Zykadia (ceritinib)

P1, N=27, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Mar 2024 --> Aug 2024

Seven different ALK-TKIs have been approved by the National Medical Products Administration (NMPA) of China, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib. On January 16, 2024, the NMPA approved iruplinalkib for the first-line treatment of locally advanced or metastatic ALK-positive NSCLC patients. In order to better understand the efficacy and safety of iruplinalkib, and facilitate more rationally clinical application of iruplinalkib, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists co-organized experts to compile the "Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)".

In this study we knock-in for the first time in a ROS1 + patient-derived cell line, three different known resistance-causing mutations using CRISPR/Cas9 in the endogenous translocated ROS1 alleles. Pharmacological assays performed in 2D and 3D cell culture revealed that spheroids are more sensitive to TKIs than cells cultured as a monolayer. This direct comparison between two culture systems could be done thanks to the implementation of normalized growth rates (NGR) to uniformly quantify drug response between 2D and 3D cell culture. Overall, this study presents the added value of using spheroids and positions lorlatinib and repotrectinib as the most effective TKIs against the studied ROS1 resistance point mutations.

P2, N=3000, Recruiting, Oslo University Hospital | N=1000 --> 3000

Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients...Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.

Notably, second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib...Despite encouraging preclinical data, challenges observed in trials assessing combinations such as nivolumab-crizotinib, mainly due to severe hepatic toxicity, emphasize the necessity for cautious exploration of these novel approaches... This comprehensive analysis covers molecular mechanisms, therapeutic strategies, and immune interactions associated with ALK-rearranged NSCLC. As a pivotal resource, the review guides future research and therapeutic interventions in ALK-targeted therapy for NSCLC.

Our study findings suggest that the prices of ceritinib and crizotinib need to be reduced significantly to justify their value for inclusion in India's publicly financed health insurance scheme for treatment of patients with locally advanced/metastatic ALK- and ROS1-positive NSCLC, respectively.

In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

HX16 is a multifunctional chemical tool based on the pharmacophore of ALK-TKI (ceritinib) and can specifically target the kinase domain of ALK with a high sensitivity...Importantly, HX16 was also applied to visualize ALK activity in a tumor biopsy from a NSCLC patient with ALK-echinoderm microtubule-associated protein-like-4 fusion gene for prediction of ALK-TKI sensitivity. These results demonstrate that strategically designed ALK-TKI-based probe allows the assessment of ALK activity in tumor tissues and hold promise as a useful diagnostic tool in predicting ALK-TKI therapy response.

As of June 27, 2023, seven ALK-TKI, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib, have garnered approval from the China National Medical Products Administration (NMPA)(ranking according to the approval time for marketing by NMPA), providing individualized treatment modalities for ALK-positive NSCLC patients. To standardize the application of ALK-TKI, the Chinese Association for Clinical Oncologists and the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care has organized experts to compile the " China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)". This treatment expert recommendation provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese advanced ALK fusion-positive NSCLC.

Furthermore, dEALK1 also exerts a potent antitumor activity against EML4-ALK-positive xenograft tumors without or with harboring ceritinib-resistant EML4-ALK mutations in vivo. Our study suggests that dEALK1-induced degradation of EML4-ALK fusion proteins is a promising therapeutic strategy for treatment of ALK-rearranged lung cancer with ceritinib resistance.

P3, N=376, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

The analysis included 9 RCTs with 2,443 patients receiving eight different treatments: alectinib (at two different dosages), brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Based on the network meta-analysis, alectinib and lorlatinib emerged as the most promising upfront treatment options. These treatments provide prolonged disease control while maintaining an acceptable safety profile.

The ability to overcome acquired resistance to prior generation TKIs (alectinib, brigatinib, ceritinib, and crizotinib) and the high intracranial activity in brain metastatic disease thanks to increased blood-brain barrier penetration are the reasons for the growing popularity and interest in this molecule. So, when prescribing lorlatinib, clinicians must face two diametrically opposed characteristics: a great therapeutic potential without the intrinsic limitations of its precursor TKIs, a cytotoxic activity threatened by suboptimal tolerability, and the unavoidable onset of resistance mechanisms we cannot properly manage yet. In this paper, we give a critical point of view on the stepwise introduction of this promising drug into clinical practice, starting from its innovative molecular and biochemical properties to intriguing future developments, without forgetting its weaknesses.

P1, N=27, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute

Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC ranging from IC 0.60 to 2.32 µM...Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis. These results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression.

Crizotinib was the drug most frequently linked to EPE (38%), followed by lorlatinib (26%), ceritinib (12%), entrectinib (8%), dabrafenib/trametinib (6%), repotrectinib (6%) and brigatinib (3%). Despite frequent EPE after TKI introduction, clinical pancreatitis are rare. Based on these results, we conclude that no routine assessment of pancreatic enzyme is required when introducing TKI treatment. To our knowledge, this is the first retrospective study about EPE linked to TKI in NSLC.

The median progression- free survival was approximately 4 months. The safety and efficacy were similar to those of previous reports, and this study confirmed that there are no problems requiring additional precautions in clinical use of Zykadia®.

Meanwhile, acridine orange-ethidium bromide staining analysis indicated that the proapoptotic effect of L6 was better than that of ceritinib at the same concentration (50 nM). Ultimately, the binding patterns of L6 to ALK and ALK were ideally established, which further confirmed the structural basis in accordance with the structure-activity relationship analysis.

P=N/A, N=111, Completed, Takeda | Active, not recruiting --> Completed | Trial completion date: Nov 2023 --> Feb 2023 | Trial primary completion date: Oct 2023 --> Feb 2023

P3, N=231, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

ALK inhibitors first-line crizotinib, second-line ceritinib, and alectinib are effective against NSCLC patients with these rearrangements. Based on the Y1278-C1097 H-bond and E1167-K1150 salt bridge interaction, I1171N strongly promotes the constitutively active kinase independent of ATP. This structural mechanism study will aid in understanding the oncogenic activity of ALK and the basis for improving the ALK inhibitors.

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2024 --> Sep 2024

P1, N=27, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Oct 2023 --> Jan 2023

After the approval of crizotinib, other ALK-TKIs, such as ceritinib, alectinib, brigatinib, and lorlatinib, have proven their efficacy on ALK IMT with sporadic case reports. The sequential treatments of targeted therapies in may provide the insight into the choice of ALK-TKIs in different lines of treatment for unresectable ALK IMT.

Median prior therapy lines was 3 (range 2-5); all pts previously received Crizotinib, two pts received also Alectinib and 1 Ceritinib as TKI treatment. Lorlatinib represents a safe and effective salvage therapy for ALK+ Lymphoma patients failing first line TKI treatment. The obtainment of CR at M1 seems to represent a pivotal prognostic factor. Lorlatinib also offers a promising bridging regimen to salvage ASCT especially for ALK+ BCL patients, with high response rates and no additional toxicities, .

In addition, these methods encompassed the advantage of high-throughput analysis. In conclusion, the three methods are valuable tools for convenient and reliable application in the pharmaceutical quality control units for CER-containing capsules.

In addition, the simultaneous handling of a large number of samples with microvolumes in the proposed methods gave them the advantage of a high-throughput analysis. The two methods are valuable tools for rapid routine application in pharmaceutical quality control units for the quantitation of CER.

P3, N=376, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2023 --> Dec 2023

With a total cost of $222,044.10 per year, Osimertinib surpasses the cost of other oral agents, including erlotinib ($113,171.90) and Afatinib ($147,204.50)...In the context of ALK-positive NSCLC, Alectinib compared to Brigatinib, Lorlatinib and Crizotinib, as well as Brigatinib compared to Lorlatinib, and Lorlatinib compared to Crizotinib, are the drugs with lower ICER values, indicating better cost-effectiveness. Alectinib emerges as the most cost-effective oral agent, followed by Ceritinib... The cost-effectiveness analysis presented in this study highlights the economic considerations associated with oral agents. The findings indicate the higher costs of Osimertinib and certain ALK inhibitors, which need to be weighed against the potential improvements in QALYs. By considering both costs and effectiveness, healthcare decision-makers can optimize treatment strategies, allocate resources efficiently and improve patient outcomes.

P=N/A, N=20605, Recruiting, Pfizer | Not yet recruiting --> Recruiting

OBJECTIVES: Anaplastic lymphoma kinase (ALK) inhibitors, including Alectinib, Brigatinib, and Ceritinib, are recommended by the National Comprehensive Cancer Network (NCCN) for treating patients with ALK-arranged non-small-cell lung cancer (NSCLC) in an advanced stage. All ALK inhibitors were not cost-effective for treating ALK-arranged NSCLC patients in Thailand. Of these, Ceritinib 450 mg/day was the most likely to be cost-effective. These results could be used as evidence to support policymakers for reimbursement decision and finding alternative Supported by solution.

From the perspective of the Chinese healthcare system, lorlatinib presents a cost-effective alternative to alectinib and ceritinib for the second-line treatment of advanced ALK-positive NSCLC.

Although heterogeneous, patients treated with SRS/SRT and ongoing CNS-active targeted systemic therapies have on average >6 month intracranial PFS and little evidence of significant toxicity. We observed <6% G2+ radiation necrosis for this cohort, and no particular class of agent was associated with a significantly higher rate of G2+ radiation necrosis.

In cases of ALK-dependent resistance mutations, lorlatinib could be the first choice as it exhibits the broadest coverage of mutations that lead to resistance against second-generation ALK - TKIs, such as G1202R, and L1196M. In cases of no resistance mutations, atezolizumab, bevacizumab and platinum-based chemotherapy could be the alternative treatment option.

P2, N=500, Recruiting, Giselle Sholler | Trial completion date: Sep 2032 --> Sep 2035 | Trial primary completion date: Sep 2027 --> Sep 2030

The toxicity spectra of ALK-TKIs differed. Alectinib might be the safest ALK-TKI drug according to the combined evidence of grades 3-4 AEs and the combined incidence.

Various small drug molecule that targets the RTKs having the same scaffold, includes Lapatinib, Tivozanib, Erlotinib, Gefitinib, Crizotinib, and Ceritinib. Lapatinib is identified as a potential inhibitor for both the RTKs. Our study thus suggests the probable direction that could be further explored in inhibiting EGFR protein harboring breast cancer.

Alectinib was the first choice for patients with ALK-positive NSCLC and even for those with BM, whereas lorlatinib was the second choice. Long-term follow-up and prospective studies are warranted to compare ALKis and to verify our conclusions directly.

P2, N=103, Active, not recruiting, Ariad Pharmaceuticals | Trial completion date: Jun 2023 --> Jun 2024