Treatment Of Anaplastic Lymphoma Kinase Research Articles

Novel High-Throughput Microwell Spectrophotometric Assay for One-Step Determination of Lorlatinib, a Novel Potent Drug for the Treatment of Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer.

Background and Objectives: Lorlatinib (LOR) belongs to the third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors. People who are diagnosed with ALK-positive metastatic and advanced non-small cell lung cancer (NSCLC) are eligible to get it as a first-line treatment option after it was given the approval by "the Food and Drug Administration (FDA)". However, no study has described constructing high-throughput analytical methodology for LOR quantitation in dosage form. For the first time, this work details the construction of a high-throughput, innovative microwell spectrophotometric assay (MW-SPA) for single-step assessment of LOR in its tablet form, for use in pharmaceutical quality control. Materials and Methods: Assay depended on charge transfer complex (CTC) formation between LOR, as electron donor, with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone (DDQ), as π-electron acceptor. Reaction conditions were adjusted, the CTC was characterized by ultraviolet (UV)-visible spectrophotometry and computational molecular modeling, and its electronic constants were determined. Site of interaction on LOR molecule was allocated and reaction mechanism was suggested. Under refined optimum reaction conditions, the procedures of MW-SPA were performed in 96-well assay plates, and the responses were recorded by an absorbance plate reader. Validation of the current methodology was performed in accordance with guidelines of "the International Council on Harmonization (ICH)", and all validation parameters were acceptable. Results: Limits of detection and quantitation of MW-SPA were 1.8 and 5.5 µg/well, respectively. The assay was applied with great success for determining LOR in its tablets. Conclusions: This The assay is straightforward, economic and has high-throughput characteristics. Consequently, the assay is recommended as a valuable analytical approach in quality control laboratories for LOR's tablets' analysis.

Alectinib as first-line treatment for advanced ALK-positive non-small cell lung cancer in the real-world setting: preliminary analysis in a Chinese cohort

Tyrosine kinase inhibitors (TKIs) have been a major advance in the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) which have been substantiated in clinical trials. However, real-world data on first-line alectinib in a Chinese patient population are limited. We enrolled patients diagnosed with advanced ALK-positive NSCLC treated with first-line alectinib at 8 centers in China, including cases with symptomatic or active CNS metastases. Continuation of alectinib was permitted after local or gradual progression at the treating clinician's discretion. Time-to-treatment failure (TTF) was defined as the period from the start of alectinib to discontinuation for any cause including disease progression, death, adverse events and patient's preference. We defined longer EML4-ALK variants as containing EML4 fusions to at least exon 13 and shorter variants had EML4 fusions up to exon 6. Of the 110 patients included, 26.4% had Eastern Cooperative Oncology Group Performance Status (ECOG) ≥2 points. The objective response rate (ORR) was 88.5% [95% confidence interval (CI): 79.9-94.3%] and median tumor shrinkage rate was 60% (range, 0-100%) in patients with target lesions. For patients with measurable central nervous system (CNS) metastases, the CNS-ORR was 92.9% (95% CI: 66.1-99.8%), additionally, 80% (8/10) of patients experienced significant improvement in CNS-related symptoms following alectinib treatment. With a median follow-up of 18.3 months, the estimated 2-year progression-free survival (PFS) rate and 2-year treatment failure-free rate were 81.1% (95% CI: 71.5-87.7%) and 81.0% (95% CI: 70.6-88.0%) respectively. Grade 3-4 adverse events occurred in 6.4% and only 2 patients (1.8%) permanently discontinued alectinib due to adverse events. Multivariate analysis indicated that patients with metastases in ≥3 distant organs and a tumor reduction rate ≤50% demonstrated more unfavorable mPFS than their counterparts. Furthermore, patients carrying longer variants showed superior mPFS to those with shorter variants (not reached vs. 24.2 months, hazard ratio =0.17, 95% CI: 0.04-0.68, P=0.004). Alectinib showed substantial efficacy and an excellent safety profile in a real-world setting of Chinese patients. Clinical outcomes and long-term survival still require longer follow-up. Tumors with shorter EML4 fusion variants, more extensive metastases and less reduction in tumor lesions may require more aggressive strategies.

Long-Term Outcomes of Crizotinib Treated ALK-Positive Lung Cancer Patients: A Retrospective Audit of Prospective Data from Resource-Constrained Settings

Purpose Crizotinib has been one of the standard treatment options for the treatment of anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) based on higher progression-free survival (PFS) and objective response rates in phase III clinical trials. However, real-world data about the long-term efficacy and toxicity of crizotinib is limited. Methods A retrospective analysis of all patients with ALK-positive NSCLC, treated with crizotinib between March 2014 and December 2016, was performed. The main outcomes measured were PFS, overall survival (OS), and adverse effects. Results One hundred and eighty-eight patients treated with crizotinib during this period were included in this study. The median age was 50 years (range: 24–74) with a majority being males (73.2%) and 80.3% with a performance status of 0 to 1. The median duration of follow-up was 49.4 months (range: 3.4–86.3%). The median PFS of crizotinib was 17.3 months (95% confidence interval [CI], 13.0–21.6) and 12.8 months (95% CI, 8.1–17.6) when used in first line or subsequent lines, respectively. The median OS was 38.3 months (95% CI, 28.4–48.2). The patients who received crizotinib in the first line had a median OS of 45.5 months (95% CI, 29.6–61.4) as compared with 29.7 months (95% CI, 22.2–37.2) for those who received in subsequent line (hazard ratio, 0.6, 95% CI, 0.4–0.9, p=0.022). The most common all grade toxicities include transaminitis, anemia, fatigue, and corrected QT prolongation. Conclusion This real-world study confirms the long-term beneficial effects of crizotinib in ALK rearranged NSCLC with favorable toxicity profile like that of the registration studies, in resource constrained settings.

Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 – a promising target for cancer immunotherapy

BackgroundAn important mechanism, by which cancer cells achieve immune escape, is the release of extracellular adenosine into their microenvironment. Adenosine activates adenosine A2A and A2B receptors on immune cells constituting...

Evaluation of the absolute oral bioavailability of the anaplastic lymphoma kinase/c-ROS oncogene 1 kinase inhibitor lorlatinib in healthy participants

PurposeLorlatinib is a third-generation tyrosine kinase inhibitor currently approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. This open-label, phase 1, randomized two-sequence, two-treatment, two-period, crossover study investigated the absolute oral bioavailability of lorlatinib in healthy participants.MethodsEligible participants were randomized to receive two treatments in one of two sequences: lorlatinib 100 mg single oral dose followed by lorlatinib 50 mg intravenous (IV) dose, or lorlatinib IV dose followed by lorlatinib oral dose, each with at least a 10-day washout between successive lorlatinib doses. Blood samples for pharmacokinetics were collected for up to 144 hours (h) after dosing. Validated liquid chromatographic-tandem mass spectrometry was used to determine plasma concentrations of lorlatinib and its benzoic acid metabolite PF-06895751.ResultsIn total, 11 participants were enrolled (mean age 37.6 years, all male). The adjusted geometric mean (90% confidence interval) for the absolute oral bioavailability was 80.78% (75.73–86.16%). Using non-compartmental analysis, the estimated arithmetic mean elimination plasma half-life of lorlatinib was 25.5 and 27.0 h after the oral and IV doses, respectively. No deaths, serious adverse events (AEs), or severe AEs were reported, and most treatment-emergent AEs were mild in severity, with two events of transaminase increase of moderate severity. All treatment-emergent AEs were resolved by the end of the study.ConclusionBoth oral and IV lorlatinib were well-tolerated in healthy participants and oral lorlatinib is highly bioavailable after oral administration.

P45.14 Real-World Experience on Treatment of crizotinib in ALK/ROS1/MET Alterated Non-Small-Cell Lung Cancer Patients in China

Although multiple clinical trials have demonstrated the efficacy of crizotinib in the treatment of anaplastic lymphoma kinase (ALK) / c-ros oncogene 1 (ROS1) fusion advanced non-small-cell lung cancer (NSCLC), the under-represented populations, as well as the complexities and diversity of day-to-day cancer care are still to be complemented.

Pharmacometric analyses of alectinib to facilitate approval of the optimal dose for the first-line treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer.

Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK‐positive non‐small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib‐failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one‐compartment models with sequential zero/first‐order input and first‐order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment‐naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression‐free survival in treatment‐naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of treatment as a significant covariate, with an optimal response achieved for concentrations above 1040 nmol/L. With 600 mg twice daily (b.i.d.), 92% of global patients are above this threshold concentration, compared with only 43% of patients with 300 mg b.i.d. In Japan, where the body weight distribution is lower, the approved 300 mg b.i.d. dose brings about 70% of Japanese patients above this threshold. Logistic regression analyses found no significant relationship between the combined alectinib–M4 molar concentration and first occurrence of adverse events. These pharmacometric results were used to expedite and facilitate regulatory approvals of 600 mg b.i.d. for first‐line ALK‐positive NSCLC in the United States and European Union in 2017 and in China in 2018.

Comparison of Clinical Efficacy of Alectinib Versus Crizotinib in ALK-Positive Non-Small Cell Lung Cancer: A Meta-Analysis.

ObjectiveTo systematically evaluate the efficacy and safety of alectinib versus crizotinib in the treatment of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer.MethodsStudies about the efficacy of alectinib versus crizotinib in the treatment of ALK-positive non-small cell lung cancer were searched in PubMed, Scopus, Embase and the Cocharane Library from inception to February 15, 2020. Two reviewers independently screened these studies, extracted the data, assessed the risk of bias in the included studies by using the Cochrane risk assessment tool, and then used review manager 5.3 software for meta-analysis.ResultsThree studies comprising a total of 697 patients with ALK-positive non-small cell lung cancer were included, 380 in the alectinib group and 317 in the crizotinib group. The dose of alectinib (300 mg) in J-ALEX were lower than the approved dose (600 mg), however the crizotinib group in all three studies received the recommended dose (250 mg). Performance bias was high in all three studies whereas, and the attrition bias was high in two studies (Toyoaki Hida 2017 and Solange peters 2017). The results of meta-analysis showed that: the overall response rate [OR = 2.07, 95% CI (1.41, 3.06), P = 0.0002], the progression free survival [HR = 0.34, 95% CI (0.21, 0.55), P <0.0001], the partial response [OR = 1.71, 95% CI (1.19, 2.46), P = 0.003], P = 0.001], in alectinib group were higher than that of crizotinib group. Though the total number of events in complete response and the disease control rate were more in alectinib group than that of crizotinib group, the meta-analysis results shows no significant differences between two drugs in the disease control rate [OR = 2.24, 95% CI (0.56, 8.88), P = 0.25], the complete response [OR = 1.82, 95% CI (0.75, 4.45), P = 0.19]. In addition, the number of events in the stable disease [OR = 0.45, 95% CI (0.28, O.74), P = 0.001], and the adverse events [OR = 0.50, 95% CI (0.23, 0.81), P = <0.0001] in alectinib group were lower than that of crizotinib group.ConclusionAlectinib in terms of overall response rate, progression-free survival and partial response is superior to crizotinib in the treatment of ALK-positive non-small cell lung cancer and is well tolerated. Compared with crizotinib, alectinib is more effective than crizotinib and has a lower incidence of total adverse reactions. Meta-analysis results confirm the strong base for alectinib as a first-line treatment for ALK-positive NSCLC.

CSF rhinorrhea following alectinib treatment for anaplastic lymphoma kinase rearranged lung adenocarcinoma - e contrario

Cerebrospinal fluid (CSF) rhinorrhea is a condition characterized by leakage of CSF from skull base through the nostril(s). It is commonly associated with trauma, surgery, infections of paranasal sinuses/skull base, and intracranial and skull base tumors. Among malignant causes, lung cancer is rarely associated with CSF rhinorrhea. Herein, we report the case of a 51-year-old lady who was initially diagnosed with metastatic lung adenocarcinoma (LUAC) with anaplastic lymphoma kinase (ALK) rearrangement and initiated on treatment with alectinib. She had good clinicoradiological response, but on follow-up developed CSF rhinorrhea that required surgical correction. We also discuss the proposed mechanisms associated with occurrence of CSF rhinorrhea in the setting of metastatic ALK-rearranged LUAC.

N-[18F]-Fluoroacetylcrizotinib: A potentially potent and selective PET tracer for molecular imaging of non-small cell lung cancer

N-[18F]fluoroacetylcrizotinib, a fluorine-18 labeled derivative of the first FDA approved tyrosine kinase inhibitor (TKI) for the treatment of Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), crizotinib, was successfully synthesized for use in positron emission tomography (PET). Sequential in vitro biological evaluation of fluoracetylcrizotinib and in vivo biodistribution studies of [18F]fluoroacetylcrizotinib demonstrated that the biological activity of the parent compound remained unchanged, with potent ALK kinase inhibition and effective tumor growth inhibition. These results show that [18F]fluoroacetylcrizotinib has the potential to be a promising PET ligand for use in NSCLC imaging. The utility of PET in this context provides a non-invasive, quantifiable method to inform on the pharmacokinetics of an ALK-inhibitor such as crizotinib prior to a clinical trial, as well as during a trial in the event of acquired drug resistance.

Acquired Resistance to Alectinib in ALK-Rearranged Lung Cancer due to ABCC11/MRP8 Overexpression in a Clinically Paired Resistance Model.

Alectinib is used as a first-line treatment for anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Whereas other ALK inhibitors have been reported to be involved in resistance to ATP-binding cassette (ABC) transporters, no data are available regarding the association between resistance to alectinib and ABC-transporters. To investigate whether ABC-transporters contribute to alectinib resistance, ABC-transporter expression in alectinib-resistant cell lines derived from a patient with ALK-rearranged NSCLC and from H2228 lung cancer cells was evaluated and compared with that in each parent cell type. ATP-binding cassette subfamily C member 11 (ABCC11) expression was significantly increased in alectinib-resistant cell lines compared with that in alectinib-sensitive lines. ABCC11 inhibition increased sensitivity to alectinib in vitro ABCC11-overexpressing cells were established by transfection of an ABCC11 expression vector into H2228 cells, while control cells were established by transfecting H2228 cells with an empty vector. ABCC11-overexpressing cells exhibited decreased sensitivity to alectinib compared with that of control cells in vitro Moreover, the tumor growth rate following alectinib treatment was higher in ABCC11-overexpressing cells than that in control cells in vivo In addition, the intracellular alectinib concentration following exposure to 100 nmol/L alectinib was significantly lower in the ABCC11-overexpressing cell line compared with that in control cells. This is the first preclinical evidence showing that ABCC11 expression may be involved in acquired resistance to alectinib.

&lt;p&gt;Alectinib Induced Regression of Renal and Hepatic Cysts Caused by Crizotinib&lt;/p&gt;

BackgroundCrizotinib is the first tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC). An increased incidence of renal cysts has been described during the crizotinib treatment.Case PresentationWe herein report the case of a 74-year-old woman who received crizotinib for metastatic ALK-positive NSCLC. During the crizotinib treatment, complex renal cystic lesions with invasion of perirenal spaces and iliopsoas muscle appeared; two complex hepatic cysts were also observed. Almost all lesions disappeared after switching to alectinib, a second-generation ALK inhibitor.ConclusionIt would seem that alectinib is able to reduce in size and number hepatic and renal cysts caused by the crizotinib treatment. Nevertheless, further studies are needed to clarify the role of both crizotinib in the onset of renal and hepatic cysts and alectinib in their disappearance.

Drug resistance mechanisms in Japanese anaplastic lymphoma kinase‐positive non–small cell lung cancer and the clinical responses based on the resistant mechanisms

The treatment for anaplastic lymphoma kinase (ALK)‐positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK‐TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK‐positive lung cancer during multiple ALK‐TKI treatments to reveal the resistance mechanisms to ALK‐TKI. Among 32 patients, 24 patients received more than two ALK‐TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P‐gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK‐TKI treatment duration was longer in the on‐target treatment group than that in the off‐target group (13.0 vs 1.2 months). In conclusion, resistance to ALK‐TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK‐TKI treatment strategies.

Crizotinib versus chemotherapy: a real-world cost-effectiveness study in China.

Aim: To assess the cost-effectiveness of crizotinib verses platinum-based doublet chemotherapy as the first-line treatment for anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in the real-world setting. Methods: Data from 163 advanced ALK positive NSCLC patients were collected from West China Hospital, Sichuan University (Chengdu, China). They were categorized into two groups as treated with crizotinib (n=83) or chemotherapy (n=80) as a first-line therapy. The progression-free survival (PFS) as the primary clinical outcome, and the direct medical costs were collected from hospital information systems. Incremental cost-effectiveness ratio (ICER) was calculated with costs, quality-adjusted life-years, as well as the costs discounted at 3% annually. Additionally, two different kinds of medical insurance (MI) for pharma-economic assessment were considered. Results: Crizotinib improved PFS versus chemotherapy in ALK positive patients (median PFS 19.67m vs 5.47m; p < 0.001). Moreover, crizotinib obtained an ICER of US$36,285.39 before the end of 2016, when crizotinib, pemetrexed and anti-angiogenesis drugs were not MI covered. This is more than the willingness to pay threshold (three-times of gross domestic product per capita in mainland China or Sichuan Province). However, ICER was US$7321.16, which is less than willingness to pay, when crizotinib and all chemotherapy drugs were covered by MI from the end of 2016. Sensitivity analysis demonstrated a 99.7% probability for crizotinib to be more cost-effective than chemotherapy, when crizotinib and all anticancer drugs were MI covered. One-way sensitivity analysis for the reimbursement ratio of crizotinib indicated that cost-effective tendency for crizotinib increased as reimbursement ratio increased. Conclusion: Crizotinib could be an effective, and cost-effective first-line treatment for ALK positive advanced NSCLC with the MI coverage currently available in Chengdu, Sichuan Province, China.

Crizotinib-induced osteitis mimicking bone metastasis in a stage IV ALK-rearranged NSCLC patient: a case report

BackgroundTargeted therapies are a standard of care for first-line treatment of Anaplastic lymphoma kinase (ALK)-rearranged non small cell lung cancer (NSCLC). Giving the rapid pace of drug discovery and development in this area, reporting of adverse effects of ALK inhibitors is crucial. Here, we report a case of osteitis induced by an ALK inhibitor mimicking bone metastasis, a previously undescribed side effect of crizotinib.Case presentationA 31-year-old woman with stage IV ALK-rearranged NSCLC presented with back pain after 3 months of crizotinib treatment. Diagnostic work-up showed osteitis on the 4th and 5th thoracic vertebrae, anterior soft tissue infiltration and epiduritis, without any sign of infection. Spinal cord decompression, histological removal and osteosynthesis were performed. Histologic examination showed necrosis with abundant peripheral neutrophils, no microorganism nor malignant cell. Symptoms and Computarized Tomography-abnormalities rapidly diseappeared after crizotinib withdrawal and did not recur after ceritinib onset.ConclusionsThis is the first report of crizotinib-induced osteitis. Crizotinib differs from other ALK inhibitors as it targets other kinases as well, which may have been responsible for the osteitis. Crizotinib can induce rapidly extensive osteitis, which can mimic tumor progression.

The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants

Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib. This phase 1, open-label, two-period, crossover study estimated the effect of oral rifampin (a strong CYP3A inducer) on the pharmacokinetics and safety of oral lorlatinib (NCT02804399). Healthy participants received single-dose lorlatinib 100mg in period 1 followed by rifampin 600mg/day (days 1-12) and single-dose lorlatinib 100mg (day 8) in period 2. Blood samples were collected for 120h after each dose of lorlatinib. When a single dose of lorlatinib was administered during daily dosing with rifampin (period 2), the area under the plasma concentration-time profile extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of lorlatinib were 14.74% [90% confidence interval (CI) 12.78%, 17.01%] and 23.88% (90% CI 21.58%, 26.43%), respectively, of those in period 1 (lorlatinib alone). A single dose of lorlatinib was well tolerated in period 1, but elevations in transaminase values were observed in all participants (grade 2-4 in 11 participants) within 1-3days after a single dose of lorlatinib was administered with ongoing rifampin in period 2. Rifampin dosing was therefore halted. Transaminase levels subsequently returned to normal (median time to recovery: 15days). No elevations in bilirubin were observed. The addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers. ClinicalTrials.gov identifier, NCT02804399.

Phase II Trial of CH5424802 (alectinib hydrochloride) for Recurrent or Refractory ALK-Positive Anaplastic Large Cell Lymphoma

Introduction: Anthracycline-based combination chemotherapy is a standard first-line treatment for anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) both in adults and children, which results in favorable clinical outcomes. However, a standard therapy has not been established for recurrent or refractory diseases. Because many treatment options, such as hematopoietic stem cell transplantation, are available, patients with diseases that are resistant to conventional chemotherapies have particularly poor prognosis. Brentuximab vedotin, an anti-CD30 antibody drug conjugate, has improved the prognosis of recurrent or refractory ALCL; however, other types of novel agents have not yet been investigated. ALK inhibition could be a promising therapeutic strategy for ALK-positive malignancies. Therefore, this study aimed to determine the efficacy and safety of alectinib, a second-generation ALK inhibitor, in patients with recurrent or refractory ALK-positive ALCL.Methods: In this open-label, phase II trial, patients with recurrent or refractory ALK-positive ALCL diagnosed by histological examination were eligible. Other major inclusion criteria were as follows: age >6 years, ECOG performance status 0-2, at least one measurable lesion, and preserved organ functions. Alectinib 300 mg was administered orally twice a day (600 mg/day). Patients who weighed <35 kg were administered reduced doses of alectinib, i.e., 150 mg twice a day (300 mg/day). The primary endpoint was the response rate according to the Revised Response Criteria for Malignant Lymphoma. The secondary endpoints were pharmacokinetics, safety in children, complete response rate, response duration, progression-free survival, event-free survival, overall survival, and adverse events (AEs). All patients who received at least one dose of alectinib were evaluated for responses and toxicities. We expected that a response rate of 85% and a statistical power of 79% could be obtained for 10 patients with an alpha level of 0.05 (one tailed). This study is registered in UMIN-CTR (UMIN 000016991).Results: Ten patients were enrolled in the study from May 2015 to November 2017. The median age was 19.5 (range, 6-70) years. Of 10 patients, 8 were administered alectinib 600 mg/day and 2 were administered with 300 mg/day. Objective tumor responses were documented in 8 of 10 patients (80%; 90% confidence interval: 56.2-95.9), with CR in 6 and PR in 2 according to the independent review committee. Two patients underwent stem cell transplantation after alectinib treatment. Five patients continued to take alectinib at the data cut-off. One-year overall survival and progression-free survival rates were 70.0% and 58.3% (Fig), respectively. Three patients died owing to disease progression. A severe AE was observed in 1 patient (grade 3 acute pharyngitis). Grade 4 AEs were observed in 1 patient (neutropenia). Common AEs observed were diarrhea in 2 patients, upper respiratory infection in 3, elevated alkaline phosphatase in 3, and maculopapular rash in 4. No unexpected AEs were experienced. The mean steady state peak concentration of alectinib was 479.5, 676.7, and 391.1 ng/mL in patients aged <15 years administered 300 mg/day, those aged <15 years admisnitered 600 mg/day, and those aged >15 years administered 600 mg/day, respectively. The mean time to reach the peak concentrations was 4, 4, and 5 h, respectively.Conclusion: Alectinib showed favorable clinical activity and was well tolerated in patients with ALK-positive ALCL who progressed on standard chemotherapy. This study demonstrated similar pharmacokinetic profiles between pediatric and adult patients. Therefore, alectinib could be a suitable treatment for both pediatric and adult patients with recurrent or refractory ALK-positive ALCL. [Display omitted] DisclosuresSekimizu:Eli Lilly and Company: Speakers Bureau. Kada:Bayer Yakuhin, Ltd: Membership on an entity's Board of Directors or advisory committees. Nagai:HUYA Bioscience International: Research Funding; Bayer Yakuhin Ltd.: Research Funding; Esai Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AstraZeneca plc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Roche Ltd.: Honoraria; SymBio Pharmaceuticals Limited: Research Funding; Celgene Corporation: Honoraria, Research Funding; Sanofi K. K.: Honoraria; Mundipharma K.K.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Gilead Sciences Inc.: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Zenyaku Kogyo Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Abbvie G. K.: Research Funding.

Administration of crizotinib via jejunostomy tube: A case report

Crizotinib is an orally available tyrosine kinase inhibitor, approved for treatment of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement-positive non-small cell lung cancer (NSCLC). According to the product leaflet, crizotinib capsules should be swallowed whole, and should not be crushed, dissolved or opened. However, this manner of administration is not always possible. At present, literature is lacking regarding the absorption of crizotinib via percutaneous endoscopic jejunostomy (PEJ) tube. We report a case of a patient with ALK+ NSCLC who was administered crizotinib via PEJ tube. An adequate steady state crizotinib trough concentration was reached, resulting in a metabolic response. Safety for the caregiver was ensured since the administration of crizotinib was made without crushing or opening the capsule. This case supports the option for providing crizotinib via PEJ tube in patients who have ALK+ NSCLC and are unable to swallow whole capsules. This option might also apply to the administration of other ALK inhibitors. Keywords Crizotinib, ALK inhibitor, percutaneous endoscopic jejunostomy tube, pharmacokinetics, non-small cell lung cancer.

Administration of crizotinib via jejunostomy tube: A case report

Crizotinib is an orally available tyrosine kinase inhibitor, approved for treatment of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement-positive non-small cell lung cancer (NSCLC). According to the product leaflet, crizotinib capsules should be swallowed whole, and should not be crushed, dissolved or opened. However, this manner of administration is not always possible. At present, literature is lacking regarding the absorption of crizotinib via percutaneous endoscopic jejunostomy (PEJ) tube. We report a case of a patient with ALK+ NSCLC who was administered crizotinib via PEJ tube. An adequate steady state crizotinib trough concentration was reached, resulting in a metabolic response. Safety for the caregiver was ensured since the administration of crizotinib was made without crushing or opening the capsule. This case supports the option for providing crizotinib via PEJ tube in patients who have ALK+ NSCLC and are unable to swallow whole capsules. This option might also apply to the administration of other ALK inhibitors. Keywords: Crizotinib, ALK inhibitor, percutaneous endoscopic jejunostomy tube, pharmacokinetics, non-small cell lung cancer.

Abstract 902: In vitro and in vivo characterization of resistance to lorlatinib treatment in ALK mutated cancers

Abstract The development of targeted therapy has significantly improved the treatment of Anaplastic Lymphoma Kinase (ALK) dependent neoplasias such as Anaplastic Large Cell Lymphoma (ALCL) and Non-Small Cell Lung Cancer (NSCLC). Despite the efficacy of ALK inhibitor crizotinib, acquired resistance is a major challenge. Lorlatinib is a second generation inhibitor with improved activity and selectivity against ALK. To investigate resistance mechanisms that may arise on lorlatinib therapy, we selected in vitro and in vivo lorlatinib resistant tumor cells. In vivo, 10 mice carrying subcutaneous Karpas299 xenografts received vehicle or lorlatinib at increasing doses, starting at 0.1 mg/kg BID. As expected, tumor size was significantly reduced in lorlatinib group compared to controls. After initial partial responses, tumors relapsed and mice were shifted to an increased dose (0.25 mg/kg). Tumors relapsed again and mice were randomized into three groups, to achieve a maximum dose of 0.5, 1 or 2 mg/kg. In all cases tumors regrew after an initial response, indicating acquired resistance to lorlatinib. Upon mice sacrifice, tumors were collected and characterized. All ex vivo cell lines were resistant to lorlatinib as assessed by proliferation assay and 2/10 showed moderate drug addiction. However, in several cases, ALK phosphorylation did not fully correlate with the observed high drug resistance, suggesting the involvement of ALK-independent mechanisms. ALK kinase domain sequencing revealed N1178H mutation in 5/10 mice, alone or in combination with other mutations and L1196M substitution in 2/10 cases. Since both mutants have been described as sensitive or moderately resistant to lorlatinib in murine BaF3 cells, further characterization of these cell lines was performed. ALK N1178H mutant was found to be predominantly localized in the cytoplasm, possibly mimicking overexpression, in human cells. Whole-exome and mRNA sequencing of cells carrying the L1196M substitution showed significant alterations in the PI3K/AKT and RAS/MAPK pathways, as well as perturbations of RAC1-related small GTPases. Functional validation by small molecule inhibitors confirmed the involvement of these pathways in resistance to lorlatinib. In vitro selected lorlatinib-resistant cell lines, representing ALCL, NSCLC and neuroblastoma, showed both ALK mutations, including G1202R and C1156F/L1198F, and ALK-independent mechanisms of resistance. In one case, NSCLC cells acquired hyper-activation of EGFR; its blockage by erlotinib restored sensitivity to lorlatinib. Whole-exome sequencing and proteomic profiling of sensitive and resistant neuroblastoma cell lines revealed NF1 and EP300 mutations, as well as hyper-activation of ErbB4, in lorlatinib-resistant cells. Altogether, our data provide an extensive characterization of resistance mechanisms that may arise in different ALK positive cancers upon lorlatinib exposure. Citation Format: Geeta G. Sharma, Sara Redaelli, Monica Ceccon, Marina Zappa, Carlo Gambacorti-Passerini, Luca Mologni. In vitro and in vivo characterization of resistance to lorlatinib treatment in ALK mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 902.