Oral Anaplastic Lymphoma Kinase Research Articles

Evaluation of the drug-drug interaction potential of brigatinib using a physiologically-based pharmacokinetic modeling approach.

Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. Invitro studies indicated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4 and inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K. Clinical drug-drug interaction (DDI) studies with the strong CYP3A inhibitor itraconazole or the strong CYP3A inducer rifampin demonstrated that CYP3A-mediated metabolism was the primary contributor to overall brigatinib clearance in humans. A physiologically-based pharmacokinetic (PBPK) model for brigatinib was developed to predict potential DDIs, including the effect of moderate CYP3A inhibitors or inducers on brigatinib pharmacokinetics (PK) and the effect of brigatinib on the PK of transporter substrates. The developed model was able to predict clinical DDIs with itraconazole (area under the plasma concentration-time curve from time 0 to infinity [AUC∞] ratio [with/without itraconazole]: predicted 1.86; observed 2.01) and rifampin (AUC∞ ratio [with/without rifampin]: predicted 0.16; observed 0.20). Simulations using the developed model predicted that moderate CYP3A inhibitors (e.g., verapamil and diltiazem) may increase brigatinib AUC∞ by ~40%, whereas moderate CYP3A inducers (e.g., efavirenz) may decrease brigatinib AUC∞ by ~50%. Simulations of potential transporter-mediated DDIs predicted that brigatinib may increase systemic exposures (AUC∞) of P-gp substrates (e.g., digoxin and dabigatran) by 15%-43% and MATE1 substrates (e.g., metformin) by up to 29%; however, negligible effects were predicted on BCRP-mediated efflux and OCT1-mediated uptake. The PBPK analysis results informed dosing recommendations for patients receiving moderate CYP3A inhibitors (40% brigatinib dose reduction) or inducers (up to 100% increase in brigatinib dose) during treatment, as reflected in the brigatinib prescribing information.

Activity of ceritinib in crizotinib-resistant ROS1-rearranged non-small-cell lung cancer patients.

As a second-generation selective oral anaplastic lymphoma kinase inhibitor, ceritinib is an effective first-line treatment for c-ros oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC). Its efficacy and safety for the treatment of crizotinib-resistant ROS1-rearranged NSCLC were explored in the study. A retrospective single-center study was conducted to investigate the efficacy of ceritinib in crizotinib-resistant ROS1-rearranged NSCLC. The objective response rate was the primary objective, while the disease control rate, progression-free survival and adverse events were secondary objectives. From December 2015 to October 2021, a total of 246 patients with ROS1-rearranged NSCLC were screened, 12 (4.9%) of whom were treated with ceritinib after the development of crizotinib resistance. Among the 12 crizotinib-resistant patients included, 3 displayed the efficacy of partial response and 3 had the efficacy of stable condition. The objective response rate, disease control rate and median progression-free survival of all patients were 25% (95% confidence interval [CI]: -3.7% to 53.7%; 3 of 12 patients), 50% (95% CI: 16.8% to 83.2%; 6 of 12 patients), and 10.5 months (95% CI, 5.7 to 15.3 months), respectively. In addition, of the 6 patients with brain metastases, an intracranial disease control rate of 66.7% (95% CI:12.5% to 120.9%) was obtained. The research results reveal that ceritinib can be a treatment option for ROS1-rearranged NSCLC patients after the development of crizotinib resistance.

A Clinical Research of Ceritinib Treating Patients with ALK-Positive Advanced Non-small Cell Lung Cancer with Brain Metastasis

Objective: As a second-generation oral anaplastic lymphoma kinase (ALK) inhibitor, ceritinib was recommended as posterior line therapy in patients with crizotinib resistance or intolerance. While in the real world, the clinical efficacy and safety of ceritinib, 450mg/d, taken with a low-fat meal in crizotinib resistant patients, especially with brain metastases, are still to be further investigated. Methods: This retrospective analysis was conducted on patients with ALK- positive advanced non-small cell lung cancer (NSCLC) between May 2017 and December 2020 in our hospital, who were crizotinib resistant or intolerant. The aim was to analyze the clinical efficacy and safety of ceritinib as posterior line therapy in patients, especially in those with brain metastases, and to further explore the efficacy against rare fusion of ALK and the option after ALK inhibitor resistance. RECIST (1.1) criteria were adopted, and for relevant statistical analysis, RStudio was used. Results: Of the 13 cases treated with ceritinib, 8 were treated as second-line therapy, 5 as third-line or fourth-line treatment. Of the total, 12 had brain metastases, 3 had received brain radiotherapy previously, and 1 had received surgical treatment for brain metastases previously. There were 8 cases evaluated as partial remission (PR), 2 evaluated as stable disease (SD), and 3 unevaluable for the response. There were 1 case of PKNOX2-ALK fusion and 1 case of IGR-ALK fusion observed as rare ALK fusion, and intracranial lesions were evaluated as PR for both. There were 6 cases received subsequent targeted therapy after progression of ceritinib, including 5 with alectinib and 1 with ensartinib, all of which showed response. In 13 cases, by the terminal time of follow-up, median progression-free survival (PFS) was 7.4 m, disease control rate (DCR) was 76.92%, overall response rate (ORR) was 61.54%, and median overall survival (OS) was 25.4m. In 12 cases with brain metastasis, 9 were suitable for intracranial response evaluation, of which, 1 case achieved CR for intracranial lesions, 7 achieved PR and 1 SD was observed, ORR was 88.89%, and DCR was 100%. The adverse events rate of any grade was 91.67%, the common adverse events were diarrhea (46.15%), AST level increased (41.67%), ALT level increased (33.33%), increased GGT (33.33%), increased ALP (25.00%), nausea (16.67%), increased creatinine (16.67%). Other reported AEs were cough, vomiting, dizziness, arthralgia and fatigue, 1 case (8.33%) each. Conclusion: Ceritinib 450mg taken with taken with low-fat meal showed good efficacy and safety in crizotinib resistant patients with central nervous system metastasis, and it is effective in some cases with rare fusion of ALK.

Oral coadministration of elacridar and ritonavir enhances brain accumulation and oral availability of the novel ALK/ROS1 inhibitor lorlatinib

Lorlatinib, a novel generation oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor with high membrane and blood-brain barrier permeability, recently received accelerated approval for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), and its further clinical development is ongoing. We previously found that the efflux transporter P-glycoprotein (MDR1/ABCB1) restricts lorlatinib brain accumulation and that the drug-metabolizing enzyme cytochrome P450-3A (CYP3A) limits its oral availability. Using genetically modified mouse models, we investigated the impact of targeted pharmacological inhibitors on lorlatinib pharmacokinetics and bioavailability. Upon oral administration of lorlatinib, the plasma AUC0-8h in CYP3A4-humanized mice was ∼1.8-fold lower than in wild-type and Cyp3a–/– mice. Oral coadministration of the CYP3A inhibitor ritonavir caused reversion to the AUC0-8h levels seen in wild-type and Cyp3a–/– mice, without altering the relative tissue distribution of lorlatinib. Moreover, simultaneous pharmacological inhibition of P-glycoprotein and CYP3A4 with oral elacridar and ritonavir in CYP3A4-humanized mice profoundly increased lorlatinib brain concentrations, but not its oral availability or other relative tissue distribution. Oral lorlatinib pharmacokinetics was not significantly affected by absence of the multispecific Oatp1a/1b drug uptake transporters. The absolute oral bioavailability of lorlatinib over 8 h in wild-type, Cyp3a–/–, and CYP3A4-humanized mice was 81.6%, 72.9%, and 58.5%, respectively. Lorlatinib thus has good oral bioavailability, which is markedly restricted by human CYP3A4 but not by mouse Cyp3a. Pharmacological inhibition of CYP3A4 reversed these effects, and simultaneous P-gp inhibition with elacridar boosted absolute brain levels of lorlatinib by 16-fold without obvious toxicity. These insights may help to optimize the clinical application of lorlatinib.

P-glycoprotein and breast cancer resistance protein restrict brigatinib brain accumulation and toxicity, and, alongside CYP3A, limit its oral availability.

Brigatinib is an FDA-approved oral anaplastic lymphoma kinase (ALK) inhibitor for treatment of metastatic non-small cell lung cancer (NSCLC). Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3 A in plasma pharmacokinetics and tissue distribution of brigatinib. In vitro, brigatinib was exceptionally well transported by human ABCB1 and mouse Abcg2, and efficiently by human ABCG2. Following oral brigatinib administration (10 mg/kg), brain accumulation was dramatically increased in Abcb1a/1b-/- (19.3-fold) and Abcb1a/1b;Abcg2-/-(41.8-fold), but not in single Abcg2-/- mice compared to wild-type mice. Brigatinib testis accumulation showed qualitatively similar behavior. mAbcb1a/1b and mAbcg2 together restricted systemic exposure of brigatinib: with both systems absent oral availability increased 1.9-fold. Coadministration of elacridar, an ABCB1/ABCG2 inhibitor, caused a pronounced increase (36-fold) in brain-to-plasma ratios of brigatinib, approaching the levels seen in Abcb1a/1b;Abcg2-/- mice. Unexpectedly, lethal toxicity of oral brigatinib was observed in mice with genetic knockout or pharmacological inhibition of mAbcb1a/1b and mAbcg2, indicating a pronounced protective role for these transporters. In Cyp3a-/- mice, brigatinib plasma exposure increased 1.3-fold, and was subsequently 1.8-fold reduced by transgenic overexpression of human CYP3 A4 in liver and intestine. The relative tissue distribution of brigatinib, however, remained unaltered. ABCB1 and ABCG2 thus limit brain accumulation, toxicity, and systemic exposure of brigatinib, whereas CYP3 A also markedly restricts its oral availability. Unexpected toxicities should therefore be carefully monitored when brigatinib is coadministered with ABCB1/ABCG2 inhibitors in patients. Collectively, these insights may support the clinical application of brigatinib.

P-glycoprotein (MDR1/ABCB1) restricts brain accumulation and cytochrome P450-3A (CYP3A) limits oral availability of the novel ALK/ROS1 inhibitor lorlatinib.

Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small-cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains. In vitro, human ABCB1 and mouse Abcg2 modestly transported lorlatinib. Following oral lorlatinib administration (at 10 mg/kg), brain accumulation of lorlatinib, while relatively high in wild-type mice, was still fourfold increased in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, but not in single Abcg2-/- mice. Lorlatinib plasma levels were not altered. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar increased the brain accumulation of lorlatinib in wild-type mice fourfold, that is, to the same level as in Abcb1a/1b;Abcg2-/- mice, without altering plasma exposure. Similar results were obtained for lorlatinib testis accumulation. In Cyp3a-/- mice, the plasma exposure of lorlatinib was increased 1.3-fold, but was then twofold reduced upon transgenic overexpression of human CYP3A4 in liver and intestine, whereas relative tissue distribution of lorlatinib remained unaltered. Our data indicate that lorlatinib brain accumulation is substantially limited by P-glycoprotein/ABCB1 in the blood-brain barrier, but this can be effectively reversed by elacridar coadministration. Moreover, oral availability of lorlatinib is markedly restricted by CYP3A4 activity. These insights may be used in optimizing the therapeutic application of lorlatinib.

In vitro metabolism of alectinib, a novel potent ALK inhibitor, in human: contribution of CYP3A enzymes

1. The in vitro metabolism of alectinib, a potent and highly selective oral anaplastic lymphoma kinase inhibitor, was investigated.2. The main metabolite (M4) in primary human hepatocytes was identified, which is produced by deethylation at the morpholine ring. Three minor metabolites (M6, M1a, and M1b) were also identified, and a minor peak of hydroxylated alectinib (M5) was detected as a possible precursor of M4, M1a, and M1b.3. M4, an important active major metabolite, was produced and further metabolized to M6 by CYP3A, indicating that CYP3A enzymes were the principal contributors to this route. M5 is possibly produced by CYP3A and other isoforms as the primary step in metabolism, followed by oxidation to M4 mainly by CYP3A. Alternatively, M5 could be oxidized to M1a and M1b via an NAD-dependent process. None of the non-CYP3A-mediated metabolism appeared to be major.4. In conclusion, this study suggests that involvement of multiple enzymes in the metabolism of alectinib reduces its potential for drug–drug interactions.

Brain accumulation of the EML4-ALK inhibitor ceritinib is restricted by P-glycoprotein (P-GP/ABCB1) and breast cancer resistance protein (BCRP/ABCG2)

We aimed to clarify the roles of the multidrug transporters ABCB1 and ABCG2 in oral availability and brain accumulation of ceritinib, an oral anaplastic lymphoma kinase (ALK) inhibitor used to treat metastatic non-small cell lung cancer (NSCLC) after progression on crizotinib. Importantly, NSCLC is prone to form brain metastases. Transport of ceritinib by human (h) ABCB1 or hABCG2 or mouse (m) Abcg2 was assessed in vitro. To study the single and combined roles of Abcb1a/1b and Abcg2 in ceritinib disposition in vivo, we used appropriate knockout mouse strains. Ceritinib was very efficiently transported by hABCB1, and efficiently by hABCG2 and mAbcg2 in vitro, and transport was specifically inhibited by the ABCB1 inhibitor zosuquidar and ABCG2 inhibitor Ko143, respectively. Absorption and 24-h oral availability were not significantly affected by the absence of Abcb1 and/or Abcg2, but the brain concentrations were greatly increased (>38-fold) in Abcb1a/1b−/− mice at 3 and 24h after oral administration of 20mg/kg ceritinib. The brain concentrations increased another ∼3-fold (to >90-fold) in Abcb1a/1b;Abcg2−/− mice, indicating that there was a significant additional effect of Abcg2-mediated transport of ceritinib as well in vivo. Overall, brain accumulation, but not the 24-h oral availability of ceritinib were profoundly restricted by Abcb1a/1b and Abcg2, with Abcb1a/1b being the dominant efflux protein. Our data suggest that coadministration of ceritinib with a dual ABCB1 and ABCG2 inhibitor may improve treatment of brain (micro) metastases positioned behind a functionally intact blood-brain barrier, and possibly also of tumors resistant to ceritinib due to ABCB1 or ABCG2 overexpression.

Ceritinib: First Global Approval

Ceritinib is an oral anaplastic lymphoma kinase (ALK) inhibitor developed by Novartis for the treatment of tumours characterised by genetic abnormalities in ALK. ALK is a member of the insulin receptor family of tyrosine kinases that can become oncogenic when fused to other proteins. Ceritinib has been approved in the US under 'Breakthrough Therapy' designation for the second-line treatment of ALK-positive non-small cell lung cancer (NSCLC). Regulatory submissions have also been made in the EU and other countries. Phase III development is ongoing worldwide to evaluate ceritinib both as a first- and second-line therapy for ALK-positive NSCLC. This article summarizes the milestones in the development of ceritinib leading to this first approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

Safety, activity, and pharmacokinetics of an oral anaplastic lymphoma kinase (ALK) inhibitor, ASP3026, observed in a “fast follower” phase 1 trial design.

2624^ Background: The efficient early development of agents intended for selected patient populations is challenging. ASP3026 is a selective, ATP-competitive, kinase inhibitor with in vitro IC50for ALK of 3.5 nM. Methods: Advancedsolid tumor patients (pts) received oral ASP3026 under fasting conditions without interruption in 3+3 dose escalation cohorts from 25 to 800 mg once daily (QD). The primary endpoint was to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ASP3026. To identify rapidly evidence of therapeutic activity a previously cleared cohort could enroll up to an additional 3 pts with advanced ALKdriven solid malignancies(ALK+) . A planned phase Ib expansion cohort was opened at the R2PD. RECIST 1.1 was used to determine response. Results: The dose escalation phase enrolled 33 pts, including 3 ALK+ pts , and the expansion cohort enrolled another 13 ALK+ pts [total pts N = 46; 48% men; median (range) age = 61 (19-77) years]. Three dose-limiting toxicities (DLTs) were observed: grade 2 nausea and vomiting leading to dose reduction at 525 mg QD; grade 3 rash at 800 mg QD leading to dose reduction and grade 3 ALT/AST elevation leading to study withdrawal at 800 mg QD, making 525 mg daily the MTD and RP2D. The most common adverse events of the entire cohort were: fatigue (44%), vomiting (39%), nausea (37%), and constipation (24%). Of 15 pts with ALK+ non-small cell lung cancer (NSCLC) who progressed on prior crizotinib 7 (44%) had a partial response (PR) and 8 (50%) had stable disease as the best response. The median progression free survival in the ALK+ pts was 5.9 (95% CI: 3.8-9.4) months. Eight pts were still receiving treatment at data cut off. There was no correlation between response and plasma ASP3026 concentrations (AUC and Cmax) in the ALK+ pts. ASP3026 demonstrated dose-proportionality for AUC and Cmax with a terminal half-life compatible with QD dosing. Conclusions: The “fast follower” design enabled enrollment of ALK+ pts who had partial responses before the MTD of 525mg QD was determined. ASP3026 had clinical activity in ALK+ NSCLC pts who progressed on crizotinib. Clinical trial information: NCT01401504.

Testing for anaplastic lymphoma kinase rearrangement to target crizotinib therapy: oncology, pathology and health economic perspectives

Crizotinib is a first-in-class oral anaplastic lymphoma kinase (ALK) inhibitor targeting ALK-rearranged non-small-cell lung cancer. The therapy was approved by the US FDA in August 2011 and received conditional marketing approval by the European Commission in October 2012 for advanced non-small-cell lung cancer. A break-apart FISH-based assay was jointly approved with crizotinib by the FDA. This assay and an immunohistochemistry assay that uses a D5F3 rabbit monoclonal primary antibody were also approved for marketing in Europe in October 2012. While ALK rearrangement has relatively low prevalence, a clinical benefit is exhibited in more than 85% of patients with median progression-free survival of 8–10 months. In this article, the authors summarize the therapy and alternative test strategies for identifying patients who are likely to respond to therapy, including key issues for effective and efficient testing. The key economic considerations regarding the joint companion diagnostic and therapy are also presented. Given the observed clinical benefit and relatively high cost of crizotinib therapy, companion diagnostics should be evaluated relative to response to therapy versus correlation alone whenever possible, and both high inter-rater reliability and external quality assessment programs are warranted.

Crizotinib: a guide to its use in previously treated advanced anaplastic lymphoma kinase-positive non-small cell lung cancer in the EU

Crizotinib (Xalkori®), an oral anaplastic lymphoma kinase (ALK) fusion protein inhibitor, was recently approved in the EU for the treatment of adults with previously treated ALK-positive advanced non-small cell lung cancer. In clinical trials in this patient population, crizotinib has shown benefits with regard to response and progression-free survival, and was associated with a generally manageable tolerability profile.

IS7-13 - Phase I/II Study of ALK Inhibitor CH5424802 in Patients with ALK-Positive Non-Small-Cell Lung Cancer

ABSTRACT Background CH5424802 was identified as a potent, selective, and oral anaplastic lymphoma kinase (ALK) inhibitor with a unique chemical scaffold. The first in human phase I/II study targeting patients with ALK-positive non-small-cell lung cancer (NSCLC) is ongoing. Here we report the outcomes of the phase I portion. Methods Patients were administered a single dose of CH5424802 under fasting conditions, followed 72 h later by twice daily dosing for 21 days. They were then evaluated for dose limiting toxicity (DLT). Administration was continued until disease progression. Results A total of 15 patients (M/F: 9/6) were treated with CH5424802 under fasting conditions in six cohorts (20 mg bid to 300 mg bid). Median age was 42 years. A DLT was not determined. Thus, the highest dose level defined in the protocol (300 mg bid) did not reach the maximum tolerated dose (MTD). Frequent toxic effects (no. of cases) were constipation (6), neutropenia (5), and myalgia (5). Grade 3 toxic effects were hypophosphatemia (2), neutropenia (2), blood CPK increased (1), and hypermagnesemia (1). Nausea was mild (2 cases of grade 1), and for eye disorders, which are thought to be characteristic of crizotinib, only 2 grade 1 cases were observed. PK data showed T1/2 ranging from 16 to 42 h, and dose-dependent increases of Cmax and AUC. All patients at all dose levels achieved tumor regression. At dose levels of 240 mg bid or more, all 7 patients with measurable lesions achieved a partial response. So far, 11 patients have been on study treatment >6 months. Conclusion CH5424802 was well tolerated with promising efficacy in patients with ALK-positive NSCLC. The phase II portion is ongoing.

Oncology Update

Crizotinib (Xalkori®), an oral anaplastic lymphoma kinase (ALK) inhibitor, has received U.S. Food and Drug Administration (FDA) approval for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has tested positive for ALK gene abnormalities.