Xalkori (crizotinib)

However, due to the paucity of solid data from randomized, controlled phase III clinical studies, clinicians often require more systematic, real-world data-based guidance for its optimal clinical use. As one of the leading countries of real-world research on crizotinib, China has contributed significantly to data on standardization of the therapeutic use of crizotinib, including its clinical treatment patterns, the timing and duration of treatment and drug resistance monitoring and management.

In this context, we endeavored to develop ALK degraders utilizing FDA-approved ALK inhibitors-crizotinib, ceritinib, brigatinib, and alectinib-as ALK binders, along with 4-methoxyphenylfumarate as a covalent handle to bind to RNF126 E3 ligase. However, the enhanced anti-proliferative activity of dALK-3 was found to be independent of RNF126, a presumed potential E3 ligase, suggesting the need for investigation of other components within the ubiquitin-proteasome system. Our findings further support the potential application of the fumarate moiety as a binder for E3 ligases in targeted protein degradation.

We evaluated crizotinib or 2nd generation ALK-TKI effectiveness in first-line treatment and lorlatinib in subsequent lines. This comprehensive study, spanning over a decade, provides crucial insights into the clinical characteristics, treatment patterns, and resistance mechanisms of advanced ALK-positive NSCLC, where median OS exceeds 5 years. Re-biopsies during treatment are essential for advancing our understanding of resistance mechanisms and the tumor dynamics evolving during ALK-TKI therapy.

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), such as alectinib and crizotinib, have been used in the treatment of NET patients with ALK rearrangement. The patient received ensartinib (225 mg/day) for 18 months until disease progression in June 2024 and achieved a radiographic partial response. Although patients with ALK fusions showed response to ensatinib in nonsmall cell lung cancer (NSCLC), this study first reports a metastatic NET case with a novel CEP44-ALK rearrangement that responded favorably to ensartinib.

Our case report strengthens the evidence that crizotinib may be a viable treatment option for patients with ICC with a c-MET tyrosine kinase fusion, necessitating additional clinical investigation.

P2, N=120, Recruiting, Sun Yat-sen University | Not yet recruiting --> Recruiting

Additionally, the combination of c-MET inhibitors with the chemotherapeutic agent doxorubicin synergistically enhanced cytotoxicity in MDR cells, as evidenced by combination index (CI) values of 0.54 ± 0.08, 0.69 ± 0.1, and 0.85 ± 0.07 for cabozantinib, crizotinib, and PHA665752, respectively...In silico analysis also suggested that the transmembrane domains (TMD) of ABCB1 transporters could be considered potential target for these agents. Our results suggest that c-MET inhibitors can serve as promising MDR reversal agents in ABCB1-medicated drug-resistant cancer cells.

Her blood test showed a high c-reactive protein (CRP) levels ; therefore, she was admitted and received levofloxacin drip infusion for 5 days. Pathology of the left kidney revealed a renal abscess, but there was no sign of malignancy. Crizotinib has been reported to cause rare adverse effects, such as polycystic renal lesions or renal abscesses.

Finally, several potential therapeutic drugs, including afatinib and crizotinib, were identified. Big data analysis established a prognostic signature that predicts survival and immunization in LUAD patients, providing new insights into survival and treatment options.

Through molecular docking, crizotinib stand out as a prioritized FES target drug repurposing opportunity with the lowest binding energy (-10.13kJ·mol-1) and CCK-8 assay showed ER+ cell groups were more sensitive to crizotinib than ER- cell groups. In conclusion, OPRL1 was identified as a prioritized target for both overall and Luminal A breast cancer. Moreover, FES and FAAH were recognized as prioritized targets for ER+ breast cancer.

His treatment was subsequently changed to crizotinib, which was well tolerated. This case was also associated with concurrent acute heart failure after entrectinib treatment which responded promptly to prednisolone (40 mg). Entrectinib-induced cardiotoxicity is an important adverse event to be aware of, particularly as patients may be asymptomatic for an initial period before significant deterioration.

After a minimum follow-up of 5 years, final analyses from the global phase 2 study confirmed substantial activity, prolonged OS, and generally consistent safety findings with lorlatinib in treatment-naïve and previously treated patients with ALK-positive NSCLC.

In total, the patient was treated with crizotinib, alectinib, and lorlatinib. As a result, after over 4 years since the initial diagnosis, she is still alive with significantly improved clinical condition and quality of life. This paper demonstrates the clinical benefits of sequential therapy of ALK inhibitors and an exceptionally long response to lorlatinib, a third-generation tyrosine kinase inhibitor.

In this study, we investigated the influence of three c-Met inhibitors, SU11274, crizotinib, and PHA665752, on molecular characteristics, tumorigenicity, and metastatic behavior in three human melanoma cell lines, M4Beu, EGFP-A375 and its metastatic variant, EGFP-A375/Rel3 (Rel3). The increased tumorigenicity of the Rel3 cells following the SU11274 treatment correlated with the elevated phosphorylation of Akt, p70 S6 and RSK kinases. Our results demonstrate pleiotropic changes induced by small-molecule inhibitors of receptor tyrosine kinases in melanoma cell lines.

P=N/A, N=40, Not yet recruiting, National Cancer Center, China

Deulorlatinib showed desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.

The outcomes in this MAIC study including Asian patients with ROS1-positive NSCLC showed a trend for greater clinical benefit with entrectinib versus crizotinib. These findings may contribute to better-informed treatment decisions.

The results showed that while proliferation rates, cell index values, mitotic index and bromodeoxyuridine labeling index decreased, caspase activity values increased. These results demonstrated that the combined application was more effective than the monotherapy application and could be used at lower concentrations than those drugs applied as monotherapy.

In this particular case, treatment with crizotinib demonstrated some initial efficacy, which suggests that this might be a promising strategy for patients with advanced MPM with an ALK gene mutation. This required further research and evaluation in the future.

P1/2, N=341, Recruiting, IDEAYA Biosciences | Trial completion date: May 2025 --> Mar 2027 | Trial primary completion date: Oct 2024 --> Dec 2026

In further analysis, lorlatinib revealed superior intracranial efficacy and prolonged time to intracranial progression compared with crizotinib. Herein, we report a case of ALK-positive NSCLC with leptomeningeal metastasis that was successfully treated with lorlatinib after progression to brigatinib and alectinib. This case demonstrates the potential of lorlatinib in managing leptomeningeal metastasis in ALK-positive NSCLC. The case suggests a paradigm shift in therapeutic approaches for CNS metastasis, including brain and leptomeningeal metastases.

A 43-year-old, female diagnosed with T4N3M1c NSCLC harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variant 1 (EML4-ALK v.1) and TP53 co-mutation, displayed only mixed response after three months and highly symptomatic progression after 6 months of first-line brigatinib treatment. The latter may represent a mechanism of intrinsic ALK-TKI resistance and its recognition by FISH, in NGS-negative cases, may be considered before initiating first-line treatment. This recognition is clinically important as combined therapy with ALK-TKI and MET-inhibitor should be the preferred first-line treatment.

The TKIs used during this period include EGFR inhibitors such as afatinib, erlotinib, gefitinib, and osimertinib and ALK inhibitors such as alectinib and crizotinib. The EGFR-targeted and ALK-targeted therapies appear to have acceptable clinical response rate and safety profile in our population. Close and frequent monitoring of adverse events is advised to ensure a good quality of life and prevent serious complications.

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.

Aim: We conducted network meta-analysis to assess cardiovascular toxicity of anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs).Materials & Eleven articles involving 2855 patients and six interventions including crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and chemotherapy were analyzed. No significant difference was observed in overall cardiovascular risk among ALK-TKIs. For vascular toxicity, crizotinib and ceritinib had a higher risk of thrombotic events than brigatinib. Crizotinib and lorlatinib were more likely to cause blood pressure abnormalities. Clinicians should carefully monitoring cardiovascular events when ALK-TKIs used in NSCLCs patients with baseline cardiovascular diseases.

P4, N=14, Pfizer, Inc

For patients with ALK+ NSCLC, treatments including next-generation ALK-TKIs were independently associated with longer survival outcomes.

A bronchoscopy with transbronchial lung biopsy of the right S5 nodule confirmed the diagnosis of adenocarcinoma. The biopsy specimen was analyzed using the AmoyDx® Pan Lung Cancer PCR Panel, which detected ROS1 fusions.

Crizotinib successfully overcomes MET amplification in ROS1-rearranged NSCLC after entrectinib failure.

Our NMA analysis adds to existing findings and supplements data gaps from other published NMAs. Findings from eight published NMAs consistently supported lorlatinib as a clinically effective 1L treatment for ALK + advanced NSCLC patients compared to other TKIs.

On-target mutations of the ROS1 kinase domain confer resistance to crizotinib and lorlatinib in more than one-third of acquired resistance cases with no current effective treatment option. The degrader can effectively inhibit ROS1-dependent cell proliferation and tumor growth by degrading the ROS1 kinase, thereby eliminating the active phospho-ROS1. More importantly, the degradation-based therapeutic modality can overcome on-target mutation resistance to tyrosine kinase inhibitors by efficient degradation of the mutated kinase to achieve greater potency than inhibition.

The 5-year results from the CROWN study showed that more people who took lorlatinib continued to benefit from their treatment than those who took crizotinib. The 5-year benefit of lorlatinib in people with ALK-positive NSCLC has never been seen before.Clinical Trial Registration: NCT03052608 (Phase 3 CROWN study) (ClinicalTrials.gov).

Our work reveals a positive feedback loop between MET and VEGF/VEGFR2, resulting in continuous downstream signal activation. Combined inhibition of MET and VEGF/VEGFR2 signaling pathway may be beneficial for reversing EGFR TKIs resistance.

Compared with chemotherapy, alectinib, lorlatinib, brigatinib and ceritinib, crizotinib significantly increased the risk of TE and VTE.

Her work exemplifies the continuing influence of Polish researchers in pioneering drug discovery and advancing therapeutic treatments over the past three centuries. These contributions highlight Poland's significant role in global pharmaceutical innovations and medical research.

Despite the initial poor response to conventional chemotherapy, the patient exhibited an exceptional and sustained response to crizotinib, with a progression-free survival of 94 months and complete metabolic response on PET scan. This case underscores the importance of molecular profiling in guiding treatment decisions and highlights the efficacy of targeted therapies for ROS1-positive NSCLC.

Collectively, resistance of ALK-positive NSCLC cells to crizotinib is induced by G1202R and L1196M mutations through activation of the MDM2/MEK/ERK signalling axis, promoting EMT process and metastasis. These findings suggest that the combination of MDM2 inhibitors and crizotinib could be a potential therapeutic strategy.

P3; Active, not recruiting --> Completed

To discover therapeutic targets to overcome crizotinib resistance (CR), we generated patient-derived xenograft CR mice and subjected them to phosphorylation profiling, together with CR mice treated with ASP3026 or alectinib. We also found that SHC1 phosphorylation was increased in CR mice and SHC1 knockdown sensitized ALK-driven cells to crizotinib. Our study provides a new view of signaling pathways leading to CR, suggesting AXL and SHC1 as potential targets for combination therapy to overcome CR.

Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact.

P2, N=90, Recruiting, Hunan Province Tumor Hospital | Phase classification: P --> P2