Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in 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.
Lung Cancer
Pat Price, Karol Sikora in Treatment of Cancer, 2020
The third-generation EGFR inhibitor osimertinib, which was initially developed for T790M-mediated resistance, has now been approved for upfront use for EGFR-mutant NSCLCs. The longer PFS compared with first-generation EGFR inhibitors is probably the result of suppression of potential resistance by T790M clones, increased CNS penetration, and increased selectivity for the activating mutant over wild-type EGFR, allowing improved drug dosing while minimizing toxicity. Similarly, for ALK-rearranged NSCLC, alectinib has now supplanted the first-generation ALK inhibitor crizotinib as first-line treatment. Alectinib more potently suppresses ALK kinase activity and can overcome most crizotinib-resistant mutations. A recent retrospective analysis of a cohort of patients that received sequential treatment of crizotinib followed by alectinib reported a time to second progression of 22.6 months, which is considerably shorter than the PFS of 34.8 months of first-line alectinib in the ALEX study. Perhaps, upfront use of the most dynamic ALK inhibitor, lorlatinib, will be propelled into first-line use. Importantly, separately from the question of whether retrospective versus real-time head-to-head and first- versus third-generation studies would be required for licensing, regulators such as the National Institute for Health and Care Excellence will need to carefully peruse the evidence for the most cost-effective approach on a population level.
EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
In an international phase 3 randomized clinical trial, 303 patients with advanced NSCLC and no prior systemic treatment received either alectinib at a dose of 600 mg twice daily or crizotinib at a dose of 250 mgs twice daily [61]. Patients with asymptomatic CNS disease were eligible to participate. As in previous studies assessing activity of ALK-TKI, PFS was the primary endpoint. As per the protocol, crossover was not allowed. Alectinib showed an improvement of median PFS of 25.7 versus 10.4 months (HR 0.50, 95% CI 0.34–0.65). The time to CNS progression was significantly longer (HR 0.16, 95% CI 0.10–0.28). However, at the time of analysis, there was no difference in overall survival rate at 12-months of 84.3 versus 82.5% (HR 0.75, 95% CI 0.48–1.20). Alectinib group experienced greater occurrences of anemia, myalgia, abnormal blood bilirubin, weigh gain, musculoskeletal pain, and photosensitivity reactions compared to crizotinib. For patients receiving crizotinib, the most commonly associated side effects included increase of nausea, diarrhea, and vomiting. Overall, grade 3/5 toxicities were less frequent with alectinib versus crizotinib (occurring in 41 vs. 50% of patients), and were most commonly laboratory abnormalities in both groups.
An updated patent review of anaplastic lymphoma kinase inhibitors (2018–2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Deyi Ma, Mengrao Guo, Xin Zhai
Crizotinib is the first-generation ALK inhibitor developed by Pfizer for the treatment of patients with ALK-positive advanced or metastatic NSCLC, which is also effective against hepatocyte growth factor receptor (c-Met/HGFR) [22–24]. Ceritinib is a second-generation ALK inhibitor developed by Novartis for the treatment of ALK-positive metastatic NSCLC in patients with crizotinib-resistance mutations, including L1196M, G1269A, S1206Y, and I1171T [25–28]. Alectinib is an ALK and EML4 dual inhibitor developed by Roche for the treatment of ALK fusion gene-positive unresectable, recurrent, or advanced NSCLC. Studies have confirmed that alectinib is able to overcome crizotinib-resistant and ceritinib-resistant ALK mutations, including L1196M, F1174L, and C1156Y [29–31]. Brigatinib was originated by Ariad Pharmaceuticals (now Takeda) as a novel orally available multi-targeted ALK, insulin-like growth factor receptor type 1 (IGF-1 R), and EGFR inhibitor, which displays inhibitory profiles against 17 known ALK resistance mutations, covering G1202R and L1196M [32,33]. The above approved drugs have made a significant contribution to the treatment of NSCLCs and other tumors, but drug-resistant mutations still remain a challenge, which accelerate the approvals of novel ALK inhibitors involving entrectinib, ensartinib, and lorlatinib in the last 5 years.
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.
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.
Related Knowledge Centers
- Anaplastic Lymphoma Kinase
- Constipation
- Contraindication
- Crizotinib
- Gastrointestinal Tract
- Nausea
- Chemotherapy
- NON-Small-Cell Lung Cancer
- Oral Administration
- Indication