Current knowledge of small cell lung cancer transformation from non-small cell lung cancer.

Lung cancer is the leading cause of cancer related death, and is divided into two major histological subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Histological transformation from NSCLC to SCLC has been reported as a mechanism of treatment resistance in patients who received tyrosine kinase inhibitors (TKIs) targeting EGFR, ALK and ROS1 or immunotherapies. The transformed histology could be due to therapy-induced lineage plasticity or clonal selection of pre-existing SCLC cells. Evidence supporting either mechanism exist in the literature. Here, we discuss potential mechanisms of transformation and review the current knowledge about cell of origin of NSCLC and SCLC. In addition, we summarize genomic alterations that are frequently observed in both "de novo" and transformed SCLC, such as TP53, RB1 and PIK3CA. We also discuss treatment options for transformed SCLC, including chemotherapy, radiotherapy, TKIs, immunotherapy and anti-angiogenic agents.

Successful Crizotinib-targeted Therapy of Pediatric Unresectable ERC1::ALK Fusion Sarcoma.

Anaplastic lymphoma kinase ( ALK )-fusion sarcomas are rare part of the emerging theoretically targetable tyrosine kinase RAS::MAPK pathway fusion myopericytic-ovoid sarcomas. We report our clinicopathologic and treatment experience with an ALK fusion sarcoma. A novel ELKS/RAB6-interacting/CAST family member 1 - unaligned ALK fusion infiltrative nonmetastatic low-grade sarcoma of the right hand of a 15-month-old male was treated with crizotinib, an ALK tyrosine kinase inhibitor as oral monotherapy, inducing complete radiographic and clinical resolution by 10 months and sustained response now over 12 months after elective discontinuation. Crizotinib can successfully be used to treat unresectable novel ALK fusion sarcomas.

[China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)].

Anaplastic lymphoma kinase (ALK) fusion represents one of pivotal driver genes within the realm of non-small cell lung cancer (NSCLC). ALK-tyrosine kinase inhibitors (ALK-TKI) have demonstrated remarkable therapeutic efficacy for patients afflicted with ALK-positive NSCLC. As of June 27, 2023, seven ALK-TKI, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib, have garnered approval from the China National Medical Products Administration (NMPA)(ranking according to the approval time for marketing by NMPA), providing individualized treatment modalities for ALK-positive NSCLC patients. To standardize the application of ALK-TKI, the Chinese Association for Clinical Oncologists and the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care has organized experts to compile the " China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)". This treatment expert recommendation provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese advanced ALK fusion-positive NSCLC.

Precision medicine in non-small cell lung cancer: Current applications and future directions.

Advances in biomarkers, targeted therapies, and immuno-oncology have transformed the clinical management of patients with advanced NSCLC. For oncogene-driven tumors, there are highly effective targeted therapies against EGFR, ALK, ROS1, BRAF, TRK, RET, and MET. In addition, investigational therapies for KRAS, NRG1, and HER2 have shown promising results and may become standard-of-care in the near future. In parallel, immune-checkpoint therapy has emerged as an indispensable treatment modality, especially for patients lacking actionable oncogenic drivers. While PD-L1 expression has shown modest predictive utility, biomarkers for immune-checkpoint inhibition in NSCLC have remained elusive and represent an area of active investigation. Given the growing importance of biomarkers, optimal utilization of small tissue biopsies and alternative genotyping methods using circulating cell-free DNA have become increasingly integrated into clinical practice. In this review, we will summarize the current landscape and emerging trends in precision medicine for patients with advanced NSCLC with a special focus on predictive biomarker testing.

Integration of Multi-omic Data in a Molecular Tumor Board Reveals EGFR-Associated ALK-Inhibitor Resistance in a Patient With Inflammatory Myofibroblastic Cancer.

Inflammatory myofibroblastic tumors (IMTs) are intermediate-grade mesenchymal neoplasms commonly characterized by chromosomal rearrangements causing constitutive activation of anaplastic lymphoma kinase (ALK) and/or ALK mutations causing reduced sensitivity to ALK tyrosine kinase inhibitors (TKI). We present a patient with an IMT who initially responded to first-line alectinib, but who later suffered disease relapse and presently survives with moderate residual disease after receiving second-line lorlatinib. Biopsy specimens were analyzed using next generation sequencing (DNA-seq and RNA-seq) and reverse phase protein microarray (RPPA) as part of an institutional Molecular Tumor Board (MTB) study. An EML4-ALK rearrangement and EGFR activation (pEGFRY1068) were present in both the primary and recurrent tumors, while a secondary ALK I1171N mutation was exclusive to the latter. EGFR signaling in the background of a secondary ALK mutation is correlated with reduced ALK TKI sensitivity in vitro, implicating an important mechanism of drug resistance development in this patient. The RPPA results also critically demonstrate that ALK signaling (ALKY1604) was not activated in the recurrent tumor, thereby indicating that standard-of-care use of third- or fourth-line ALK TKI would not likely be efficacious or durable. These results underscore the importance of real-time clinical integration of functional protein drug target activation data with NGS in the MTB setting for improving selection of patient-tailored therapy.

Unfavorable immunotherapy plus tyrosine kinase inhibition outcome of metastatic renal cell carcinoma after radical nephrectomy with increased ADAM9 expression.

Immunotherapy plus tyrosine kinase inhibitor (IO-TKI) has become the standard first-line therapy for advanced renal cell carcinoma (RCC). However, the modest response rate of IO-TKI therapy and the absence of biomarkers limited the selection of treatment strategies for RCC patients. There were three cohorts enrolled: two from our facility (ZS-MRCC and ZS-HRRCC) and one from a clinical study (JAVELIN-101). By RNA sequencing, the expression of ADAM9 in each sample was measured. By flow cytometry and immunohistochemistry, immune infiltration and T cell function were examined. Primary outcomes were established as treatment response and progression-free survival (PFS). Patients with low-ADAM9 expression had a higher objective response rate (56.5% vs 13.6%, P = 0.01) and longer PFS in both cohorts. In the ZS-HRRCC cohort, the expression of ADAM9 was associated with increased tumor-infiltrating T cells, which was proved by immunohistochemistry (P < 0.05) and flow cytometry (Spearman's ρ = 0.42, P < 0.001). In the high-ADAM9 group, CD8+ and CD4+ T cells revealed an exhausted phenotype with decreased GZMB (Spearman's ρ = - 0.31, P = 0.05, and Spearman's ρ = - 0.49, P < 0.001, respectively), and fewer Macrophages were identified. A predictive RFscore was further constructed by random forest approach, involving ADAM9 and immunologic genes. Only in the subgroup with the lower RFscore did IO-TKI outperform TKI monotherapy. High-ADAM9 expression was associated with immunosuppression and IO-TKI resistance. Expression of ADAM9 was also associated with the exhaustion and dysfunction of T cells. ADAM9-based RFscore has the potential to be used as a biomarker to distinguish the optimal patient treatment methods between IO-TKI and TKI monotherapy.

Efficacy and safety of iruplinalkib (WX-0593) in ALK-positive crizotinib-resistant advanced non-small cell lung cancer patients: a single-arm, multicenter phase II study (INTELLECT).

BACKGROUND: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. METHODS: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). RESULTS: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. CONCLUSIONS: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. TRIAL REGISTRATION: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.

ROS1 as a possible prognostic biomarker of cervical adenocarcinoma: An exploratory analysis with next-generation sequencing.

OBJECTIVES: Given the differences in clinical and biological characteristics between cervical adenocarcinoma and squamous cell carcinoma, this study aimed to conduct an exploratory analysis to examine the molecular characteristics of cervical adenocarcinoma in a Japanese population. METHODS: This study explored the simultaneous testing of multiple mutations targeting cervical adenocarcinoma using next-generation sequencing (NGS). The following genes were analyzed: BCAR4, CD274, PDCD1LG2, KRAS, ARID1A, PTEN, ALK, EGFR, ROS1, BRAF, PIK3CA, EP300, EBXW7, SHCBP1, TGFBR2, SMAD4, ERBB2, ERBB3, and KLF5. Tumor tissue and blood samples were obtained at the time of primary treatment. The NGS-based molecular profiles obtained from Tokai University (49 specimens) were compared with the registered data in The Cancer Genome Atlas (TCGA) database (133 specimens). RESULTS: The study cohort had higher rates of adenocarcinoma than the TCGA cohort (44.9% vs. 18.0%; P = 0.001). The adenocarcinomas in the study cohort had more alterations in ROS1, EGFR, EP300, SHCBP1, ALK, and PIK3CA than those in the TCGA cohort. Among them, ROS1 had the highest number of gene alterations (median, 7.00 ± 2.63). In the study cohort, patients with a high number of ROS1 alterations had a significantly higher recurrence rate (5-year recurrence rate, 48.8% vs. 14.6%; hazard ratio [HR], 4.32; 95% confidence interval [CI], 1.20-15.50; P = 0.014) and lower overall survival than those with low alterations (5-year survival rate, 70.7% vs. 93.1%; HR, 7.15; 95% CI, 1.08-58.22; P = 0.032). CONCLUSION: The current exploratory analysis suggests that ROS1 gene alteration may be a prognostic biomarker in cervical adenocarcinoma in Japanese patients.

Effectiveness of crizotinib in patients with ROS1-positive non-small-cell lung cancer: real-world evidence in Japan.

Aim: Crizotinib, approved in Japan (2017) for ROS1-positive NSCLC, has limited real-world data. Materials & methods: Crizotinib monotherapy real-world effectiveness and treatment status were analyzed from claims data (June 2017-March 2021; Japanese Medical Data Vision; 58 patients tested for ROS1-NSCLC). Results: Median duration of treatment ([DoT]; primary end point), any line: 12.9 months; 22 patients on crizotinib, 23 discontinued, 13 receiving post-crizotinib treatment. 1L (n = 27) median DoT: 13.0 months (95% CI, 4.4-32.0 months); 13 patients on crizotinib; seven discontinued; seven receiving post-crizotinib treatment. 2L (n = 13) median DoT: 14.0 months (95% CI, 4.6-22.2 months); 2L+ (n = 31): nine patients on crizotinib; 16 discontinued; six receiving post-crizotinib treatment. Post-crizotinib treatments (chemotherapy, cancer immunotherapy, anti-VEGF/R) did not affect crizotinib DoT. Conclusion: Data supplement crizotinib's effectiveness in ROS1-positive NSCLC previously seen in clinical trials/real-world.

Non-small-cell lung cancer (NSCLC) is a common type of cancer in the lung that is often caused by mutations in specific genes in the DNA. One type of NSCLC occurs when you have mutations in a gene called ROS1, whose normal function is not well understood. Crizotinib, an oral medicine, was approved in Japan for the treatment of NSCLC with mutations in ROS1 in 2017; however, this was based upon data from controlled clinical trials. This study was looking at crizotinib use in Japan based upon claims data from the Japanese Medical Data Vision database, which captures all use of medications provided in Japan. Data was collected from June 2017 to March 2021 for 58 Japanese patients who had NSCLC, tested positive for ROS1 mutations, and received crizotinib. Patients took crizotinib for a median of 13.0 months as a first treatment option and 14.0 months as a second treatment option for their NSCLC. The type of and duration of anticancer treatments given before crizotinib did not have an effect on the length of time crizotinib was used. Other treatments outside of crizotinib were given before or after crizotinib and include chemotherapy, therapy that modifies the immune system to treat cancer, or treatments that inhibit the growth of blood vessels that help the cancer grow/spread. Together, these real-world data provide evidence supporting the use of crizotinib in the treatment of patients with NSCLC and ROS1 mutations.

Genetic determinants of lung cancer: Understanding the oncogenic potential of somatic missense mutations.

BACKGROUND: Treatment of lung cancer is getting more personalized nowadays and medical practitioners are moving away from conventional histology-driven empirical treatments, platinum-based chemotherapy, and other invasive surgical resections and have started adopting alternate therapies in which therapeutic targets are patient's molecular oncogenic drivers. AIM: The aim of the current study is to extract meaningful information from the online somatic mutation data (retrieved from cBioPortal) of 16 most significantly mutated oncogenes in non-small-cell lung cancer (NSCLC), namely EGFR, NRAS, KRAS, HER2 (ERBB2), RET, MET, ROS1, FGFR1, BRAF, AKT1, MEK1 (MAP2K1), PIK3CA, PTEN, DDR2, LKB1 (STK11) and ALK, for improving our understanding of the pathobiology of the lung cancer that can aid decision-making on critical clinical and therapeutic considerations. METHODS: Using an integrated approach comprising 4 steps, the oncogenic potential of 661 missense non-synonymous single nucleotide polymorphisms (nsSNPs) in 16 genes was ascertained using 2059 NSCLC (1575 lung adenocarcinomas, 484 lung squamous cell carcinomas) patients' online mutation data. The steps used comprise sequence/structure homology-based prediction, scoring of conservation of mutated residues and positions, prediction of resulting molecular and functional consequences using machine-learning and structure-guided approach. RESULTS: Out of a total of 661 nsSNPs analyzed, a set of 29 nsSNPs has been identified as conserved high confidence mutations in 10 of 16 genes relevant to the under study. Out of 29 conserved high confidence nsSNPs, 4 nsSNPs (EGFR N1094Y, BRAF M620I, DDR2 R307L, ALK P1350T) have been found to be putative novel rare genetic markers for NSCLC. CONCLUSIONS: The current study, the first of its kind, has provided a list of deleterious non-synonymous somatic mutations in a selected pool of oncogenes that can be considered as a promising target for future drug design and therapy for patients with lung adenocarcinomas and squamous cell carcinomas.

[Chinese Medical Association guideline for clinical diagnosis and treatment of lung cancer (2023 edition)].

To standardize the prevention and clinical management of lung cancer, improve patients' survival outcomes, and offer professional insight for clinicians, the Oncology Society of Chinese Medical Association has summoned experts from departments of pulmonary medicine, oncology, thoracic surgery, radiotherapy, imaging, and pathology to formulate the Oncology Society of Chinese Medical Association guideline for clinical diagnosis and treatment of lung cancer in China (2023 edition) through consensus meetings. Updates in this edition include 1) cancer screening: deletion of high-risk traits of lung cancer based on epidemiological investigations in the Caucasian population, while preserving features confirmed by research on the Chinese population. Advice on screening institutions is also added to raise awareness of the merits and demerits of lung cancer screening through detailed illustrations. 2) Principles of histopathologic evaluation: characteristics of four types of neuroendocrine tumors (typical carcinoid, atypical carcinoid, large cell carcinoma, and small cell carcinoma) are reviewed. 3) Surgical intervention: more options of resection are available for certain peripheral lesions based on several clinical studies (CALGB140503, JCOG0802, JCOG1211). 4) neoadjuvant/adjuvant therapy: marked improvement in the prognosis of non-small cell lung cancer (NSCLC) patients receiving neoadjuvant immunotherapy are reviewed; more options for consolidation immunotherapy after radiochemotherapy have also emerged. 5) Targeted and immune therapy: tyrosine kinase inhibitors of sensitive driver mutations such as EGFR and ALK as well as rare targets such as MET exon 14 skipping, RET fusion, ROS1 fusion, and NTRK fusion have been approved, offering more treatment options for clinicians and patients. Furthermore, multiple immune checkpoint inhibitors have been granted for the treatment of NSCLC and SCLC, resulting in prolonged survival of late-stage lung cancer patients. This guideline is established based on the current availability of domestically approved medications, recommendations of international guidelines, and present clinical practice in China as well as integration of the latest medical evidence of pathology, genetic testing, immune molecular biomarker detection, and treatment methods of lung cancer in recent years, to provide recommendations for professionals in clinical oncology, radiology, laboratory, and rehabilitation.

[Chinese Medical Association guideline for clinical diagnosis and treatment of lung cancer (2023 edition)].

To standardize the prevention and clinical management of lung cancer, improve patients' survival outcomes, and offer professional insight for clinicians, the Oncology Society of Chinese Medical Association has summoned experts from departments of pulmonary medicine, oncology, thoracic surgery, radiotherapy, imaging, and pathology to formulate the Chinese Medical Association Guideline for Clinical Diagnosis and Treatment of Lung Cancer in China (2023 edition) through consensus meetings. Updates in this edition include 1) cancer screening: deletion of high-risk traits of lung cancer based on epidemiological investigations in the Caucasian population, while preserving features confirmed by research on the Chinese population. Advice on screening institutions is also added to raise awareness of the merits and demerits of lung cancer screening through detailed illustrations. 2) Principles of histopathologic evaluation: characteristics of four types of neuroendocrine tumors (typical carcinoid, atypical carcinoid, large cell carcinoma, and small cell carcinoma) are reviewed. 3) Surgical intervention: more options of resection are available for certain peripheral lesions based on several clinical studies (CALGB140503, JCOG0802, JCOG1211). 4) neoadjuvant/adjuvant therapy: marked improvement in the prognosis of non-small cell lung cancer (NSCLC) patients receiving neoadjuvant immunotherapy are reviewed; more options for consolidation immunotherapy after radiochemotherapy have also emerged. 5) Targeted and immune therapy: tyrosine kinase inhibitors of sensitive driver mutations such as EGFR and ALK as well as rare targets such as MET exon 14 skipping, RET fusion, ROS1 fusion, and NTRK fusion have been approved, offering more treatment options for clinicians and patients. Furthermore, multiple immune checkpoint inhibitors have been granted for the treatment of NSCLC and SCLC, resulting in prolonged survival of late-stage lung cancer patients. This guideline is established based on the current availability of domestically approved medications, recommendations of international guidelines, and present clinical practice in China as well as integration of the latest medical evidence of pathology, genetic testing, immune molecular biomarker detection, and treatment methods of lung cancer in recent years, to provide recommendations for professionals in clinical oncology, radiology, laboratory, and rehabilitation.

Effectiveness of crizotinib versus entrectinib in ROS1-positive non-small-cell lung cancer using clinical and real-world data.

Aims: To compare clinical trial results for crizotinib and entrectinib in ROS1-positive non-small-cell lung cancer and compare clinical trial data and real-world outcomes for crizotinib. Patients & methods: We analyzed four phase I-II studies using a simulated treatment comparison (STC). A STC of clinical trial versus real-world evidence compared crizotinib clinical data to real-world outcomes. Results: Adjusted STC found nonsignificant trends favoring crizotinib over entrectinib: objective response rate, risk ratio = 1.04 (95% CI: 0.85-1.28); median duration of response, mean difference = 16.11 months (95% CI: -1.57- 33.69); median progression-free survival, mean difference = 3.99 months (95% CI: -6.27-14.25); 12-month overall survival, risk ratio = 1.01 (95% CI: 0.90-1.12). Nonsignificant differences were observed between the trial end point values and the real-world evidence for crizotinib. Conclusions: Crizotinib and entrectinib have comparable efficacy in ROS1-positive non-small-cell lung cancer.

ROSALINE: a phase II, neoadjuvant study targeting ROS1 in combination with endocrine therapy in invasive lobular carcinoma of the breast.

Invasive lobular carcinoma (ILC) is the most common histologic subtype of breast cancer after invasive ductal carcinoma (i.e., no special type [NST]). ILC differs from NST in clinical presentation, site-specific metastases and response to conventional therapies. Loss of E-cadherin protein expression, due to alterations in its encoding gene CDH1, is the most frequent oncogenic event in ILC. Synthetic lethality approaches have shown promising antitumor effects of ROS1 inhibitors in models of E-cadherin-defective breast cancer in in vivo studies and provide the rationale for testing their clinical activity in patients with ILC. Entrectinib is a tyrosine kinase inhibitor targeting TRK, ROS1 and ALK tyrosine kinases. Here, the authors present ROSALINE (NCT04551495), a phase II study testing neoadjuvant entrectinib and endocrine therapy in women with estrogen receptor-positive, HER2-negative early ILC.

Breast cancer is the most common cancer among women worldwide. Breast cancer is not a unique disease, but rather a heterogeneous disease, with different subtypes. Lobular breast cancer is the second most common histologic subtype of breast cancer after ductal breast cancer. Lobular breast cancer has some peculiar characteristics that make it a distinct entity in the context of breast cancer. Nevertheless, few clinical studies so far have focused specifically on this subtype. ROSALINE is a clinical study aimed to test entrectinib, a new drug that showed promising activity in preliminary research studies, in combination with endocrine therapy in women with lobular breast cancer before surgery. Trial Registration Number: NCT04551495 (ClinicalTrials.gov).

[Current Status and Future Perspectives of Molecular Targeted Therapies for Lung Cancer].

Molecular targeted therapies are now guideline-recommended treatments for unresectable non-small cell lung cancer( NSCLC) patients harboring driver gene mutations as a front-line treatment. Currently, 17 agents have been approved in Japan for the treatment of patients with NSCLC harboring EGFR mutation, ALK/ROS1/NTRK/RET fusions, BRAF V600E mutation, or MET exon 14 skipping mutation. In addition, many novel agents are being developed against NSCLCs with the other driver mutations such as EGFR or HER2 exon 20 insertion mutations and KRAS G12C mutation. In the era of personalized medicine, thoracic surgeons are expected to play an important role, as one of specialists for multidisciplinary treatments of NSCLCs, at the tumor boards/cancer boards, therefore, the knowledge of genetic testing and molecular targeted drugs is becoming essential for thoracic surgeons. In this review, from the standpoint of thoracic surgeons, we briefly summarize current topics on molecular testing in NSCLCs, approved molecular targeted drugs in Japan, acquired resistance mechanisms to these agents, and attempts to use molecular targeted drugs in adjuvant/neoadjuvant settings.

Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer's Disease.

OBJECTIVE: Preclinical evidence with nilotinib, a US Food and Drug Administration (FDA)-approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in cerebrospinal fluid, and alters biomarkers and clinical decline in Alzheimer's disease. METHODS: This single-center, phase 2, randomized, double-blind, placebo-controlled study investigated the safety, tolerability, and pharmacokinetics of nilotinib, and measured biomarkers in participants with mild to moderate dementia due to Alzheimer's disease. The diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg versus matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg versus placebo for another 26 weeks. RESULTS: Of the 37 individuals enrolled, 27 were women and the mean (SD) age was 70.7 (6.48) years. Nilotinib was well-tolerated, although more adverse events, particularly mood swings, were noted with the 300 mg dose. In the nilotinib group, central nervous system (CNS) amyloid burden was significantly reduced in the frontal lobe compared to the placebo group. Cerebrospinal fluid Aß40 was reduced at 6 months and Aß42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (-27%) at 12 months and phospho-tau-181 was reduced at 6 months and 12 months in the nilotinib group. INTERPRETATION: Nilotinib is safe and achieves pharmacologically relevant cerebrospinal fluid concentrations. Biomarkers of disease were altered in response to nilotinib treatment. These data support a larger, longer, multicenter study to determine the safety and efficacy of nilotinib in Alzheimer's disease. ANN NEUROL 2020 ANN NEUROL 2020;88:183-194.

ROS1 Targeted Therapies: Current Status.

PURPOSE OF REVIEW: Molecular drivers are increasingly identified as therapeutic targets for non-small cell lung cancer (NSCLC). This review focuses on the role of ROS1 inhibitors in treating relapsed/metastatic ROS-1 altered (ROS1+) NSCLC. RECENT FINDINGS: Four FDA-approved drugs have significant activity against ROS1+ NSCLC: crizotinib, ciritinib, lorlatinib, and entrectinib. Each drug yields an overall response rates exceeding 60% with ciritinib, lorlatinib, and entrectinib possessing intracranial activity. The drugs have manageable toxicity profiles. ROS1 alterations are rare molecular drivers of NSCLC that can be effectively treated with a variety of ROS1-targetd drugs. New agents are being identified that may treat resistance mutations.

Rapid Response to Lorlatinib in a Patient With TFG-ROS1 Fusion Positive Inflammatory Myofibroblastic Tumor of the Chest Wall Metastatic to the Brain and Refractory to First and Second Generation ROS1 Inhibitors.

Most inflammatory myofibroblastic tumors (IMTs) harbor ALK fusions but oncogene fusions involving ROS1, RET, NTRK, and PDGFR also occur. The recognition that most IMTs harbor receptor tyrosine kinase fusions has provided a rationale for the use of tyrosine kinase inhibitors to target these oncogenic drivers in advanced IMTs. Crizotinib has been effective in ALK and ROS1-positive IMTs but resistance eventually develops. Here we report the successful use of lorlatinib in a patient with heavily pretreated ROS1-positive IMT of the chest wall with acquired crizotinib-resistance and metastasis to the brain.

[Targeted therapies for non-small cell lung cancer : state of the art in 2021]. / Traitements ciblés et cancer bronchique non à petites cellules : le point en 2021.

The majority of non-small cell lung cancers are diagnosed as advanced disease. Subsets of adenocarcinomas and of squamous cell carcinomas in nonsmokers present a molecular aberration leading to tumour survival. Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK) and Repressor Of Silencing1 (ROS1) have been identified and targeted with good efficacy for fifteen years. Newer inhibitors brought even greater efficacy with a generally better tolerability. Other molecular aberrations (Kirsten Rat Sarcoma, Rearranged during Transfection, MET, NeuroTrophic Receptor yrosine kinase) are targets for newly developed, more selective drugs. As more and more patients will benefit from targeted therapies, the identification of molecular aberration is more than ever crucial for optimal lung cancer patient care.

La majorité des cancers pulmonaires non à petites cellules se présentent à un stade avancé. Une faible proportion des adénocarcinomes et des cancers épidermoïdes des non-fumeurs est porteur d'(une) anomalie(s) génétique (s) et moléculaire(s) dont dépend leur survie. Depuis une quinzaine d'années, les anomalies de l'«Epidermal Growth Factor Receptor¼ (EGFR), «Anaplastic Lymphoma Kinase¼ (ALK) et Repressor Of Silencing1 (ROS1) sont connues et ciblées par des inhibiteurs efficaces. De nouvelles générations permettent actuellement d'augmenter leur efficacité thérapeutique pour une toxicité globalement moindre. De nouvelles anomalies («Kirsten Rat Sarcoma¼, «Rearranged during Transfection¼, MET, «NeuroTrophic Receptor tyrosine kinase¼) sont, elles aussi, à présent ciblées de manière efficace. La recherche des anomalies moléculaires dans ces sous-types histologiques est devenue incontournable car elle modifie fondamentalement la prise en charge thérapeutique et le pronostic d'une proportion grandissante de patients.

Protective effects of combined Losartan and Nilotinib on carbon tetrachloride (CCl4)-induced liver fibrosis in rats.

Tyrosine kinase inhibitors (TKIs) have been developed as therapeutic compounds for inhibiting the progression of liver fibrosis. In the present study, the simultaneous treatment of Nilotinib (TKIs) and Losartan was studied. Forty rats were divided into eight groups of fibrosis induced by carbon tetrachloride (CCl4) and therapeutics (Nilotinib, Losartan, and combination therapy). In the end, serum parameters of the liver and gene expression analysis of transforming growth factor-ß1, its receptors (TßRII), platelet-derived growth factor, its receptors (PDGFRß), matrix metalloproteinases (MMP-2 and MMP-9), tumor necrosis factor-α, cytochrome P450 2E1, and collagen1 type 1 were performed. The oxidant/antioxidant factors were also analyzed. Histopathology analysis along with α-SMA immunohistochemistry and hydroxyproline evaluation was also conducted for a more in-depth study. The overall results indicated a better therapeutic effect of co-treatment of Nilotinib-Losartan in comparison with the treatment of each of them alone. Interestingly, some gene and protein factors and fibrotic indices were reduced even to the normal levels of the control group. The results of this study suggest that co-administration of these two combinations, strengthens their anti-fibrotic properties and, due to the routine use of these compounds against AML and blood pressure, these compounds can be used with caution against human liver fibrosis.