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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
Since the discovery of the role of ALK in lung cancer in 2007 [35], there have been a number of agents that have shown to inhibit ALK tyrosine kinase. Similar to the results seen with EGFR inhibitors, ALK inhibitors have been shown to be superior to chemotherapy in terms of PFS, but not OS, for these patients. Currently, crizotinib, ceritinib, alectinib and brigatinib have been approved for clinical use in this setting. The randomized clinical trials of some of these agents are described in Table 2. The recent results of the ALEX study establish alectinib as the preferred agent for the management of treatment naïve ALK positive lung cancer [36].
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Alectinib was approved in Japan in 2014 for the treatment of ALK fusion-gene positive, unresectable, advanced, or recurrent non-small-cell lung cancer (NSCLC). This was followed by an accelerated approval by the FDA in 2015 to treat patients with advanced ALK-positive NSCLC who had failed on crizotinib (XalkoriTM), which was converted into a full approval in 2017. In the same year it was also approved by the FDA for first-line treatment of ALK-positive metastatic non-small-cell lung cancer, and also received conditional approval by the EMA for the same indication. These approvals were based, in part, on the J-ALEX Phase III study comparing alectinib with crizotinib which was terminated prematurely in 2016 because an interim analysis showed that progression-free survival was longer with alectinib.
EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Francisco E. Vera-Badillo, Janet E. Dancey
A second phase 3 randomized clinical trial confirmed the efficacy and safety of alectinib in Japanese patients [62]. At the time of analysis, that median PFS had not yet been reached with alectinib versus 12 months with crizotinib (HR 0.34, 95% CI 0.17–0.71). The rate of side effects was less for the alectinib arm (26 vs. 52% of patients).
An update on Alectinib: a first line treatment for ALK-positive advanced lung cancer
Published in Expert Opinion on Pharmacotherapy, 2023
Yourong Zhou, Yiming Yin, Jiangxin Xu, Zhifei Xu, Bo Yang, Qiaojun He, Peihua Luo, Hao Yan, Xiaochun Yang
The common adverse events relating to alectinib treatment include cardiovascular disorders, skin disorders, gastrointestinal disorders, musculoskeletal disorders, hepatic disorders, lung disorders, and general disorders. At present, the exact mechanisms drive adverse events and drug resistance of alectinib occurred remained unclear. In addition, how to properly manage the adverse events related to alectinib for long-term use and reduce the occurrence of intolerance is of great significance to achieving its long-term application. In this review, we summarize the toxicity profile of alectinib in the treatment of ALK+ NSCLC, discussed the clinical management of related adverse events. In addition, some patients may have multiple coexisting diseases and require concomitant administration of other drugs, which may enhance the efficacy of alectinib but may also exacerbate its adverse events and influence the clinical selection of patients. Therefore, here, also we explored the feasibility of combination with other drugs to provide a reference for the clinical application of alectinib.
Have molecular hybrids delivered effective anti-cancer treatments and what should future drug discovery focus on?
Published in Expert Opinion on Drug Discovery, 2021
Some prominent carbazole-based hybrids with promising anti-cancer properties are published in US, European, and other international patents [42–46]. In addition, there are some carbazole-based hybrids, which are either marketed drugs or under different phases of clinical trials for cancer therapy. Alectinib (Alecensa®) was approved in 2015 by US-FDA and EMA for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) [47]. Midostaurin (Rydapt®) is the second carbazole hybrid, which got approval by FDA and EMA in 2017 and is recommended for the treatment of newly diagnosed acute myeloid leukemia (AML) and for advanced systemic mastocytosis (SM) [48]. At present, around four carbazole-based hybrids are in clinical trials. For example, Edotecarin (J-107,088) and Becatecarin (XL119) have shown the ability to intercalate DNA, stabilize the DNA-topoisomerase I complex and are in Phase III and Phase II clinical trials, respectively. CEP-2563, currently in Phase I clinical trial, has shown the potential against MTC (medullary thyroid carcinoma) and is a potent inhibitor of tyrosine kinase and platelet-derived growth factor (PDGF) receptor tyrosine kinase. UCN-01 is an inhibitor of protein kinase and currently in Phase II clinical trial for its evaluation against pancreatic, lymphoma, and breast cancer, see Figure 2 and Table 2.
RET rearrangements in non–small cell lung cancer and implications for the future of precision drug development
Published in Expert Review of Precision Medicine and Drug Development, 2018
Alectinib which is a known inhibitor of ALK was shown to inhibit RET kinase activity (IC50 = 4.8nmol/L) and the growth of RET fusion–positive cells by suppressing RET phosphorylation [32]. In addition, alectinib showed kinase inhibitory activity against RET gatekeeper mutations (RET V804L, and V804M). Lin and colleagues described four patients with advanced RET-rearranged lung cancers who were treated with alectinib. In total, two of four patients had objective responses with durations of therapy of 6 months and more than 5 months [33]. Given its more favorable safety profile, alectinib may be dosed more effectively to target RET and can represent an alternative to multi-kinase inhibitors. Alectinib 450 mg BID was the recommended dose for a phase 2 study based on the results from the dose-finding portion of a phase I/II, open-label, single-arm study of alectinib for patients with advanced non-small-cell lung cancer harboring a RET fusion gene[34].