ALK fusion

The patient demonstrated a significant clinical benefit from sequential treatment with crizotinib and alectinib, highlighting TTC7A-ALK as a novel therapeutic target for ALK inhibitors. These findings extend the spectrum of actionable ALK fusions and promote the inclusion of rare fusion detection in clinical diagnostic processes and treatment strategies.

P=N/A, N=825, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Jan 2024 --> Jan 2026

P2, N=120, Recruiting, Hunan Province Tumor Hospital | Phase classification: P1 --> P2

Using data from 515 The Cancer Genome Atlas (TCGA) samples, SplitFusion showed the highest sensitivity and uncovered two cases of SLC34A2::ROS1 that were missed in previous studies. These capabilities make SplitFusion highly suitable for clinical applications and the study of fusion-defined tumor heterogeneity.

This is the first investigation to explore the impact of circulating anti-ALK a-abs on BM. Prospective studies with longer follow-up are warranted to further explore the impact of anti-ALK a-abs on BM.

ctDNA testing to detect oncogenic fusions or METexon14 mutations in advanced NSCLC patients is useful, even if type of gene alterations and clinical characteristics could influence the driver detection rate. Liquid biopsy represents a complementary tool to tissue genotyping, however more sensitive approaches for gene fusions and METexon14 detection are needed to implement its strength and reliability.

This study demonstrates marked improvements in survival for patients with Stage IV NSCLC, particularly in the last six years, despite the increase in brain metastases and elderly patients. This finding suggests the crucial role of novel therapies in enhancing survival outcomes.

P2, N=321, Active, not recruiting, Sichuan Kelun Pharmaceutical Research Institute Co., Ltd. | Recruiting --> Active, not recruiting | Trial primary completion date: Oct 2024 --> Dec 2025

Our data highlights the genetic landscape of Chinese PPTC patients, with RTK fusions being associated with aggressive clinicopathologic features. The rare fusions BEND7::ALK, DLG5::RET, and CCDC30::ROS1 may contribute to PPTC development with a BRAF-like effect.

P1, N=15, Not yet recruiting, Nationwide Children's Hospital | Trial completion date: Sep 2034 --> Jun 2035 | Initiation date: Sep 2024 --> Jun 2025 | Trial primary completion date: Sep 2027 --> Jun 2028

The activation of downstream pathways and the response to ALK inhibitors crizotinib and alectinib were demonstrated by western blotting (WB). We identified and functionally validated PLCXD3-ALK as a novel rare fusion in NSCLC that has not been previously reported. It can serve as a meaningful therapeutic target for ALK inhibitors of ALK + NSCLC.

P1, N=65, Active, not recruiting, New Approaches to Neuroblastoma Therapy Consortium | Trial primary completion date: Dec 2024 --> Dec 2025

However, the effect of different types of gene changes in molecular targeted therapy is different. Therefore, this paper introduced the relevant contents of different variants of ALK gene, focused on the research progress of targeted therapy, and proposed the future development direction..

The patient developed resistance to Lorlatinib treatment accompanied by mesenchymal-epithelial transition factor (MET) amplification. Effective tumor control was achieved with the combined use of Crizotinib and Lorlatinib, providing a valuable reference for further exploration of treatment strategies following resistance to ALK-TKIs in clinical practice..

P2, N=770, Recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences | Not yet recruiting --> Recruiting | Trial completion date: Jul 2023 --> Jul 2028 | Trial primary completion date: Jul 2022 --> Jul 2026

Despite early termination, camrelizumab demonstrated a trend toward improved iPFS and PFS in BM of NSCLC, with an acceptable safety profile.

The structural instability of ALK and partner genes, coupled with the inherent variability of breakpoint sequences, leads to the formation of potent kinase-activated oncogenes, which play a critical role in tumorigenesis. While the occurrence of ALK fusions with partner genes is random, specific combinations lead to the generation of oncogenes.

The tumor was completely excised with negative margins. The patient is doing well at 17 months follow-up with no signs of recurrence.

In addition to reporting the identification of a novel ALK fusion, XPO1-ALK (intergenic), and the sensitivity and safety of brigatinib treatment for lung cancer, this study increased the list of known ALK fusion partners in ALK-positive NSCLC. This case report has a significant clinical reference.

For patients with ALK-positive SCLC, ALK inhibitors may be a reliable treatment option.

The patient experienced progression on initial iruplinalkib and subsequent alectinib therapy within 5 months. After the failure of third-line therapy with cisplatin-pemetrexed combined with bevacizumab, she received sintilimab plus anlotinib which led to a progression-free survival of 6.5 months. She received sintilimab combined with albumin-paclitaxel plus carboplatin and achieved partial response after 6 months...After progression on ICB-based therapy, the patient was treated with lorlatinib and still under follow-up with overall survival of more than 3 years. Our findings highlight the therapeutic potential of ICB-based regimens in patients with MSI-H and ALK-rearranged NSCLC.

P2, N=18, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2025 --> Jan 2026

Currently, olaparib is available for maintenance therapy of BRCA1/2 mutation-positive PDAC. Further therapeutic developments are ongoing for genetic abnormalities involving BRAF V600E and the fusion genes RET, NTRK, NRG, ALK, FGFR2, and ROS1. Overcoming advanced PDAC remains a formidable challenge; however, this review outlines the latest therapeutic strategies that are expected to lead to significant advancements.

This evolution in clinical practice provides a lens through which to review the lessons learned from drug development in oncogene-addicted lung cancers, guided by translational insights into tumor biology and mechanisms of therapeutic resistance. For oncogenic drivers that are less sensitive to single-agent targeted therapies, rationally designed combination strategies will be needed to enable first-line use of targeted agents.

P1/2, N=42, Recruiting, Hoffmann-La Roche | Trial completion date: Jun 2033 --> Feb 2032 | Trial primary completion date: Jun 2033 --> Feb 2028

Patients with thoracic IMT patients are typically young with early-stage disease. ALK fusion were the most common genetic alteration, particularly in spindle-cell patterns. Characterization of the tumor microenvironment indicates the potential of immune profiling in the tumor biology and targeted immunotherapy approaches.

The mechanistic target of rapamycin (mTOR) inhibitor everolimus could not be obtained due to lack of insurance coverage, so the patient was treated with single-agent pembrolizumab. The patient was then followed at an outside institution and was transitioned to hospice at time of progression per his preference. He died 4 years after his initial diagnosis.

P1/2, N=37, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

EML4-ALK short variants and TP53 mutations are both adverse factors for first-line alectinib efficacy, but they have little effect on first-line crizotinib.

Our model calculations suggested that the effect of the translocation was to induce the dimerization of ALK into a complex that distorted the binding pocket, which is the same for alectinib, lorlatinib and crizotinib. Our observations suggest that molecular modelling based on artificial intelligence (AI) tools may offer potential predictive information in fusions with rare partner genes. Further retrospective and prospective studies are warranted to demonstrate the predictive robustness of these tools.

The main adverse events of TKIs were grade 3 liver damage and grade 3 skin rash, which required a change in the drug from gefitinib to afatinib and dose reduction, respectively. Successful long-term outcomes were achieved after sequential targeted therapy and chemotherapy, followed by surgery for stage III NSCLC. However, it is noteworthy that postoperative treatment may have also contributed to minimizing postoperative recurrence.

LUAD patients with short ALK fusion variant-driven tumors exhibited worse prognosis than those with long ALK fusion variant-driven tumors. The tumor immune microenvironments are heterogeneous across different ALK fusion variants with short variants characterized by higher levels of TIL, especially NK cells, but by less TLS development than long variants ALK+ LUAD, which disfavor disease outcomes.

P2, N=20, Recruiting, The Second Affiliated Hospital of Chongqing Medical University; The Second Affiliated Hospital of Chongqing Medical University

P2, N=30, West China Hospital of Sichuan University; West China Hospital of Sichuan University

P2, N=88, Recruiting, SWOG Cancer Research Network | Trial completion date: May 2029 --> May 2028

We report the first case of ALK-RCC with concurrent ALK amplification and fusion. This article presents the clinical data, morphology, immunohistochemistry, and molecular characteristics of this case, with the aim of enhancing the clinical and pathological understanding of ALK-RCC among clinicians and pathologists.

In conclusion, EBC samples provide a valuable, noninvasive medium for detecting clinically relevant and previously uncharacterized fusion transcripts in non-small cell lung cancer (NSCLC). The high concordance between EBC and tissue biopsies suggests that EBC could complement tissue biopsy for effective diagnosis and monitoring of NSCLC. These findings underscore the importance of comprehensive molecular profiling using multiple sample types to enhance diagnostic precision and optimize therapeutic outcomes in lung cancer management.

P2, N=116, Active, not recruiting, SWOG Cancer Research Network | Recruiting --> Active, not recruiting

This case illustrates one way in which NGS can reveal diagnoses such as collision tumor that are wholly unexpected based on clinical and histological grounds. Such diagnoses can have important implications for patient care, particularly in cases where there is discordance for targetable molecular alterations.

This report describes a case of a locally advanced NSCLC patient with dual driver gene mutations (EGFR L858R combined with primary METamp), the tumor did not shrink after 1 month of Gefitinib monotherapy, but significantly subsided after 4 months of Savolitinib monotherapy. After radical surgery, the pathological results proved pathological complete response (pCR) of the tumor, and the patient had a good response to postoperative continual Savolitinib treatment, with no recurrence nor metastasis observed to date. This case reports the feasibility and effectiveness of neoadjuvant targeted therapy for locally advanced NSCLC with primary METamp, aiming to provide effective reference for perioperative treatment of locally advanced NSCLC with primary METamp..

In recent years, there are increasing clinical evidences suggesting that the combination of ALK inhibitors with surgical treatment holds significant potential for clinical application in resectable early and locally advanced non-small cell lung cancer (NSCLC) patients. This review aims to summarize the advances in neoadjuvant targeted therapy for ALK fusion positive NSCLC and discuss its advantages and challenges in clinical practice..

Notably, patients with c-RET had a better prognosis than those with s-RET (median TTF: NR versus 5.67 months, P=0.037, median OS: NR versus 9.83 months, P=0.047). In conclusion, pralsetinib-based therapy may be a potential strategy to overcome acquired RET fusion after resistance to EGFR/ALK-TKIs.