Dacomitinib (PF-00299804), An Irreversible Pan-Her Tyrosine Kinase Inhibitor (TKI), For First-Line Treatment of EGFR-Mutant or Her2-Mutant or -Amplified Lung Cancers

9033 Background: EGFR tyrosine kinase inhibitors (TKI) are the recommended first line treatment for EGFR-mutant lung cancers. Osimertinib, an EGFR TKI that inhibits both sensitizing EGFR mutations and EGFR T790M, is approved for use after progression on an EGFR TKI with evidence of EGFR T790M, and is currently being assessed as initial treatment for EGFR-mutant lung cancers. The addition of bevacizumab to erlotinib resulted in improved progression free survival (PFS) compared to erlotinib alone as initial treatment (16 vs 10 months, HR 0.41). This phase 1/2 study is assessing osimertinib and bevacizumab as initial treatment for patients with EGFR-mutant lung cancers. Methods: We evaluated toxicity and efficacy of osimertinib and bevacizumab as initial treatment for patients with advanced EGFR-mutant lung cancers. Using a 3+3 design, full doses of osimertinib (80mg PO daily) and bevacizumab (15mg/kg IV q3 weeks) were given, with a planned dose de-escalation (osimertinib 40mg PO daily) should grade 3 or greater toxicity be seen. Six patients must be treated without a dose-limiting toxicity (DLT) to determine the MTD. 43 additional patients will be treated at the MTD in the phase 2 study, with a primary endpoint of PFS at 12 months. Response was evaluated by RECIST 1.1. Results: From Sept 2016 to Jan 2017, 15 patients were enrolled. Median age: 63; Women 11; EGFR L858R = 8, Ex19del = 6, G709A/G719S = 1. After median duration of treatment of 2.7 months, no DLTs were seen in any patient. The MTD was determined to be osimertinib 80mg, bevacizumab 15mg/kg q3 weeks. In total, 15 patients are being treated at the MTD to date. Treatment-related adverse events (AE) were all grade 1-2, except for grade 3 hypertension. The most frequent treatment-related AEs (any grade) were rash (53%), diarrhea (40%), hypertension (33%), fatigue (20%), and itching (20%). All 15 patients continue on study. Conclusions: Combination osimertinib and bevacizumab is a tolerable first-line treatment for patients with EGFR-mutant lung cancers and the MTD is osimertinib 80mg and bevacizumab 15mg/kg q3 weeks. Assessment of efficacy with an endpoint of PFS at 12 months is ongoing. Supported by AstraZeneca (NCT02803203). Clinical trial information: NCT02803203.

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First-in-human phase I study of PF-06747775, a third-generation mutant selective EGFR tyrosine kinase inhibitor (TKI) in metastatic EGFR mutant NSCLC after progression on a first-line EGFR TKI

Annals of Oncology ◽

10.1093/annonc/mdx380.060 ◽

2017 ◽

Vol 28 ◽

pp. v485-v486 ◽

Cited By ~ 4

Author(s):

H. Husain ◽

R.G. Martins ◽

S.B. Goldberg ◽

P. Senico ◽

W. Ma ◽

...

Keyword(s):

Tyrosine Kinase ◽

Phase I ◽

Tyrosine Kinase Inhibitor ◽

Phase I Study ◽

Kinase Inhibitor ◽

Third Generation ◽

First Line ◽

Egfr Tyrosine Kinase Inhibitor ◽

Egfr Mutant ◽

Egfr Tki

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Cardiovascular Toxicities of Tyrosine Kinase Inhibitor in CML

Blood ◽

10.1182/blood-2020-143216 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-6

Author(s):

Samip R Master ◽

Richard Preston Mansour

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Conflicts Of Interest ◽

Line Treatment ◽

Front Line ◽

First Line ◽

First Line Treatment

Background: Cardiovascular (CV) toxicity is a known toxicity of tyrosine kinase inhibitors (TKI) used for chronic myeloid leukemia (CML). Imatinib, dasatinib, nilotinib and bosutinib are all approved for first line treatment for CML. We did a retrospective analysis on adverse effects (AE) of TKIs that has been made available to public by the FDA. Methods: The FDA has made the data on AEs of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the CV AEs of various TKIs for the years 2017-2019. Results: The percentage of CV AE compared to total AEs reported for Imatinib, Dasatinib, Bosutinib , Nilotinib and Ponatinib were 7.2%, 10.5%, 15.8%, 23.4% and 23.5% respectively. The percentage of CV AE leading to death for Imatinib, Dasatinib, Bosutinib , Nilotinib and Ponatinib were 8.3%, 9.1%, 9.1%, 13.7 % and 18.6% respectively. Conclusions: Out of the reported cases of AEs to TKIs approved for front line CML, nilotinib appears to have more CV AE compared to imatinib, dasatinib and bolutinib. Imatinib appears to have least CV AE out of the total AEs reported Disclosures No relevant conflicts of interest to declare.

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First-line treatment outcomes of CML patients in a real-world data setting in Lebanon.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19031 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19031-e19031

Author(s):

Fadi Nasr ◽

Intissar Yehia ◽

Reem El Khoury ◽

Saada Diab ◽

Ahmad Ghoche ◽

...

Keyword(s):

Tyrosine Kinase ◽

Treatment Failure ◽

Real World ◽

Second Generation ◽

Kinase Inhibitor ◽

Molecular Response ◽

Line Treatment ◽

First Line ◽

Real World Data ◽

First Line Treatment

e19031 Background: BCR–ABL-targeting tyrosine kinase inhibitors (TKIs) constitute the cornerstone of treatment of CML leading to a life expectancy that is currently very close to that of age matched individuals in the general population. The aim of the current study was to describe aspects of CML in a real world data setting in Lebanon including responses to first lines with a specific focus on the impact of first-line treatment with imatinib compared to that of the second-generation TKI, dasatinib and nilotinib. We also evaluated what proportion of patients become eligible to attempt to stop their TKI treatment. Methods: Chronic myeloid leukemia registry was analyzed to evaluate response rates in the first line and eligibility for a treatment cessation attempt in adults diagnosed between 2003 and 2019. The registry covered 60 patients. 46 eligible patients were included in the study. BCR-ABL1 levels of ≤ 0.1%, ≤0.01% and ≤0.0032% on the international scale were defined as the molecular response end-points major molecular response(MMR), MR4.0 and MR,4.5 respectively. In the case of a switch in TKI therapy, the clinical chart was reviewed for the reason why the treating physician had changed the therapy (‘treatment failure’ or ‘TKI intolerance’). For the determination of eligibility to stop TKI, the inclusion criteria for the EURO-SKI trial were applied. Results: Seventy-two percent of the patients were treated with imatinib, 28% with a second-generation tyrosine kinase inhibitor (nilotinib and dasatinib). 15% of patients had discontinued their first-line treatment, mainly due to intolerance (10%) or treatment failure (5%). At 24 months, deep molecular response (MR 4.0 and MR4.5) were achieved at 16.7% and 38.9% respectively for imatinib, and at 22.2% and 33.3% respectively for second generation (p=1). The 5-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 37%. Conclusions: In the current study we report the experience in CML from two health care institutions in Beirut, Lebanon. Our findings showed no statistically significant difference in response between the first and second generations. The criteria for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients.

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