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Introduction: Aberrant expression of anaplastic lymphoma kinase (ALK) is found in 3%–7% of patients with non-small cell lung cancer (NSCLC). Alectinib is a tyrosine kinase inhibitor used as first-line treatment targeting ALK-positive tumors. We herein report two cases of appendicitis highlighting it as a rare, possible adverse event of treatment with alectinib. Case presentation: The first case is a 60-year-old woman with a previous history of stage 1 lobular breast cancer and early-stage lung cancer treated with segmentectomy, subsequently presenting with ALK-positive advanced NSCLC. Treatment with alectinib resulted in partial response, but she developed gastrointestinal symptoms that were assessed with computed tomography (CT) of the abdomen revealing right lower quadrant stranding without appendiceal visualization. Her symptoms continued despite an antibiotic course with re-imaging concerning for acute appendicitis, which was successfully treated with appendectomy and amoxicillin–clavulanic acid. The second case is a previously healthy 58-year-old man with advanced ALK-positive NSCLC who was started on first-line treatment with alectinib and subsequently diagnosed with asymptomatic acute appendicitis on re-staging CT abdomen. Signs on CT resolved with amoxicillin–clavulanic acid. Definitive treatment was conducted with a delayed elective appendectomy. Both patients remained on alectinib over the courses of appendicitis without interruption. Conclusion: While appendicitis has not been previously described as an adverse effect of alectinib, its incidence in two patients at our center within several months following the administration of alectinib raises its suspicion as a possible adverse effect. [ABSTRACT FROM AUTHOR]

Enabling drug formulations are often required to ensure sufficient absorption after oral administration of poorly soluble drugs. While these formulations typically increase the apparent solubility of the drug, it is widely acknowledged that only molecularly dissolved, i.e., free fraction of the drug, is prone for direct absorption, while colloid-associated drug does not permeate to the same extent. In the present study, we aimed at comparing the effect of molecularly and apparently (i.e., the sum of molecularly and colloid-associated drug) dissolved drug concentrations on the oral absorption of a poorly water-soluble drug compound, Alectinib. Mixtures of Alectinib and respectively 50 %, 25 %, 12.5 %, and 3 % sodium lauryl sulfate (SLS) relative to the dose were prepared and small-scale dissolution tests were performed under simulated fed and fasted state conditions. Both the molecularly and apparently dissolved drug concentrations were assessed in parallel using microdialysis and centrifugation/filtration sampling, respectively. The data served as the basis for an in vitro-in vivo correlation (IVIVC) and as input for a GastroPlusTM physiologically-based biopharmaceutics model (PBBM). It was shown that with increasing the content of SLS the apparently dissolved drug in FeSSIF and FaSSIF increased to a linear extent and thus, the predicted in vivo performance of the 50 % SLS formulation, based on apparently dissolved drug, would outperform all other formulations. Against common expectation, however, the free (molecularly dissolved) drug concentrations were found to vary with SLS concentrations as well, yet to a minor extent. A systematic comparison of solubilized and free drug dissolution patterns at different SLS contents of the formulations and prandial states allowed for interesting insights into the complex dissolution-/supersaturation-, micellization-, and precipitation-behavior of the formulations. When comparing the in vitro datasets with human pharmacokinetic data from a bioequivalence study, it was shown that the use of molecularly dissolved drug resulted in an improved IVIVC. By incorporating the in vitro dissolution datasets into the GastroPlusTM PBBM, the apparently dissolved drug concentrations resulted in both, a remarkable overprediction of plasma concentrations as well as a misprediction of the influence of SLS on systemic exposure. In contrast, by using the molecularly dissolved drug (i.e., free fraction) as the model input, the predicted plasma concentration-time profiles were in excellent agreement with observed data for all formulations under both fed and fasted conditions. By combining an advanced in vitro assessment with PBBM, the present study confirmed that only the molecularly dissolved drug, and not the colloid-associated drug, is available for direct absorption. [Display omitted] [ABSTRACT FROM AUTHOR]

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare subtype of inflammatory myofibroblastic tumor, characterized to be an aggressive disease with high frequency of ALK rearrangement, rapid recurrence, and poor prognosis. Primary EIMS of thoracic origin is rarely observed. Herein, we described a case of 28-year-old female developed primary EIMS in the anterior mediastinum with hepatic metastasis. The EIMS displayed sheet-like growth of epithelioid and spindle cells with enlarged nuclei, abundant and eosinophilic cytoplasm, and infiltration of inflammatory cells. Immunohistochemical staining revealed positive expression of ALK in the nuclear membrane, and ALK rearrangement was identified by polymerase chain reaction assay. Alectinib showed partial response, and achieved a meaningful survival benefit for four months. Based on this case report and literature review, ALK inhibitor reveals promising activity on the rare but aggressive EIMS. Awareness of EIMS in thoracic disease and its clinicopathological features is essential to avoid erroneous diagnosis. [ABSTRACT FROM AUTHOR]

This is the first case report of a non‐small‐cell lung cancer (NSCLC) patient harboring HIP1‐ALK (H28:A20) and CTNNB1 p.S45del treated with first‐line alectinib. Approximately 5% of NSCLC patients are reported to have anaplastic lymphoma kinase (ALK) rearrangements, and among these EML4‐ALK is the most frequent fusion variant. However, in recent years the use of next‐generation sequencing (NGS) in clinical laboratories has become increasingly widespread, identifying a lot of new ALK fusion partners as well as a large quantity of co‐occurring genomic alterations. Unfortunately, the growing number of genomic alterations detected by NGS does not always correspond to adequate knowledge of their clinical significance, often resulting in an empiric treatment of patients harboring uncommon mutations. [ABSTRACT FROM AUTHOR]

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an extremely rare and aggressive form of inflammatory myofibroblastic tumor. Clinically, it has a high risk of relapse and peripheral organ infiltration, and it responds poorly to conventional chemotherapy. Anaplastic lymphoma kinase (ALK) inhibitors are currently the most effective targeted therapy for EIMS. This report discusses a typical case of abdominal EIMS in a 43-year-old woman. The tumors recurred rapidly within one month after surgery. Alectinib was promptly administered upon diagnosis. However, the patient developed a severe allergic reaction to the medication. After a comprehensive assessment and symptomatic treatment, her condition stabilized, leading to a favorable prognosis. This study summarizes cases of abdominal EIMS, highlights the successful use of Alectinib for treatment, and discusses the management of medication-related complications. [ABSTRACT FROM AUTHOR]

Purpose: In exposure–response analyses of oral targeted anticancer agents, longitudinal plasma trough concentrations are often aggregated into a single value even though plasma trough concentrations can vary over time due to dose adaptations, for example. The aim of this study was to compare joint models to conventional exposure–response analyses methods with the application of alectinib as proof-of-concept. Methods: Joint models combine longitudinal pharmacokinetic data and progression-free survival data to infer the dependency and association between the two datatypes. The results from the best joint model and the standard and time-dependent cox proportional hazards models were compared. To normalize the data, alectinib trough concentrations were normalized using a sigmoidal transformation to transformed trough concentrations (TTC) before entering the models. Results: No statistically significant exposure–response relationship was observed in the different Cox models. In contrast, the joint model with the current value of TTC in combination with the average TTC over time did show an exposure–response relationship for alectinib. A one unit increase in the average TTC corresponded to an 11% reduction in progression (HR, 0.891; 95% confidence interval, 0.805–0.988). Conclusion: Joint models are able to give insights in the association structure between plasma trough concentrations and survival outcomes that would otherwise not be possible using Cox models. Therefore, joint models should be used more often in exposure–response analyses of oral targeted anticancer agents. [ABSTRACT FROM AUTHOR]

The crystal structure of alectinib hydrochloride has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional theory techniques. Alectinib hydrochloride crystallizes in space group P 21/ n (#14) with the following parameters: a = 12.67477(7), b = 10.44076(5), c = 20.38501(12) Å, β = 93.1438(7)°, V = 2693.574(18) Å3, and Z = 4 at 295 K. The crystal structure consists of stacks of molecules along the b -axis, and the stacks contain chains of strong N–H⋯Cl hydrogen bonds. One density functional theory calculation moved a proton from an N atom to the Cl, but another calculation yielded a more chemically reasonable result. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®) [ABSTRACT FROM AUTHOR]

Abstract Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare subtype of inflammatory myofibroblastic tumor, characterized to be an aggressive disease with high frequency of ALK rearrangement, rapid recurrence, and poor prognosis. Primary EIMS of thoracic origin is rarely observed. Herein, we described a case of 28-year-old female developed primary EIMS in the anterior mediastinum with hepatic metastasis. The EIMS displayed sheet-like growth of epithelioid and spindle cells with enlarged nuclei, abundant and eosinophilic cytoplasm, and infiltration of inflammatory cells. Immunohistochemical staining revealed positive expression of ALK in the nuclear membrane, and ALK rearrangement was identified by polymerase chain reaction assay. Alectinib showed partial response, and achieved a meaningful survival benefit for four months. Based on this case report and literature review, ALK inhibitor reveals promising activity on the rare but aggressive EIMS. Awareness of EIMS in thoracic disease and its clinicopathological features is essential to avoid erroneous diagnosis.