ALK rearrangement

The case provides additional support that IT pemetrexed can offer symptomatic relief and may be considered as a treatment option in advanced LM. Furthermore, the case illustrates that an increased dose of lorlatinib may efficiently control LM in patients with ALK-rearranged NSCLC, following progression on standard lorlatinib dosage.

The pathological manifestations from a liver biopsy showed the hepatocytes with scattered focal necrosis, bile stasis, and vesicular steatosis, bile emboli in capillaries, and star-shaped fibers proliferation in the portal area. This is the first report of alectinib-induced hyperbilirubinemia which was confirmed by liver histopathology and successfully relieved by ALSS treatment and drug discontinuation.

While first-line treatment options include alectinib, brigatinib, and lorlatinib per National Comprehensive Cancer Network (NCCN) guidelines, therapeutic challenges arise in cases of disease progression. Direct comparison of second and third-generation ALK inhibitors is essential to elucidate their comparative efficacy and adverse event profiles, which could refine current management guidelines. Furthermore, if lorlatinib proves superior in terms of progression-free survival, it may offer the potential to delay or obviate the need for radiation therapy, thus mitigating the risk of neurotoxic adverse events associated with these modalities.

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.

No abstract available

P2, N=175, Active, not recruiting, German Cancer Research Center | Recruiting --> Active, not recruiting

P2, N=0, Withdrawn, Sun Yat-sen University | N=128 --> 0 | Recruiting --> Withdrawn

Recognition of rare ALK fusions This case highlights the importance of identifying rare ALK fusions, such as SQSTM1-ALK, in non-small cell lung cancer (NSCLC), which can guide personalised treatment strategies.Utility of advanced molecular diagnostics The use of next-generation sequencing alongside immunohistochemistry is crucial for accurately detecting ALK and ROS1 rearrangements, avoiding false positives and enabling the identification of druggable mutations.Impact of personalised medicine This case reinforces the value of personalised medicine in NSCLC, where molecular profiling can uncover unique genetic alterations, allowing for more tailored and potentially more effective treatments.

LUADMuc represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments.

P2, N=29, Active, not recruiting, Sheba Medical Center | Recruiting --> Active, not recruiting

P1, N=5, Active, not recruiting, City of Hope Medical Center | Trial completion date: Nov 2024 --> Jun 2025 | Trial primary completion date: Nov 2024 --> Jun 2025

P=N/A, N=200, Recruiting, Takeda | Trial completion date: Dec 2026 --> Dec 2029

ALK-RCC represents a distinct entity with clinicopathological, genetic, and immunophenotypic heterogeneity. ALK IHC analysis during primary screening may aid diagnosis in difficult cases. For progressive ALK-RCCs, postoperative adjuvant immunotherapy may be best selected according to IP features. Patients with immune-excluded phenotypes may not benefit from immunotherapy.

P3, N=1350, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | Trial completion date: Feb 2027 --> Nov 2027 | Trial primary completion date: Feb 2027 --> Nov 2027

Alectinib combined with cobimetinib demonstrated limited activity in alectinib-resistant tumors. Despite dose-limiting dermatologic and muscle enzyme toxicities, durable responses were observed in alectinib-naïve patients.

P=N/A, N=200, Recruiting, Takeda | Trial primary completion date: Dec 2024 --> Mar 2025

RNAseq exon coverage analysis can effectively detect ALK rearrangements.

P1/2, N=450, Recruiting, DualityBio Inc. | N=280 --> 450 | Trial completion date: Apr 2025 --> Sep 2026 | Trial primary completion date: Apr 2025 --> Sep 2026

The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK-high group, which had more frequent copy number changes and was enriched with pathways associated with cell growth, proliferation, and metabolism. Altogether, these findings suggest that there is molecular heterogeneity within pediatric ALK+ ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers.

Some of these targeted therapies have already been approved by the Food and Drug Administration (FDA), and many others are currently undergoing clinical trials. This review summarizes recent advances in NSCLC treatment with molecular targets, highlighting progress, challenges, and their impact on patient prognosis.

This scoping review highlights that the poor prognostic ALK phenotype is likely composed of a heterogeneous variety of genomic factors. There remains an unmet need for a genomic assay to integrate these various molecular markers to predict this ALK phenotype.

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.

Finding and confirming these biomarkers is essential for improving early detection, tracking the course of the disease, and directing focused treatments. As research progresses, combining molecular, genetic, and environmental insights might improve lung cancer care, prevention, and early diagnosis, thereby lowering the disease's worldwide burden.

Here we report a case of a 71 year-old man with metastatic pulmonary IMT harboring a DCTN1::ALK fusion that progressed during alectinib TKI treatment...To our knowledge, this is the first report of acquired p. V1180L mutation in IMTs treated with TKIs. In cases of ALK-positive IMTs that progress on TKI therapy, targeted sequencing for acquired ALK mutations may inform clinical decisions to adopt second-line therapeutic strategies.

Among the alterations discussed, we focused on the ones that could be treated with already available drugs, such as MET-driven papillary RCC, mechanistic target of rapamycin altered chromophobe RCC, anaplastic lymphoma kinase-rearranged RCC, and fumarate-hydratase deficient RCC. Furthermore, we focused on the currently ongoing clinical trials and further evidence for all the other entities, such as SMARCB1-deficient RCC, TFE3 and transcription factorEB (TFEB)-altered RCC, and Elongin C (ELOC)-mutated RCC. The vast heterogeneity of nccRCC does not allow a one-size-fits-all solution; therefore, molecular characterization is the path toward effective therapies and fully personalized medicine for these entities.

We have, for the first time, identified the presence of SQSTM1-ALK fusion in pericardial effusion, with the favorable response to ensartinib validating the oncogenic potential of SQSTM1-ALK fusion. The substantial advancements and extensive utilization of NGS have facilitated the identification of rare fusion variants.

Immunohistochemically, the tumors diffusely expressed S100 and CD34, with strong ALK-D5F3 positivity, confirmed by ALK gene rearrangement. These findings further expand the clinical and pathological spectrum of ALK-rearranged neoplasms and highlight the need for continued research on their biological behavior and classification.

A Lebanese expert panel of oncologists was convened to describe the management paradigm and the clinical evidence supporting the optimal use of next-generation TKIs in patients with ALK-rearranged NSCLC and to provide an expert overview of local challenges and recommendations for optimizing the management of advanced NSCLC in Lebanese patients. The experts agreed that these recommendations should be part of a healthcare strategy to be implemented at the national level.

4 pts received TT at recurrence, within clinical trials: one with grade 3 meningioma and ALK rearrangement treated with alectinib, one with PTCH1 mutant medulloblastoma treated with vismodegib, and two with high TMB treated with nivolumab/ipilumumab. The incidence of targettable molecular alterations in adult CNS tumor patients was lower than in GBM. Nevertheless, in a few selected cases TT have the potential to increase treatment options at recurrence and improve outcomes.

We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further interpreted its impact on the resistant signatures through drug-induced RNA-sequencing data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy.

The predictive model composed of these features or combined with sex and smoking habits exhibited statistically significant differences for mutation status as a criterion (P<0.01). Collectively, the findings of the present study confirmed that, in addition to clinical characteristics, certain cytological and histological features of lung adenocarcinoma are associated with the mutational status of the tumor.

Clinical T1-2 N0 ALK-rearranged lung adenocarcinoma is an aggressive disease with a specific tropism for lymph nodes and the brain. High-grade tumors are predictive of nodal upstaging. Adjuvant treatment significantly improves DFS and OS in upstaged patients, highlighting the need for personalized preoperative staging and post-surgical management in this cohort.

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.

It is feasible to yield actionable molecular testing results from cytology specimens within 2 to 3 hours of the patient's diagnostic procedure, and aspirate smears can be triaged for this use at the time of the rapid on-site evaluation. Targetable genetic alterations can be detected from destained cytology aspirate smear slides and unstained FFPE cell blocks with high accuracy, precision, and analytical sensitivity and specificity. The cost of each cartridge ranges from $127 to $462 and is covered by the average national reimbursement schemes.

Screening for ALK rearrangements with IHC is both reliable and cost effective. In-house testing with IHC removes reliance on send-out testing for ALK detection, effectively cutting costs and decreasing TAT. Additionally, the creation of a reflex algorithm can improve lung cancer biomarker testing processes within hospitals.

The AVENIO CGP Assay demonstrated high agreement with 2 established CGP tests, F1CDx and PGDx, in variant reporting, and closely aligned with F1CDx in HRDsig analysis across various tissue types. These results highlight the assay's reliability and demonstrate its utility in translational research.

P4, N=71, Completed, Pfizer | Active, not recruiting --> Completed

Alectinib, as adjuvant therapy, demonstrated favorable efficacy and manageable safety in patients with completely resected ALK-positive stage I B-IIIB non-small cell lung cancer. A limitation of this study is the small sample size, and a larger-scale real-world sample study is needed to further evaluate the efficacy and safety of alectinib as adjuvant therapy.

These findings further substantiate the hypothesis that SAMS and epithelioid FH may represent a morphologic and genetic spectrum. The differential diagnosis, clinical follow up, and the molecular genetic findings will be discussed.

P2, N=117, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

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.