Zykadia (ceritinib)

Crizotinib showed no significant difference in progression-free survival (PFS) or overall survival (OS) between first-line and post-chemotherapy use (PFS: p = 0.803; OS: p = 0.761). For second-generation ALK-TKIs, first-line treatment had numerically longer PFS compared to post-chemotherapy (alectinib: 41 vs 24 months; ceritinib: 30 vs 8 months), but these differences were not statistically significant after adjustment (p = 0.120 and 0.284, respectively)...Among patients treated with alectinib, there appears to be a trend toward shorter PFS and OS in those with MET overexpression. In a limited number of matched samples, PD-L1 expression did not change significantly after TKI resistance, although a slight increase was observed.

ALK inhibitors, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib has significantly improved clinical outcomes in ALK-rearranged NSCLC patients. To overcome these resistance mechanisms, the development of novel therapeutic strategies are required. By integrating structural biology, mutation evolution patterns, and emerging therapeutic approaches, this review underscores the need for next-generation inhibitors to overcome resistance and improve long-term outcomes in patients with ALK-positive NSCLC.

This multinational registry-based analysis highlights evolving global treatment patterns, supports newer TKIs' effectiveness, and identifies clinical and molecular factors associated with treatment duration.

The efficacy of tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, lorlatinib, entrectinib, and repotrectinib was systematically evaluated. Our findings underscore that although G2032R and L2026M mutations reside within the kinase active site, their impact extends far beyond steric hindrance, altering overall kinase domain dynamics. Collectively, these data establish a robust panel of patient-derived ROS1 cell lines that recapitulate clinical resistance patterns and, together with complementary computational modeling, provide a valuable framework to dissect ROS1 tumor biology and support rational design of next-generation inhibitors.

P2, N=25, Recruiting, University Health Network, Toronto | Not yet recruiting --> Recruiting

In this real-world Vietnamese cohort, first-line alectinib showed superior intracranial and systemic efficacy over ceritinib. In resource-limited settings, ceritinib combined with upfront brain RT is a reasonable clinical alternative. The differential benefit of brain RT between the two TKIs remains hypothesis-generating.

P2, N=216, Completed, Melanoma Institute Australia | Trial completion date: Dec 2025 --> Mar 2026

P1/2, N=1000, Recruiting, Oslo University Hospital HF | N=6000 --> 1000

In vivo, ceritinib suppresses tumor growth, while GLUT1 knockdown reduces its efficacy and ferroptotic response. These findings reveal a novel mechanism whereby ceritinib induces ferroptosis via GLUT1 downregulation and AMPK-dependent ferritinophagy, supporting its potential repurposing for breast cancer therapy.

Specifically, we utilized a human naïve phage display library to identify humanized monoclonal antibodies with high affinities for PD-L1, followed by constructing the single-chain variable fragments (scFvs) and chemically conjugating to ceritinib-loaded biomimetic exosomes (Cer-BEs) that were prepared via two different methods of ultrasonic extrusion and freeze-thaw...Compared to freeze-thaw, ultrasonic extrusion yielded PD-L1@Cer-BEs with smaller particle sizes, higher homogeneity, superior encapsulation efficiency and stability, enhanced anti-tumor effectiveness in vitro and vivo, indicating ultrasonic extrusion is more suitable for constructing PD-L1@Cer-BEs with desirable physicochemical properties and bioactivity. These findings not only prove the novelty and effectiveness of PD-L1@Cer-BEs targeting PDAC but also underscore the critical role of BE preparation in determining the efficacy of antibody-drug conjugate (ADC)-like targeted BEs.

Alectinib demonstrated a clear survival advantage over crizotinib, consistent with trial findings. Lorlatinib showed potential benefit over alectinib, though limited by sample size and wide confidence intervals. This study provides the largest claims-based analysis of 1 L ALK TKIs and may help guide differentiation among agents with equivalent guideline placement.

P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Apr 2026 --> Mar 2027