. We also cover the progresses of the recent development of tyrosine kinase inhibitors that are currently in the clinical trials at the phases I, II, and III, targeting the VEGFR, EGFR and/or mTOR pathways. Combination therapy intended to overcome drug resistance is also discussed. Recent TKI design based on the activation loop and the "DFG" conformation, is also discussed.

Tyrosine kinase inhibitors in the treatment of advanced renal cell carcinoma: focus on pazopanib.

Advances in our understanding of renal cancer biology have led to a new treatment paradigm in renal cancer. Tyrosine kinase inhibitors (TKI), that target the intracellular kinase domain of the VEGF receptor, have become established as the most successful class of agent in this disease. Three TKIs are currently approved for use in patients with advanced disease. Newer, more potent inhibitors have reached phase III clinical testing, meaning others are likely to follow. In 2009, pazopanib became the most recent TKI to receive FDA approval. This review sets out to discuss the key opportunities and challenges associated with TKI use in RCC, focusing particularly on pazopanib. We also review the current place of pazopanib in the management of patients with advanced disease, in what is a rapidly evolving therapeutic landscape.

The European Leukemia Net CML Registry - Objectives, Achievements and First Results.

In 2004/2005, the European Chronic Myeloid Leukemia (CML) Registry was established within the European Leukemia Net (ELN) which is funded by the EU. The purpose is to collect prospectively baseline, follow-up and outcome data of CML patients treated with imatinib or with more recent tyrosine kinase inhibitors in a standardized format. Among the objectives are the development and validation of prognostic scores, the analysis of various prespecified subgroups, e.g. of patients with imatinib failure or of patients who discontinued imatinib after complete cytogenetic remission and to support the design and analysis of future clinical trials. At present individual patient data of about 1460 bcr/abl positive CML patients from France, Germany, Italy, Poland, Romania and Spain are in the data bank. Patients were treated either with 400 or 800 mg imatinib/day as mono or combination treatment. About 40% of the patients are female. Using the New CML Score the proportion of low risk patients varies between 35% – 89% (high risk: 0% – 13%) among the participating countries. First analyses of outcome data, here the proportion of cytogenetic remissions at month 12, indicate that the results of the IRIS trial can be reproduced. With more countries participating and longer observation times the European CML Registry promises to provide highly interesting data.