Symptomatic androgen deficiency and sexual dysfunctions in male patients receiving alectinib for ALK-positive advanced non-small cell lung cancer.

BACKGROUND: It is reported that treatment with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) induces hypogonadism both in male patients with ALK-positive cancer and in murine models. METHODS: In this study, three groups, including an experimental group of male patients with ALK-positive, advanced non-small cell lung cancer (ANSCLC) who were receiving alectinib (cohort A), a control group of female patients with ALK-positive ANSCLC who were receiving alectinib (cohort B), and a control group of male patients with ALK-negative ANSCLC (cohort C), prospectively underwent a full hormone assessment for androgen deficiency at 8 weeks after the start of treatment and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to an endocrinologist. RESULTS: Ninety-five patients were consecutively enrolled onto the study. Among sixty-eight male patients, both median total testosterone levels (2.93 vs. 4.92 ng/ml; p = .0001) and free testosterone levels (0.11 vs. 0.17 pg/ml; p = .0002) were significantly lower in ALK-positive ANSCLC patients in cohort A compared with ALK-negative patients in cohort C; conversely, median FSH (10.32 vs. 17.52 mUI/ml; p = .0059) and LH levels (4.72 vs. 7.49 mUI/ml; p = .0131) were significantly higher in cohort C compared to cohort A. Median inhibin B levels were higher in ALK-positive male patients (74.3 vs. 44.24 pg/ml; p = .0038), but all patients had inhibin B values within the normal range. The percentage of male patients who had positive scores on the Androgen Deficiency in Aging Males (ADAM) questionnaire was 62% in cohort A and 26.8% in cohort C, including eight patients who reported at least one major symptom and were referred to Andrology Unit. No significant differences in the endocrine assessment were reported between cohorts A and B. CONCLUSIONS: Symptoms of androgen deficiency should be tracked in male patients with ALK-positive ANSCLC who are receiving alectinib, and testosterone replacement should be considered, as appropriate.

Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Here, we explore the role of AHR in the pathogenesis of PAH. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. Sprague-Dawley rats treated with the potent endogenous AHR agonist, 6-formylindolo[3,2-b]carbazole, in combination with hypoxia develop severe pulmonary hypertension (PH) with plexiform-like lesions, whereas Sprague-Dawley rats treated with the potent vascular endothelial growth factor receptor 2 inhibitors did not. Ahr-knockout (Ahr-/- ) rats generated using the CRISPR/Cas9 system did not develop PH in the SU5416/hypoxia model. A diet containing Qing-Dai, a Chinese herbal drug, in combination with hypoxia led to development of PH in Ahr+/+ rats, but not in Ahr-/- rats. RNA-seq analysis, chromatin immunoprecipitation (ChIP)-seq analysis, immunohistochemical analysis, and bone marrow transplantation experiments show that activation of several inflammatory signaling pathways was up-regulated in endothelial cells and peripheral blood mononuclear cells, which led to infiltration of CD4+ IL-21+ T cells and MRC1+ macrophages into vascular lesions in an AHR-dependent manner. Taken together, AHR plays crucial roles in the development and progression of PAH, and the AHR-signaling pathway represents a promising therapeutic target for PAH.

Safety and efficacy of alectinib versus crizotinib in alk-positive non-small cell lung cancer: An update meta-analysis.

Our study aimed to evaluate the efficacy and toxicity of alectinib compared with crizotinib and provide a reference for clinical use of ALK-TKI, systematically. We searched articles published update till October, 2021 based on the electronic databases, including PubMed, EMBASE and Cochrane Library. All trials analyzed the summary odds ratios (ORs) of the interesting outcomes. Three RCTs, including six studies were included. The pooled hazard ratio (HR) =0.33 (95%CI=0.21-0.51, P<0.00001) shown that the alectinib group achieved significant progress-free survival (PFS) superiority than crizotinib, consistent with those for the with (P=0.001) or without (P<0.00001) measurable CNS lesions at baseline. Also, the regimen of the alectinib did achieved benefit in the ORR (OR=2.07, 95% CI=1.41-3.06, P=0.0002) than crizotinib. Due to the limited data, the pool result of the difference of overall survival (OS) was without statistically significant (P=0.35). With regard to the safety, grade 3 to 5 adverse events were less frequent with alectinib than crizotinib (OR=0.53, 95% CI=0.31-0.90, P=0.02). As compared with crizotinib, alectinib demonstrated better PFS efficacy and comparable safety as a first-line treatment for advanced ALK-positive Non-Small Cell Lung Cancer (NSCLC). OS data remain immature, further trials with long-term survival rate have future to look forward to.

[Expert consensus on ensartinib in the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer].

The mutation rate of anaplastic lymphoma kinase (ALK) in patients with non-small cell lung cancer is 3% to 7%. Due to its low mutation rate and better long-term survival compared with epidermal growth factor receptor-positive non-small cell lung cancer patients, therefore, it's called "diamond mutation". At present, there are three generations of ALK tyrosine kinase inhibitor (TKI) drugs in the world. The first-generation ALK-TKI drug approved in China is crizotinib, and the second-generation drugs are alectinib, ceritinib and ensartinib. Among them, ensartinib is an ALK-TKI domestically developed, and its efficacy is similar to that of alectinib. The main adverse event is transient rash, and compliance to ensartinib is better from the perspective of long-term survival of patients. The manifestation of rash caused by ensartinib is different from that of other ALK-TKI drugs. In order to facilitate clinical application and provide patients with more treatment options, under the guidance of the Committee of Cancer Rehabilitation and Palliative Care of China Anti-Cancer Association, this article collects and summarizes the common adverse reactions of ensartinib. Based on the clinical practice, a clear adverse classification and specific treatment plan are formulated, in order to provide a corresponding reference for clinicians to make more comprehensive clinical decisions.

Mixed responses to first-line alectinib in non-small cell lung cancer patients with rare ALK gene fusions: A case series and literature review.

Anaplastic lymphoma kinase (ALK) fusion is a well-defined biomarker for ALK tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC). Alectinib, a second-generation ALK-TKI, has been shown to have significantly longer progression-free survival (PFS) than first-generation ALK inhibitors in untreated ALK-rearranged NSCLC patients. However, its clinical efficacy on rare ALK fusions remains unclear. Herein, two advanced NSCLC patients received first-line alectinib treatment, given their positive ALK fusion status as determined by immunohistochemistry (IHC) testing results. Patients showed limited clinical response (PFS: 4 months) and primary resistance to alectinib respectively. Molecular profiling using next-generation sequencing (NGS) further revealed a striatin (STRN)-ALK fusion in the first patient accompanied by MET amplification, and a LIM domain only protein 7 (LMO7)-ALK fusion in another patient without any other known oncogenic alterations. Both patients demonstrated improved survival after they switched to second-line crizotinib (PFS: 11 months) and ensartinib (PFS: 18 months), respectively, up till the last follow-up assessment. In conclusion, the clinical efficacy of ALK-TKIs including alectinib for lung cancer with uncommon ALK gene fusions is still under evaluation. This study and literature review results showed mixed responses to alectinib in NSCLC patients who harboured rare ALK fusions. Comprehensive molecular profiling of tumour is thus strongly warranted for precise treatment strategies.

A retrospective study of alectinib versus ceritinib in patients with advanced non-small-cell lung cancer of anaplastic lymphoma kinase fusion in whom crizotinib treatment failed.

BACKGROUND: Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking. METHODS: Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy. RESULTS: Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib. CONCLUSION: Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with ALK-rearranged: a meta-analysis of clinical trials.

BACKGROUND: Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC. METHODS: We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases. RESULTS: A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg and 600 mg), brigatinib, lorlatinib and ensartinib yielded the most favorable PFS. Whereas there was no significant OS or ORR difference among the ALK-TKIs. According to Bayesian ranking profiles, lorlatinib, alectinib 600 mg and alectinib 300 mg had the best PFS (63.7%), OS (35.9%) and ORR (37%), respectively. On the other hand, ceritinib showed the highest rate of severe adverse events (60%). CONCLUSION: Our analysis indicated that alectinib and lorlatinib might be associated with the best therapeutic efficacy in first-line treatment for major population of advanced NSCLC patients with ALK-rearrangement. However, since there is little comparative evidence on the treatment options, there is need for relative trials to fully determine the best treatment options as well as the rapidly evolving treatment landscape.

ALTA-2: Phase II study of brigatinib in patients with ALK-positive, advanced non-small-cell lung cancer who progressed on alectinib or ceritinib.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved outcomes in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC). However, almost all patients eventually develop progressive disease on first-line ALK TKIs (e.g., crizotinib, alectinib and ceritinib). Brigatinib, a second-generation ALK TKI, may show efficacy in alectinib- and ceritinib-refractory ALK+ NSCLC. We describe the rationale and design of ALTA-2, a Phase II study of brigatinib in patients with locally advanced/metastatic ALK+ NSCLC and documented progressive disease on alectinib or ceritinib. The primary end point is confirmed objective response rate per independent review committee using response evaluation criteria in solid tumors version 1.1. Secondary end points include duration of response, progression-free survival, overall survival, safety and health-related quality of life.

Lay abstract Tyrosine kinase inhibitor medications (like crizotinib, alectinib or ceritinib) may work as the first treatment for people with non-small-cell lung cancer (NSCLC) that has spread to other parts of the body and has the ALK+ mutation (ALK+ NSCLC) in tumor testing. However, after a while, many people stop responding to treatment with one of these medicines. Brigatinib is a tyrosine kinase inhibitor medicine that may be effective in people with ALK+ NSCLC who have stopped responding to alectinib or ceritinib treatment. We describe the need for and design of a study of brigatinib in people with ALK+ NSCLC whose disease got worse on alectinib or ceritinib. Clinical trial registration: NCT03535740 (ClinicalTrials.gov).

Cutaneous sarcoid-like drug reaction caused by an anaplastic lymphoma kinase inhibitor.

Anaplastic lymphoma kinase (ALK) rearranged lung cancers represent 4% to 6% of all pulmonary adenocarcinomas, and echinoderm microtubule associated protein like 4 (EML4)-ALK fusions are the most common subgroup. Herein, we report a case of two successive drug reactions due to ALK inhibitors. A 69-year-old female with stage IVB EML4-ALK fused lung adenocarcinoma developed a generalized morbilliform eruption 10 days after starting alectinib. Skin biopsy findings were consistent with a drug reaction. Her findings resolved after alectinib was discontinued. Another ALK inhibitor, lorlatinib was started and she developed multiple asymptomatic cutaneous and oral nodules 4 months later. Biopsies from these nodules showed sarcoidal granulomas without evidence of metastases or infection. ALK inhibitors are associated with numerous adverse events, including various cutaneous eruptions. However, a sarcoidal drug reaction involving the skin has not been reported. Identification of drug reactions to targeted therapy can avoid long-term sequelae and misinterpretation of the clinical findings as disease progression or infection.

Successful rechallenge of alectinib after remission of severe alectinib-induced interstitial lung disease.

INTRODUCTION: Even though alectinib is a potent second-generation ALK inhibitor with a favorable safety profile, alectinib-induced interstitial lung disease (ILD) could be fatal. There are case reports described successful alectinib rechallenge in mild ILD. However, the feasibility and safety of rechallenge in severe cases remains to be elucidated. CASE REPORT: A 76-year-old female was a case of stage IV lung adenocarcinoma harboring ALK rearrangement. Respiratory failure following severe ILD developed one month after alectinib administration. She received mechanical ventilation in intensive care uint. ILD subsided gradually after methylprednisolone pulse therapy and discontinuation of alectinib.Management and outcome: After the recovery from ILD, the patient attempted a re-escalation of alectinib from a lower dose under close clinical and radiological monitoring. No ILD happened even after 480 days of alectinib rechallenge. DISCUSSION: Given that the ALK inhibitors are the treatment of choice for advanced lung cancer patients with ALK rearrangement. Our report demonstrated the potential feasibility of alectinib re-use in cases of severe druginduced ILD.

Alectinib for relapsed or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: An open-label phase II trial.

Anaplastic lymphoma kinase (ALK) inhibition is expected to be a promising therapeutic strategy for ALK-positive malignancies. We aimed to examine the efficacy and safety of alectinib, a second-generation ALK inhibitor, in patients with relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL). This open-label, phase II trial included patients (aged 6 years or older) with relapsed or refractory ALK-positive ALCL. Alectinib 300 mg was given orally twice a day (600 mg/d) for 16 cycles, and the duration of each cycle was 21 days. Patients who weighed less than 35 kg were given a reduced dose of alectinib of 150 mg twice a day (300 mg/d). Ten patients were enrolled, and the median age was 19.5 years (range, 6-70 years). Objective responses were documented in eight of 10 patients (80%; 90% confidence interval, 56.2-95.9), with six complete responses. The 1-year progression-free survival, event-free survival, and overall survival rates were 58.3%, 70.0%, and 70.0%, respectively. The median duration of therapy was 340 days. No unexpected adverse events occurred. The most common grade 3 and higher adverse event was a decrease in neutrophil count in two patients. Alectinib showed favorable clinical activity and was well tolerated in patients with ALK-positive ALCL who had progressed on standard chemotherapy. Based on the results of the current study, the Ministry of Health, Labour and Welfare of Japan approved alectinib for the treatment of recurrent or refractory ALK-positive ALCL in February 2020.

Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. METHODS: In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. RESULTS: During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib). CONCLUSIONS: As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .).

Successful alectinib desensitization in a patient with anaplastic lymphoma kinase-positive adenocarcinoma of the lung and alectinib-induced drug rash.

INTRODUCTION: Alectinib is an oral tyrosine kinase inhibitor currently recommended by the National Comprehensive Cancer Network (NCCN) as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase (ALK) gene rearrangement-positive non-small cell lung cancer (NSCLC). Skin toxicity is a known adverse effect of this medication, yet current recommendations are unclear regarding how to best manage patients who develop severe skin toxicity while taking alectinib. CASE REPORT: Here, we describe a case of successful rechallenge with alectinib by utilizing a desensitization procedure in a patient who had developed severe alectinib-induced skin toxicity about two weeks into treatment.Management and outcome: Upon resolution of the initial skin toxicity symptoms, the patient was rechallenged with alectinib using a modified version of a previously published desensitization procedure. The patient tolerated the rechallenge with no recurrence of skin toxicity or other adverse effects and was able to continue treatment with alectinib. DISCUSSION: Alectinib is currently recommended as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase gene rearrangement-positive NSCLC due to improved progression-free survival when compared to crizotinib. The development of skin toxicity can lead to early discontinuation of alectinib treatment, forcing providers and patients to select alternative, potentially less effective options. This case report provides evidence that patients who have experienced severe skin toxicity due to alectinib may be able to continue this first-line treatment option by rechallenging them using a desensitization procedure.

Life-threatening hypertriglyceridemia-induced pancreatitis related to alectinib successfully treated by plasmapheresis: A review of the literature on metabolic toxicities associated with anaplastic lymphoma kinase inhibitors.

INTRODUCTION: Actionable mutations are tested as standard of care for all new metastatic non-small cell lung cancers. Tumors harboring an anaplastic lymphoma kinase mutation respond to tyrosine kinase inhibitors targeting anaplastic lymphoma kinase pathway. Patients are monitored for common adverse effects, although we occasionally encounter unexpected side effects. CASE REPORT: A 52-year-old male presented with a right hilar lung mass, and workup revealed a stage IIIA adenocarcinoma. He underwent treatment with concurrent chemoradiation; however, disease recurred one year later with a right hilar mass and contralateral mediastinal lymphadenopathy, biopsy of which resulted positive for adenocarcinoma. Molecular analysis showed anaplastic lymphoma kinase rearrangement and alectinib was started. Six months into therapy, he presented with hematochezia, nausea, and epigastric pain and was diagnosed with acute pancreatitis. Triglyceride level resulted above the measurable level at >5680mg/dL, thought to be the inciting event of pancreatitis.Management and outcome: Despite treatment with intravenous hydration, insulin infusion, and antibiotics, he decompensated with development of respiratory failure, shock requiring intensive care. Therapeutic plasmapheresis was initiated due to persistently elevated triglyceride. Following the third plasmapheresis, triglyceride level decreased to 359 mg/dL. With aggressive multidisciplinary management, he made a complete recovery. Follow-up imaging studies at three and six months show a stable mass-like abnormality in the right hilum without evidence of disease progression. DISCUSSION: Prior to starting alectinib, our patient's triglyceride level was 420 mg/dL. While he consumed alcohol, he had no other traditional risk factor. To our knowledge, this is the first reported case of hypertriglyceridemia-induced acute pancreatitis related to treatment with an anaplastic lymphoma kinase inhibitor.

Effect of non-steroidal anti-inflammatory drugs on glomerular filtration rate and urinary N-acetyl-ß-D-glucosaminidase activity in cats after dental surgery.

OBJECTIVE: To compare the effects of meloxicam or carprofen on glomerular filtration rate (GFR), and to evaluate the effect of meloxicam on urinary N-acetyl-ß-D-glucosaminidase (NAG) activity, of cats after dental surgery. STUDY DESIGN: Randomized, blinded, controlled trial. ANIMALS: A total of 24 mixed breed cats. METHODS: Cats were randomly assigned to one of three groups (n = 8 per group): meloxicam (0.2 mg kg-1); carprofen (4 mg kg-1); or saline (2 mL). Acepromazine (0.04 mg kg-1) and buprenorphine (0.02 mg kg-1) were administered intramuscularly as preanaesthetic medication. Test drugs were injected subcutaneously at the time of preanaesthetic medication. Anaesthesia was induced with intravenous propofol and maintained with isoflurane in oxygen. Mean arterial blood pressure (MAP), respiratory rate (fR), heart rate (HR) and haemoglobin oxygen saturation values (SpO2) were recorded. All cats underwent ultrasonic dental scaling with polishing. Teeth extraction involved mucosal flap creation, removal of alveolar bone and flap closure. Plasma iohexol clearance (ICL), a measure of GFR, was estimated before and 24 hours after anaesthesia induction in all cats. Urinary NAG index was estimated in saline and meloxicam groups at the same time points as GFR. Between-group and -time point differences in GFR and NAG index were compared using mixed model analyses. Data are presented as mean ± standard deviation (p < 0.05). RESULTS: There was no significant difference in plasma ICL rate (range: from 1.22 ± 0.05 to 1.27 ± 0.04 mL kg minute-1) between groups or between time points. Urinary NAG index (range: from 1.0 ± 0.19 to 1.36 ± 0.29 Units gram-1) was not significantly different between meloxicam and saline groups. MAP, HR, fR and SpO2 did not differ significantly between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam and carprofen appeared to produce nonsignificant effects on GFR, and meloxicam did not affect the urinary NAG activity, of cats after dental surgery.

Safety and effectiveness of alectinib in a real-world surveillance study in patients with ALK-positive non-small-cell lung cancer in Japan.

We conducted a large-scale surveillance study as a post-marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice-daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (all grades, 19.8%; grade ≥3, 2.0%), decreased neutrophil and/or white blood cell count (all grades, 7.6%; grade ≥3, 1.1%), and interstitial lung disease (all grades, 3.8%; grade ≥3, .7%). Median OS was not estimable. The 18-month cumulative OS rate was longer in patients with ECOG performance status ≤1 (vs 2 or ≥3; 83.7% vs 44.5% or 27.2%), without prior crizotinib (vs with; 81.1% vs 73.4%), receiving first-line alectinib (vs second and third or later line; 83.0% vs 79.2% or 71.9%), without brain metastases (vs with; 79.5% vs 71.5%). These data confirm the favorable safety and effectiveness of alectinib in patients with ALK-positive NSCLC in Japan.

Overexpression of CD 133 and BCL-2 in non-small cell lung cancer with neuroendocrine differentiation after transformation in ALK rearrangement-positive adenocarcinoma.

Transformation to small cell lung cancer is one phenomenon of acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Few case reports have focused on other types of histological transformation. We report a case of transformation of ALK rearrangement-positive adenocarcinoma to NSCLC with neuroendocrine differentiation during alectinib therapy. A 36-year-old woman presented with a tumor in the left lower lobe and bone metastases. She was diagnosed with ALK rearrangement-positive adenocarcinoma by histopathology of the primary tumor. Alectinib had been effective for 8 months before new lesions appeared. Histopathological re-examination of a recurrent tumor revealed poorly differentiated carcinoma with insulinoma-associated protein 1 (INSM1) expression, which remained ALK-positive. Expression of CD133, BCL-2, and SOX2 was positive in comparison to the initial tumor. Expression of SOX2 became more strongly positive than it was before treatment. The immunohistochemical findings of these markers associated with cancer stem-like cells and/or neuroendocrine differentiation suggest that cancer stem cells play a role in the mechanisms of histological transformation and acquired resistance of ALK rearrangement-positive cancer. To our knowledge, this is the first report to suggest an association between cancer stem-like cells and histological transformation in ALK rearrangement-positive lung cancer.

Successful re-introduction of alectinib after inducing interstitial lung disease in a patient with lung cancer.

Alectinib is a member of the family of anaplastic lymphoma kinase inhibitors. This agent is effective in the treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung cancer and has excellent blood-brain barrier penetrability. It is generally well tolerated; however, significant toxicities such as interstitial lung disease have been reported. We present herein an instance of interstitial lung disease four weeks into alectinib treatment. Alectinib was held, and the patient showed clinical and radiographic improvement of her interstitial lung disease. Alectinib was then resumed at half dosage without further complications. Prompt recognition of adverse reactions to this targeted agent is paramount. Cessation of therapy may be needed on a case-to-case basis. However, as our case highlights, safe re-introduction of alectinib can be accomplished in some cases.

Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.

BACKGROUND: Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib. METHODS: J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316). FINDINGS: Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17-0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3-not estimated) and was 10·2 months (8·2-12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group. INTERPRETATION: These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study. FUNDING: Chugai Pharmaceutical Co, Ltd.

The use of guideline recommended beta-blocker therapy in primary prevention implantable cardioverter defibrillator patients: insight from Danish nationwide registers.

Aims: We aimed to examine the use of guideline recommended beta-blocker therapy prior to and after primary prevention implantable cardioverter defibrillator (ICD) implantation in a 'real-life' setting. Methods and results: From the Danish Pacemaker and ICD Registry we identified all 1st-time primary prevention ICD and cardiac resynchronization therapy defibrillator (CRT-D) implantations in Denmark from 2007-12 (n = 2935). Use of beta-blocker, type and dose was acquired through the Danish Prescription Registry. According to guideline recommendations, we defined target daily doses as ≥50 mg carvedilol and ≥200 mg metoprolol. Prior to implantation 2427 of 2935 (83%) patients received beta-blocker therapy, with 2166 patients (89%) having initiated treatment 3 months or more prior to implantation. The majority of patients was prescribed carvedilol (52%) or metoprolol (41%). Patients on carvedilol reached target dosages more frequently than patients on metoprolol, with 39% of patients on carvedilol and 26% of patients on metoprolol at the time of implantation (P < 0.001 for all time-points). Increase in proportion of patients reaching target daily doses was observed for both carvedilol and metoprolol after ICD implantation. Carvedilol treatment was a strong predictor for being on target dose of BB at time of implant, as was treatment with angiotensin-converting enzyme inhibitors and/or spironolactone, no history of myocardial infarction, younger age and less pronounced heart failure symptoms. Conclusion: In a real-life setting of primary prevention ICD patients, 39% and 26% of patients were titrated to optimal target dose of carvedilol or metoprolol prior to implantation. A higher proportion of patients on carvedilol reached target dose, as compared with metoprolol.