ALK (Anaplastic lymphoma kinase)

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.

Combining cases from our oncology center and previous literature, we found that NSCLC patients with coexisting ALK fusion mutations and other mutations have poorer response to targeted therapy and poorer prognosis, and we also compared the efficacy rates of various types of coexisting mutations for different treatment regimens. Therefore, this review can help to evaluate the prognosis of NSCLC patients with coexisting mutations and the efficacy of targeted therapies and to find more favorable treatment options for patients with this type of coexisting mutations.

Genomic profiling of sarcomas offers valuable insights into their molecular drivers and can support personalized therapeutic approaches. Further research is needed to validate these findings and optimize treatment strategies for sarcoma patients.

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.

P2, N=40, Recruiting, ImmunityBio, Inc. | Active, not recruiting --> Recruiting | N=147 --> 40

EGFR mutations, especially rare variants (G724A, L747P, Q701 L, G719C, V769 L and S768I), exhibited significant enrichment in the non-AM group (P<0.001)...Meanwhile, patients with adrenal metastases harboring ALK or KRAS mutations have a poor prognosis and require more aggressive treatment. The TNF and TGF-β pathways might be associated with adrenal metastasis.

The lack of association between molecular alteration status and recurrence risk prevailed after multivariable adjustment for tumor stage and perioperative treatment (P=0.82 for KRAS G12C mutation and P=0.43 for any other molecular alteration). NSCLC patients with resected tumors that harbor molecular alterations have the same recurrence risk as patients with tumors without molecular alterations if treated with surgery plus chemotherapy when indicated.

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.

The authors review the sparse literature on molecular-genetic aberrations involving the epidermal growth factor receptor family of receptor tyrosine kinases (ERBB1/EGFR, ERBB2, ERBB3, and ERBB4) in uterine mesenchymal tumors, a review that suggests that such tumors may be pathologically heterogeneous. The potential clinical significance of demonstrating a targetable ERBB2/ERBB3 tyrosine kinase mutation or other EGFR family aberrations, as well as its distinctive pathologic profile, supports the segregation of the tumor reported herein as a distinct and emerging entity.

No abstract available

P1, N=230, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Feb 2025 --> Jun 2025 | Trial primary completion date: Feb 2025 --> Jun 2025

This study is the largest clinical study to date utilizing the TSO 500. It provides an opportunity to further characterize the landscape of NSCLC using this newer technology and show its clinical utility in detecting known and novel facets of NSCLC to inform treatment decision-making.

P=N/A, N=825, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

In our patient with SGC, NGS revealed a GPHN-ALK variant that allowed off-label treatment with alectinib, with a remarkable response in primary and metastatic foci. Similarly, the use of NGS in a cutaneous neoplasm in which no definitive diagnosis could be reached by pathology and which had progressed through standard of care treatment elucidated a PIK3CA mutation in which alpelisib was added and ultimately halted POD. Here, we discuss the use of NGS, future projections, and our recommendations.

Ultimately, the patient was diagnosed with primary unilateral adrenal anaplastic large cell lymphoma. Although he achieved complete response to chemotherapy, he died 4 months after complete response due to cholecystitis and lymphoma recurrence.

P2, N=401, Active, not recruiting, AstraZeneca | Trial completion date: Sep 2024 --> Sep 2025

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

P1/2, N=20, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Feb 2026 --> Jan 2025

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.

P2, N=11, Terminated, MedPacto, Inc. | N=55 --> 11 | Trial completion date: Dec 2025 --> Aug 2024 | Recruiting --> Terminated | Trial primary completion date: Aug 2022 --> Aug 2024; This is because Medpacto decided to modify its development strategy as the business and development environment changed.

High-throughput sequencing identified EWSR1::CREM fusion in case 1, whereas fluorescence in situ hybridization detected EWSR1::CREB1 fusion in case 2. These cases expand the morphological and immunophenotypic characteristics of malignant epithelioid tumors with EWSR1::CREB fusion, highlighting the diagnostic challenges of immunohistochemistry and value of molecular testing for accurate diagnosis.

Importantly, X4 exhibited high specificity in targeting ALK and ROS1 across a range of kinases. In an H2228 xenograft model, X4 achieved a tumor inhibition rate of 54.71 %, underscoring its considerable potential in ALK/ROS1 inhibition.

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

This real-world data analysis demonstrated that targeted therapies improve the survival of patients with NSCLC with actionable mutations, which supports a recommendation for widening access to broad-based genomic testing and targeted therapies.

P2, N=29, Completed, Zhejiang Cancer Hospital | Recruiting --> Completed | Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Dec 2021 --> Sep 2024

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

The results of this study suggest that pyrrolitinib is a safe and effective therapeutic option that can significantly improve the outcome of HER2-positive breast cancer. More studies are needed to further validate this finding.

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

P3, N=900, Recruiting, Genmab | Trial primary completion date: Sep 2028 --> Jun 2027

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.

In NSCLC, therapies such as osimertinib have improved efficacy in treating EGFR-mutant BM, with emerging combinations such as amivantamab and lazertinib offering promising alternatives for patients resistant to frontline therapies. In HER2-positive breast cancer, significant advancements with tucatinib and trastuzumab deruxtecan (T-DXd) have transformed the treatment landscape, achieving improved survival and intracranial control in patients with BM. Similarly, in triple-negative breast cancer (TNBC), novel therapies such as sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) offer new hope for managing BM. For melanoma, the combination of immune checkpoint inhibitors such as nivolumab and ipilimumab has proven effective in enhancing survival for patients with BM, both in BRAF-mutant and wild-type cases...Future research should optimise combination therapies, overcome resistance, and refine treatment sequencing. Continued emphasis on personalized, biomarker-driven approaches offers the potential to further improve outcomes, even for complex cases.

P4, N=50, Completed, Samsung Medical Center | Recruiting --> Completed

P1, N=36, Recruiting, Transgene | Trial completion date: Mar 2025 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

Significant differences occurred in PFS on the basis of PD-L1 expression with values of 13.6 (95% CI: 10.5-NA), 18.7 (95% CI: 15.1-26.9), and 24.7 (95% CI: 20.7-NA) months for TPS of 0, 1-49, and 50 or higher, respectively (p = 0.02). Durvalumab maintenance therapy after definitive CCRT in unresectable locally advanced NSCLC patients with EGFR or ALK mutation demonstrates comparable clinical outcomes to those with wild-type EGFR/ALK when PD-L1 expression is present.

Female patients encounter more severe toxicity due to higher alectinib exposure, which warrants further exploration. PPAR-α 209G>A significantly increased relevant alectinib-induced toxicity, most likely due to an increase in alectinib exposure. Pre-treatment testing for genetic variants with a subsequent dose reduction could provide a viable approach to reduce alectinib-related toxicity.

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.

In conclusion, results revealed generally unfavourable clinical presentations and outcomes with a diverse range of FH mutations. These findings, along with the histopathological and immunohistochemical features, can be used to guide diagnosis and treatment.