Zykadia (ceritinib)

P3, N=603, Completed, Institut National de la Santé Et de la Recherche Médicale, France | Active, not recruiting --> Completed

Although FDA (Food and Drug Administration) approved inhibitors such as crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib have improved clinical outcomes, their efficacy is often challenged by resistance mechanisms, including secondary kinase domain mutations and activation of bypass pathways. Binding free energies and per-residue contributions were computed using MMGBSA. Boltz-2 machine learning platform to predict KD values and the top three hits were validated using PCA and free energy landscape.

P2, N=10, Terminated, National Cancer Institute (NCI) | Trial completion date: Mar 2027 --> Mar 2026 | Active, not recruiting --> Terminated; Inadequate accrual rate

In this phase IV open-label study, patients with ALK-positive metastatic NSCLC that progressed on first-line alectinib or ceritinib received lorlatinib 100 mg once daily. Lorlatinib continued to show clinically meaningful benefit in patients with previously treated ALK-positive metastatic NSCLC. clinicaltrials.gov identifier is NCT04362072.

Concurrent targeting of PI3K and IR/IGF-1R signaling effectively overcomes adaptive resistance in PIK3CA-mutant NSCLC, supporting the rationale for further clinical evaluation of this combined therapeutic strategy.

We report a 19-year-old male with ALK-rearranged, radioiodine-refractory PDTC who started systemic therapy with ceritinib, achieving a complete metabolic response. Treatment with the third-generation ALK inhibitor led to a deep and durable complete metabolic response, sustained for more than four years, including persistence of remission after treatment discontinuation, with minimal toxicity. This case highlights the potential role of sequential ALK inhibition to overcome acquired resistance in ALK-rearranged TC and underscores the importance of comprehensive molecular profiling to guide personalized treatment strategies in rare aggressive thyroid cancers.

Our findings reveal that ceritinib disrupts mitochondrial dynamics via the MCU/calpain/Drp1 axis. This study identifies a previously unreported mechanism for ceritinib in thyroid carcinoma, suggesting a novel therapeutic strategy.

Treatment of cancer patients with selective ALK inhibitors, such as Ceritinib, causes dysgeusia. Mice receiving Ceritinib had a dramatic reduction in taste bud volume and innervation, and a significant portion of PHOX2B+ neurons died, demonstrating that ALK is critical for development and maintenance of oral sensory neurons.

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

This study sought primarily to characterize the inhibition effects of four well-known ALK inhibitors, crizotinib, ceritinib, alectinib, and brigatinib, on human UDP-glucuronosyltransferases (UGTs) in vitro and to assess their potential DDI risks in vivo. In vitro-in vivo extrapolation (IVIVE) suggested that all four ALK inhibitors have potential for DDIs due to their inhibitory effects on UGTs. Among them, the DDI risks of alectinib and brigatinib were much higher than the FDA standard, which may have an impact on the safety of clinical drug use.

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026

Although allosteric GLS inhibitors such as BPTES (Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide) and later-generation analogs such as CB-839 (Telaglenastat) have pharmacologically validated this target, their clinical utility has been constrained by suboptimal drug-like properties, including poor solubility and bioavailability...This biochemical potency translated to a functional effect in a cellular model of glutamine dependence, as evidenced by a significant depletion of intracellular glutamate pools in LDK378-resistant (LR) cells. Furthermore, TRG-192 demonstrated a favorable preclinical safety profile in initial toxicological assessments. Collectively, these data-encompassing potent target engagement, functional on-target activity, and preliminary safety-provide a compelling rationale for the advancement of TRG-192 into in vivo efficacy studies.