ALK mutation

P1, N=169, Completed, Astellas Pharma Global Development, Inc. | Phase classification: P1b --> P1

P=N/A, N=100, Completed, Chongqing University Three Gorges Hospital（Chongqing Three Gorges Central Hospital）; Chongqing University Three Gorges Hospital（Chongqing Three

P4, N=100, Not yet recruiting, Anhui Chest Hospital; Anhui Chest Hospital

P1/2, N=540, Not yet recruiting, Shanghai East Hospital; CSPC Megalith Biopharmaceutical Co., Ltd.

All first-line treatments applied pembrolizumab (median dose: 12 cycles)...Of the patients with PRs or CRs, 75% were treated with platinum plus pemetrexed...The current response to second-line platinum-based therapies for patients with advanced NSCLC after immunotherapy appears to achieve favourable response rates and be an optimal treatment after progression to immunotherapy. Prior immunotherapy appears to enhance these patients' platinum response, though future confirmatory studies are necessary.

We have therefore identified a number of case series and phase II trials using targeted therapy in resectable EGFR-mutant and ALK-fused NSCLC. Current evidence suggests that targeted therapies might be effective in patients with resectable EGFR-mutant and ALK-positive NSCLC, but ongoing trials will need to provide further evidence on the safety and efficacy of perioperative TKI therapy.

This Indian study identified novel somatic mutations and fusion genes in PTC, revealing a distinct genomic landscape with implications in precision diagnostics and personalized therapies. NGS with intraoperative live sampling shows promise in prognostication and therapeutic optimization of advanced/metastatic PTC cases.

No abstract available

NSCLC with co-expression of p40 and TTF1 exhibits distinct clinicopathological features, immunophenotypes, molecular alterations, and clinical outcomes, characterized by rapid progression and poor prognosis. Pathologists should be vigilant in recognizing this entity to avoid misdiagnosis and missed diagnosis.

Finally, intravenous injection of CIGB-300 in a cell line-based xenograft corroborated CIGB-300's anti-tumor effects and suggested concurrent in situ reductions of CSNK2ɑ subunit and downstream RPS6s235/236 phosphorylation. Overall, CIGB-300 therapeutic hypothesis and antineoplastic effects demonstrated herein, further support the evaluation of this clinical-grade CK2 inhibitor in advanced NSCLC with limited therapeutic options.

Patients with ALK mutant, BRAF mutant or NRAS mutant were more prone to metastasis, while the HER 2 mutation group was less metastatic. Patients with EGFR mutant NSCLC are more likely to develop bone, lung, or brain metastasis.

Among them, 16 patients received systemic chemotherapy based on etoposide, of which 13 cases could be evaluated for efficacy, 11 cases could be calculated for PFS...After SCLC transformation, the standard chemotherapy regimen for SCLC is generally used for treatment. The OS after SCLC transformation is related to the stage, and the prognosis is better in the limited stage.

Dose adjustment due to AEs occurred in 17.9% of patients. Anlotinib combined with WBRT is effective and well-tolerated in patients with NSCLC with multiple BMs.

After the initial treatment with ensartinib, the patient experienced intracranial disease progression...Subsequent thoracic RT resulted in a partial response of the primary tumor; however, new brain and bone metastases were detected, prompting a switch to lorlatinib...Despite pembrolizumab treatment, the patient's condition deteriorated, and she passed away...Our findings revealed heterogeneity in ALK mutations and responses to ALK-TKIs, necessitating the close monitoring of genetic subtypes and associated mutations for tailored treatment strategies. Maintaining a heightened awareness of potential intestinal metastasis and vigilance in monitoring intestinal symptoms and abdominal metastases are pivotal for managing advanced lung adenocarcinoma.

Pulmonary sarcomatoid carcinoma (PSC) is a rare disease with strong aggressiveness, low response rates to treatment, short survival span and poor prognosis, belonging to a group of non-small cell lung carcinomas (NSCLC) that remains incompletely understood. Here, we presented three PSC cases with epidermal growth factor receptor (EGFR) L858R, BRAF V600E and ALK mutations respectively, described their clinical characteristics and conducted a review of literature, in order to improve its therapeutic level, which also provided evidence-based medical evidence for driver gene screening and molecular targeted drug application in PSC patients.

The tight binding of TPX-0131 to residues Arg1202, Met1199 and Arg1120 contribute significantly to overcoming lorlatinib resistance in ALKL1196M/G1202R mutant. These research results are expected to offer insights into the mechanism of TPX-0131 in treating ALKG1202R/L1196M-induced NSCLC resistance and optimizing of ALK inhibitors.

P2, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: Feb 2025 --> Feb 2026

Administration in combination with PPIs, amlodipine, and magnesium oxide significantly increases the risk of ILD. These results provide risk prediction for ILD related to ALK TKIs and support pharmacovigilance to promote safe prescribing in oncology.

The results of the in vitro stability experiment showed that the selected mixed micelle (F6) was stable at both room temperature and 4 °C, with only minor changes in size and PDI. Our results indicate great potential for the developed Soluplus-TPGS mixed micelles as a delivery system for BGT.

P4, N=14, Pfizer, Inc

Subsequent in vitro bioassay of the top 40 hits identified two compounds with low micromolar IC50 values. Remarkably, one of the identified leads possesses a novel chemotype compared to known ALK inhibitors.

P1, N=56, Completed, Haihe Biopharma Co., Ltd. | Unknown status --> Completed | N=113 --> 56

ORNi-PCR followed by ddPCR/real-time PCR enables highly sensitive and accurate detection of ALK mutations by liquid biopsy. Although the clinical data are limited, our results show that these methods are potentially useful for identifying ALK-TKI-resistant NSCLC at the early recurrent phase.

Similarly, more frequent surveillance imaging than what is considered standard-of-care may identify disease progression earlier than what is expected in real-world clinical practice and therefore embellish the magnitude of benefit between a targeted therapy and the control arm. While targeted therapies have provided clinical benefit for individuals with oncogenic driven NSCLC, physicians and patients must be cognizant that clinical trial deviations from standard-of-care imaging practices may have embellished the magnitude of benefit for several of these therapies.

P1, N=102, Recruiting, Bayer | Trial primary completion date: Jul 2025 --> Mar 2027

In PD-L1 TPS ≥50% EGFR/ALK wild-type patients, only patients who have never smoked benefited from first-line Chemo-IO over IO-alone, suggesting IO-alone may be preferable for patients with smoking history to spare chemotherapy toxicity. Tobacco-related mutational signature may potentially reduce stigma, improve patient stratification, and guide more precise IO-based treatment in patients with NSCLC.

P1/2, N=180, Active, not recruiting, Genprex, Inc. | Trial completion date: Nov 2028 --> Dec 2025 | Trial primary completion date: Nov 2027 --> Dec 2024

This gap may be driven by the under-representation of important patient populations, including populations defined by clinical or molecular characteristics. In this review, we summarize the data outlining the evidence of ICIs in patients with poor Eastern Cooperative Oncology Group performance status (ECOG PS), underlying autoimmune disease (AID), older age, active brain metastases (BMs), and molecular aberrations such as EGFR mutations, ALK fusions, BRAF mutations and ROS1 fusions.

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.

Zotizalkib (TPX-0131), a fourth-generation macrocyclic anaplastic lymphoma kinase (ALK) inhibitor, is designed to overcome resistance due to secondary ALK mutations in non-small cell lung cancer (NSCLC)...ABCB1-mediated efflux of zotizalkib was completely inhibited by elacridar, a dual ABCB1/ABCG2 inhibitor, increasing brain exposure without any signs of acute CNS-related toxicities...Notably, the hepatic expression of human CES1 did not affect zotizalkib plasma exposure or tissue distribution. The obtained pharmacokinetic insights may be useful for the further development and optimization of therapeutic efficacy and safety of zotizalkib and related compact macrocyclic ALK inhibitors.

P2, N=49, Active, not recruiting, Sun Yat-sen University | Recruiting --> Active, not recruiting

P=N/A, N=100, Not yet recruiting, Peking University People's Hospital; Peking University People's Hospital

P4, N=100, Not yet recruiting, Huai'an First People's Hospital; Huai'an First People's Hospital

P=N/A, N=186, Recruiting, Yongchang Zhang | Trial primary completion date: Jan 2024 --> Jan 2025

Massive parallel sequencing and personalized therapeutic targets for personalized mutational status might allow patients with adenosquamous carcinomas to improve survival at the different levels of progression. Adapted criteria in the classification recognized by WHO 2021, which tumoural cellular level sub-classification might be a particular sub-typing with particular outcomes as exemplified in the present mutational exercise. This small series, defined after routine IHC classification correlated with tumoural heterogeneity/clonality previewed for adenosquamous carcinoma.

KRAS is an attractive therapeutic strategy due to its high prevalence and its role in initiating and sustaining tumour growth. Approval of KRAS G12C inhibitors in locally advanced or metastatic NSCLC has brought hope to many patients. Studies show that non G12C KRAS mutation are found in 53% of adenocarcinomas.

Oncogenic activation of genes-drivers are responsible for resistance mechanisms either understood has resistance to METtargeted therapies and as primary resistance. Recently it has been reported that PI3K pathway alteration is common in concomitancy with METex14 and believed that confers primary resistance to MET TKI. Early identification of alterations in MET kinase domain at diagnosis, is crucial for understanding progression and resistance mechanism, to develop novel therapies or to design treatment strategies in order to improve patient outcomes.

Emerging biomarkers with the potential for clinical actionability across tumor types include gene fusions involving NRG1, FGFR1/2/3, BRAF, and ALK, mutations in TP53 Y220C, KRAS G12C, FGFR2/3, and BRAF non-V600 (Class II). We explore the growing evidence for clinical actionability of these biomarkers in patients with advanced solid tumors.

We present a female advanced non-small cell lung cancer (NSCLC) case with positive EML4-ALK gene fusion, in which disease progression occurred in only 3 months after first-line treatment with alectinib...Ensartinib and ceritinib were administered as second-line and third-line treatments...The secondary mutation E803Q located in exon 14 seems resistant to most second-generation ALK-TKIs. If there is an opportunity, the efficacy of the third-generation ALK-TKI loratinib should be tested.

The patient was treated with lorlatinib as the first-line treatment. This case is the first to describe the effectiveness of lorlatinib in treating an advanced high-grade PMEC with EML4-ALK fusion V2 mutation patient.

These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion-positive non-small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers.

PMEC combined with ALK mutation is an extremely rare primary lung cancer, and the diagnosis is mainly based on pathology, histology and immunohistochemistry. The application of molecularly targeted drugs to patients with mutations can significantly improve the prognosis of patients with PMEC, which is expected to be a new breakthrough in the treatment of PMEC.