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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Developed by Pfizer, crizotinib (XalkoriTM) (Figure 6.59), which has a central aminopyridine ring, was the first ALK inhibitor. It gained FDA approval in 2011 for the treatment of late-stage locally advanced or metastatic non-small-cell lung cancers expressing the abnormal Anaplastic Lymphoma Kinase (ALK) gene. It was also shown to be a ROS1 inhibitor, and in 2016 was approved by the FDA for the treatment of ROS1-positive NSCLC. It is also being evaluated in clinical trials for the treatment of advanced disseminated anaplastic large-cell lymphoma and neuroblastoma. Structure of crizotinib (XalkoriTM).
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
Patients with metastases to the brain were allowed in all ALK inhibitor trials. Patients were eligible to participate in the study if the metastases were neurologically stable for at least 2 weeks before enrollment and patients had no ongoing requirement for glucocorticoids. The proportion of patients with brain metastases enrolled in the randomized trials of ALK-TKIs varies from 26% for the initial crizotinib trial [25] to 59% in the cetirinib trial. As patients with brain metastases are very likely to respond to ALK-TKI, local therapy with either surgery or radiation can be deferred, if clinically stable and unlikely to deteriorate during initial ALK-TKI therapy.
Lung Cancer
Published in Pat Price, Karol Sikora, 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.
Use of ALK-tyrosine kinase inhibitors (ALK TKI) in clinical practice, overall survival, and treatment duration – a Swedish nationwide retrospective study
Published in Acta Oncologica, 2022
Rosa Lauppe, Fredrik O. L. Nilsson, Hanna Fues Wahl, Mathias Lilja, Anders Vikström, Sandra T. Asanin
We found that the majority (95%) of patients treated in Swedish clinical practice received their therapy in line with conventional, scientifically grounded, and/or regulatorily approved and reimbursed ALK TKI sequences. An Australian study by Itchins et al. [13] found that about half of the patients received at least two lines of ALK inhibitor therapy. In Sweden, the corresponding number was 33%, indicating that 67% of identified patients had only received one line of ALK TKI. This may be partly explained by the difference in median follow-up, which was twice as long compared to the present study. Davies et al. [14] studied treatment patterns for crizotinib and ceritinib patients in the US, showing predominant use of the two TKI from first- to third-line therapy. In general, a majority of the assessed ALK TKI sequences began with crizotinib followed by second generation ALK TKI [15–19]. In the present study crizotinib and alectinib were predominantly used from first- to third-line therapy, with crizotinib being first-line therapy for more than 60% of patients. Differences in sequencing of ALK TKI in comparison with previous findings likely depend on factors that change over time such as clinical evidence and access to treatment.
Clinically-meaningful improvements in therapy for unresectable NSCLC
Published in Expert Review of Anticancer Therapy, 2022
Seigo Katakura, Shuji Murakami
Anaplastic lymphoma kinase (ALK): In patients with ALK-positive NSCLC, ALK inhibitors significantly increase PFS and produce a better response rate than conventional cytotoxic chemotherapy [42,43]. In phase III trials of representative first-line treatments with different ALK inhibitors, the median PFS was 10.9 months for crizotinib, 34.8 months for alectinib, 29.4 months for brigatinib, and was not reached for lorlatinib [42–46]. The current focus is on sequential treatment after an initial ALK inhibitor. Sequential treatment with other ALK inhibitors may be effective depending on the resistance mutation, but re-biopsy during disease progression and sequential treatment guided by specific resistance mutations has not been established. Increased research in this field will translate into daily practice in the coming years.
Comparison of lorlatinib, alectinib and brigatinib in ALK inhibitor–naive/untreated ALK-positive advanced non-small-cell lung cancer: a systematic review and network meta-analysis
Published in Journal of Chemotherapy, 2022
Lida Wang, Zhixin Sheng, Junying Zhang, Jiwu Song, Lili Teng, Liping Liu, Qianpeng Li, Baohong Wang, Bin Li
Studies were eligible for inclusion in the meta-analysis if they met all the following criteria: (1) They were published up to Jan 2021 and written in English. (2) They dealt only with ALK inhibitor–naive or previously untreated (ALK inhibitor-naive and chemotherapy-naive) advanced NSCLC. (3) We included studies that provided sufficient information to allow the calculation of crude Hazard Ratios (HRs) for progression free survival (PFS), overall survival (OS), response rates, adverse events in patients with ALK inhibitor–naive or previously untreated (ALK inhibitor-naive and chemotherapy-naive) advanced NSCLC. We excluded studies if they were not reporting outcomes of interest. Multiple reports of a single study were considered as one publication, and only the most recent or complete article was examined. All potentially relevant articles were reviewed by two independent investigators (L.D.W. and B.L.).