Zykadia (ceritinib)

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.

After 3 months, targeted lesions regressed significantly, and progression-free survival exceeded 24 months with ongoing response. This demonstrates efficacy of the ALK inhibitor ceritinib in ALK-rearranged SMARCA4-dNSCLC and underscores the clinical value of genomic-guided therapy.

Among patients who received next-generation ALK TKIs as first-line therapy, continuation of next-generation ALK TKI with PT/Pem led to longer PFS and OS than PT/Pem alone, with no unanticipated toxicities. The modest efficacy of PT/Pem-based regimens overall underscores the need for more effective therapies for TKI-refractory ALK+ NSCLC.

P1, N=57, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Apr 2026 --> Apr 2027

P2, N=36, Recruiting, National University Hospital Singapore

In contrast, permanent discontinuation was associated with higher weight/BSA in brigatinib/ceritinib/crizotinib-treated patients. Higher weight and larger BSA at the start of ALK TKI treatment were associated with higher likelihood of toxicity, leading to more DRs and TIs-particularly in males and patients receiving alectinib and lorlatinib. However, weight and BSA were not associated with treatment outcomes.

This effort culminated in the identification of compound 8q, which demonstrated potent and selective anti-tumor efficacy against ALK (anaplastic lymphoma kinase) -positive cancer cells (NCI-H2228 and Karpas-299), significantly outperforming ceritinib in enzymatic and cellular assays...The RMSD and RMSF analyses confirmed enhanced conformational stability of the 8q-ALK complex compared to the apo protein. Collectively, these findings highlight 8q as a promising lead compound for the development of novel ALK inhibitors with a favorable efficacy and safety profile.

P3, N=603, Active, not recruiting, Institut National de la Santé Et de la Recherche Médicale, France | Trial completion date: Oct 2025 --> Jan 2026