ROS1 rearrangement

P2, N=117, Recruiting, Fox Chase Cancer Center | Trial completion date: Jan 2027 --> Jan 2028 | Trial primary completion date: Jan 2025 --> Jan 2026

No abstract available

P2, N=54, Active, not recruiting, Intergroupe Francophone de Cancerologie Thoracique | Recruiting --> Active, not recruiting | N=84 --> 54 | Trial completion date: Jan 2026 --> Feb 2027

P1, N=162, Completed, MacroGenics | Active, not recruiting --> Completed

Our report highlights attention to details, judicious use of immunostains, and ancillary molecular studies in complex pathology cases. Cytohistological findings are also correlated with molecular test results.

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.

P1, N=16, Recruiting, Centre Hospitalier Universitaire Vaudois | Trial completion date: Sep 2024 --> Jun 2027 | Trial primary completion date: Sep 2024 --> Jun 2027

P3, N=136, Recruiting, Beijing Pearl Biotechnology Limited Liability Company | Active, not recruiting --> Recruiting

Combination therapy targeting RET and ROS1 using pralsetinib and lorlatinib achieved a partial response with limited durability of only four months. This is the first reported case of a RET fusion as a potential mechanism of resistance to lorlatinib, it identifies a novel RET fusion partner, and it emphasizes the importance of testing for acquired resistance mutations with both DNA and RNA at the time of progression in patients with targetable oncogenic drivers.

P2, N=107, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2025 --> Jan 2026

In contrast, rwRFS significantly improved for patients without common mutations (HR 0.342, 95 % CI 0.203 - 0.577, p< 0.001). These findings suggest that consolidation durvalumab may not be beneficial for patients with common driver mutations, underscoring the need for personalized treatment strategies in this population.

PE cfDNA genotyping has clinical applicability for NSCLC patients and can serve as an additional source for molecular testing. Incorporating PE NGS cfDNA analysis into genetic testing enhances diagnostic yield and aids in identifying actionable mutations in clinical practice.

P2, N=534, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Apr 2025 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

The upregulation of GJB2 may serve as a prognostic biomarker, along with IL20RB, a known mediator of bone metastases. Furthermore, TDFP1 and ISL1 were identified as relevant transcription factors that could potentially regulate the biological processes in ROS1-rearranged NSCLC.

We reported a case of lung adenocarcinoma without driver alteration that developed resistance to pembrolizumab and newly emerged CD74-ROS1 fusion, and achieved a partial response after entrectinib treatment. We propose that new therapeutic targets may emerge for this patient population following long-term immunotherapy. Thus, we advocate for regular monitoring of tumor genetic status, which could yield unexpected benefits.

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.

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.

The patient presented with upper airway obstruction, which was an asthma mimic. The tumour demonstrated rapid recurrence after mechanical coring, which subsequently controlled with radiotherapy.

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

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

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.

Oral administration of entrectinib was highly effective, and his serum carcinoembryonic antigen (CEA) level improved from 247 to 10.8 ng/mL. The present case has clinical significance because a pathological and genetic diagnosis was made from the pericardial effusion fluid, and the clinical manifestations of cardiac tamponade due to lung cancer were well controlled by the administration of entrectinib.

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.

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

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.

Our study showed the heterogeneity in PD-L1 expression with respect to major oncogenic drivers in Turkey. KRAS, BRAF, MET mutations and ALK and ROS1 rearrangements were more frequent, while EGFR and HER2 mutations were less frequent compared with the overall PD-L1 expression levels. Molecular testing of non-small cell lung carcinomas (NSCLC) for oncogenic driver mutations has become standard in pathology practice.

Multiple tyrosine kinase inhibitors (TKIs) are now available for the effective treatment of ROS1-rearranged NSCLC in the metastatic setting including crizotinib, entrectinib, and repotrectinib as first-line therapy options. In addition, newer targeted therapies with increased selectivity for ROS1 over other targets are also emerging. As treatment of the disease continues to evolve, understanding the clinical course of patients with ROS1-rearranged NSCLC as well as the data supporting the latest therapy options is key to timely, effective, and longitudinal care.

The patient was ultimately diagnosed with ROS1 rearranged lung adenocarcinoma and achieved a dramatic response with entrectinib. This case highlights the variable presentation of non-small cell lung cancer (NSCLC) and the importance of comprehensive molecular testing for newly diagnosed metastatic NSCLC.

Notably, individuals with exclusive reciprocal rearrangements of RET or ROS1 might be less prone to co-mutations in TP53, ATM, and ARID1A, than are those with detectable activating rearrangements. This emphasizes the significance of evaluating co-mutations in DNA repair genes alongside fusions to refine treatment approaches.

For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

P2, N=114, Active, not recruiting, Assistance Publique Hopitaux De Marseille | Recruiting --> Active, not recruiting | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Oct 2023 --> Oct 2024

P2, N=12, Active, not recruiting, Oncology Institute of Southern Switzerland | Recruiting --> Active, not recruiting | N=20 --> 12 | Trial completion date: Dec 2022 --> Dec 2024

We discuss the role of NGS as well as its potential benefit in patients with unresectable, ALK-negative metastatic disease. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment.

Among patients who exhibited resistance to crizotinib, follow-up treatment of entrectinib and lorlatinib showed remarkable survival benefits. Newer-generation ALK/ROS1-targeted drugs showed efficacy in a cohort of crizotinib resistant ROS1 + patients. These results, when validated, could assist efficiently accruing ROS1 + patients.

The improvement of the non-tertiary hospital pathology departments' detection capabilities and the physicians' awareness are needed for enhancing the rate of genomic testing and targeted therapy in NSCLC patients in China.

In this study we knock-in for the first time in a ROS1 + patient-derived cell line, three different known resistance-causing mutations using CRISPR/Cas9 in the endogenous translocated ROS1 alleles. Pharmacological assays performed in 2D and 3D cell culture revealed that spheroids are more sensitive to TKIs than cells cultured as a monolayer. This direct comparison between two culture systems could be done thanks to the implementation of normalized growth rates (NGR) to uniformly quantify drug response between 2D and 3D cell culture. Overall, this study presents the added value of using spheroids and positions lorlatinib and repotrectinib as the most effective TKIs against the studied ROS1 resistance point mutations.

In patients without known driver oncogenes, mutations associated with approved therapeutic implications were detected in 12.0%. The detection of gene rearrangements using liquid biopsy may be limited compared with genetic mutations.

The knowledge of molecular drivers is of great interest in the field of melanocytic diagnostics, and it is important to consider that in addition to immunohistochemistry, molecular techniques such as FISH, PCR, and/or NGS are essential to confirm and classify the different patterns of mutation. Future studies with large case series and molecular sequencing techniques are needed to allow for a more complete and comprehensive understanding of the role of fusion kinases in the spitzoid tumor family.

P2, N=132, Recruiting, Shanghai Henlius Biotech | N=60 --> 132

P2, N=107, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=117, Recruiting, Fox Chase Cancer Center | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=162, Active, not recruiting, MacroGenics | Trial completion date: Sep 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Jul 2024