Lung cancer and mesothelioma
Peter Hoskin, Peter Ostler in Clinical Oncology, 2020
Tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib are orally delivered treatments that inhibit intracellular pathways. Patients with EGFR sensitizing mutations (15% of non-squamous lung cancer) have improved response rates, PRS and QOL (quality of life) when treated with these agents compared to initial chemotherapy. An increasing number of these agents are becoming available, often termed second- or third-generation TKIs. These agents have different activity and side-effect profiles such that when a patient's cancer has stopped responding to one agent it may respond to another – indeed it is recognized that further mutations can arise and should be tested for with new biopsies when possible (e.g. T790M), as if present different TKIs may still be active. There is also significant interest as some agents have been shown to have activity in patients with metastases to the brain, this is exciting as traditionally the brain has been a sanctuary site and many systemic therapies do not penetrate the brain. Crizotinib is active in ALK mutated tumours and further agents in this class of drug are being developed allowing further therapy options.
Lung cancer
Pat Price, Karol Sikora in Treatment of Cancer, 2014
Kwak evaluated 82 patients with advanced NSCLC, PS 0 to 2 and ALK-positive fluorescence in situ hybridization (FISH) in the PROFILE 1005 phase II trial.23 FISH positivity was defined by greater than 15% of tumour with split ALK 5′ and 3′ probe signals. This trial confirmed that crizotinib treatment resulted in marked tumour response in most patients. Subsequently, the PROFILE 1007 phase III trial in 347 second- line patients with ALK-positive tumours, randomized between chemotherapy (pemetrexed or docetaxel) and crizotinib (with crossover permitted on progression), reported a significantly improved PFS (7.7 vs. 3 months) for crizotinib,23 leading to licensing of the drug. As with all targeted therapies resistance eventually develops, and several resistance mechanisms have been described, including secondary ALK mutations, gain in ALK copy number or new driver mutations in EGFR or KRAS.
Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
Interestingly, while the efficacy of crizotinib in ALK-positive NSCLC is well established [4], it was initially developed as a potent MET inhibitor [59]. Ou et al. described a case of ALK negative but MET amplified stage IV adenocarcinoma of lung where crizotinib was used after the progression of disease on chemotherapy with an excellent partial response and a progression-free interval of at least six months [60]. In another case, crizotinib was used after radiation in c-MET amplified squamous cell lung cancer with significant partial response for at least eight weeks [61]. In an ongoing phase 1 study (NCT00585195), crizotinib was reported to have some antitumor activity in patients with c-Met-amplified NSCLC, with the response rate as high as 50% in the subgroup with high MET/CEP7 ratio [62].
Synthesis and in vitro anticancer activity of certain novel 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas as apoptosis-inducing agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Wagdy M. Eldehna, Ghada S. Hassan, Sara T. Al-Rashood, Tarfah Al-Warhi, Ahmed E. Altyar, Hamad M. Alkahtani, Abdulrahman A. Almehizia, Hatem A. Abdel-Aziz
On the other hand, non-fused pyridines have stood out as a promising class of anticancer agents with efficient pro-apoptotic activity. Regorafenib (Stivarga®, Figure 1), a pyridine-based biphenyl urea derivative developed by Bayer4, inhibits angiogenickinases VEGFR-1/3, FGFR1, PDGFRb, and Tie-2. Regorafenib was approved by FDA, in September 2012, for the treatment of metastatic colorectal cancer (mCRC)5. The anticancer effect of Regorafenib is thought to be mediated by apoptosis induction, in addition to its anti-angiogenic and anti-proliferative effects6,7. Crizotinib (Xalkori®, Figure 1) is an orally active inhibitor of multiple receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK), Hepatocyte Growth Factor Receptor (HGFR, c-Met), and Recepteur d’Origine Nantais (RON)8. Crizotinib was approved for the treatment of adults with previously treated, ALK-positive, advanced non-small cell lung cancer (NSCLC)9. Crizotinib likely exerts its anticancer activity via multiple distinct mechanisms such as apoptosis10.
Treatment patterns, clinical and economic outcomes of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer receiving ceritinib: a retrospective observational claims analysis
Published in Journal of Drug Assessment, 2018
Anand A. Dalal, Annie Guerin, Alex Mutebi, Kenneth W. Culver
Using data from two large administrative commercial claims databases, this study described patient characteristics, treatment patterns, and HRU and costs among patients with ALK-positive NSCLC receiving ceritinib in US clinical practice. Study results showed that patients with ALK-positive NSCLC who initiated ceritinib generally had a high comorbidity burden and extensive metastatic involvement. The large majority of patients were previously treated with crizotinib. While ceritinib was generally initiated shortly after crizotinib discontinuation (2.1 months), the initiation of ceritinib was delayed for about one fourth of the patients as they received other non-ALK inhibiting treatments between crizotinib discontinuation and ceritinib initiation. Most patients initiated ceritinib on the recommended dose (750 mg) and maintained that dose until the end of the observation period or ceritinib discontinuation. By the end of the observation period, 62.8% of the patients were still on ceritinib.
Crizotinib and ceritinib trigger immunogenic cell death via on-target effects
Published in OncoImmunology, 2021
Adriana Petrazzuolo, Maria Perez-Lanzon, Peng Liu, M. Chiara Maiuri, Guido Kroemer
Several years ago, we found that crizotinib, a tyrosine kinase inhibitor used for the treatment of cancers with oncogenic activating inversions or translocations of anaplastic lymphoma kinase (ALK, which is activated in anaplastic large cell lymphoma, ALCL, as well as in a fraction of lung adenocarcinomas) and ROS proto-oncogene 1 (ROS1, which is activated in another small fraction of non-small cell lung cancers) can be employed at relatively high doses (≥10 µM) to induced ICD in lung adenocarcinoma cells as well as in unrelated malignant cell lines (such as skin fibrosarcomas) that lack activating mutations of ALK and ROS1, meaning that these effects must be considered as “off-target”.6 Indeed, high-dose crizotinib turned out to inhibit DNA-to-RNA transcription.5 Thus, in preclinical models, high-dose crizotinib can be advantageously combined with chemotherapy and immunotherapy to eradicate established lung cancers.6
Related Knowledge Centers
- Aminopyridine
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- Fusion Gene
- Protein Kinase
- Chemotherapy
- Chromosome
- NON-Small-Cell Lung Cancer
- Ros1
- Indication
- Adenosine Triphosphate