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Littérature scientifique sur le sujet « Lorlatinib »

Auteur : Grafiati

Publié le 9 mars 2023

Mis à jour le 10 mars 2023

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Articles de revues sur le sujet "Lorlatinib"

Hibma, Jennifer E., Melissa O’Gorman, Sunil Nepal, Sylvester Pawlak, Katherine Ginman et Yazdi K. Pithavala. « Evaluation of the absolute oral bioavailability of the anaplastic lymphoma kinase/c-ROS oncogene 1 kinase inhibitor lorlatinib in healthy participants ». Cancer Chemotherapy and Pharmacology 89, n^o 1 (26 octobre 2021) : 71–81. http://dx.doi.org/10.1007/s00280-021-04368-1.

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Abstract Purpose Lorlatinib 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. Methods Eligible 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. Results In 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. Conclusion Both oral and IV lorlatinib were well-tolerated in healthy participants and oral lorlatinib is highly bioavailable after oral administration.

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Yildiz, Ibrahim. « Liver and Pancreatic Injury in Response to ALK Inhibitors in a Patient with Primary Signet Ring Cell Carcinoma of the Lung : A Case Report ». Case Reports in Oncology 14, n^o 1 (26 février 2021) : 107–11. http://dx.doi.org/10.1159/000512829.

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We report a patient with stage IV anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (primary lung signet ring cell adenocarcinoma) who received serial crizotinib, chemotherapy, and lorlatinib over more than 4 years. The patient discontinued crizotinib after approximately 4 months due to crizotinib-associated hepatotoxicity. Twenty-five days later, when transaminases had normalized, crizotinib was resumed. However, the patient’s liver enzymes rapidly increased again, and crizotinib was discontinued. After 6 cycles of platinum-based chemotherapy, lorlatinib was initiated. Hepatotoxicity did not recur with lorlatinib, a next-generation ALK inhibitor, but grade 4 hypertriglyceridemia and acute pancreatitis were induced by lorlatinib after 4 months. To our knowledge, this is the first case report of acute pancreatitis with lorlatinib. Additionally, stereotactic body radiation therapy (SBRT) was performed for residual small primary lesions in the lung without stopping lorlatinib. Given the rarity of radiation pneumonitis, especially with the relatively small fields treated by SBRT, we suspect that lorlatinib enhanced the pulmonary toxicity. Physicians should be aware that ALK inhibitors, such as lorlatinib and crizotinib, have potentially lethal side effects.

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Lin, Jessica Jiyeong, Ted Johnson, Jochen K. Lennerz, Charlotte Lee, Harper Grace Hubbeling, Beow Y. Yeap, Ibiayi Dagogo-Jack, Justin F. Gainor et Alice Tsang Shaw. « Resistance to lorlatinib in ROS1 fusion-positive non-small cell lung cancer. » Journal of Clinical Oncology 38, n^o 15_suppl (20 mai 2020) : 9611. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.9611.

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9611 Background: Lorlatinib is a potent, brain-penetrant ROS1/ALK tyrosine kinase inhibitor (TKI), which has demonstrated efficacy in advanced ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC), including in patients (pts) previously treated with crizotinib. Despite initial benefit, however, most pts experience disease progression on lorlatinib. Mechanisms of resistance to lorlatinib in ROS1+ NSCLC are poorly understood. Methods: We analyzed repeat tumor biopsies derived from advanced ROS1+ lung cancer pts progressing on lorlatinib. Next-generation sequencing (NGS, n = 17) or whole exome sequencing (n = 1) was performed to detect mutations, indels, and copy number alterations. Results: Sixteen pts underwent a total of 18 repeat tumor biopsies after progression on lorlatinib. Fourteen had received prior crizotinib; two received prior crizotinib and entrectinib. Median duration of therapy on lorlatinib was 13.5 months (95% CI, 8.3-18.4). Among the 18 cases analyzed by sequencing, 7 (38.9%) harbored a ROS1 resistance mutation, including G2032R (4/18, 22.2%), S1986F/L2000V (1/18, 5.6%), L2086F (1/18, 5.6%), and G2032R/S1986F/L2086F (1/18, 5.6%). Of note, ROS1 L2086F was a novel resistance mutation not previously reported in the literature, but analogous to ALK L1256F (a lorlatinib-resistant ALK mutation). Structural modeling studies showed that ROS1 L2086F causes steric interference with binding of lorlatinib, as well as crizotinib and entrectinib. In addition to ROS1 kinase domain mutations, NGS analyses also identified MET copy number gain in a lorlatinib-resistant case, validated by fluorescence in situ hybridization as high-level focal MET amplification (MET/CEP7 copy number ratio 6.3) without a concomitant ROS1 resistance mutation. Duration of therapy on lorlatinib was significantly shorter in pts with a post-lorlatinib ROS1 resistance mutation compared to those without (8.3 vs 18.1 months; p = 0.005). Conclusions: ROS1 resistance mutations are observed in over one-third of cases progressing on lorlatinib, including the solvent front mutation G2032R and a novel L2086F mutation. These findings underscore the importance of developing next-generation ROS1 TKIs with activity against ROS1 mutations, and the need to elucidate ROS1-independent resistance mechanisms.

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Romero, Diana. « Lorlatinib CROWNed ». Nature Reviews Clinical Oncology 18, n^o 1 (1 décembre 2020) : 6. http://dx.doi.org/10.1038/s41571-020-00458-w.

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Verdura, Sara, José Antonio Encinar, Salvador Fernández-Arroyo, Jorge Joven, Elisabet Cuyàs, Joaquim Bosch-Barrera et Javier A. Menendez. « Silibinin Suppresses the Hyperlipidemic Effects of the ALK-Tyrosine Kinase Inhibitor Lorlatinib in Hepatic Cells ». International Journal of Molecular Sciences 23, n^o 17 (1 septembre 2022) : 9986. http://dx.doi.org/10.3390/ijms23179986.

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The third-generation anaplastic lymphoma tyrosine kinase inhibitor (ALK-TKI) lorlatinib has a unique side effect profile that includes hypercholesteremia and hypertriglyceridemia in >80% of lung cancer patients. Here, we tested the hypothesis that lorlatinib might directly promote the accumulation of cholesterol and/or triglycerides in human hepatic cells. We investigated the capacity of the hepatoprotectant silibinin to modify the lipid-modifying activity of lorlatinib. To predict clinically relevant drug–drug interactions if silibinin were used to clinically manage lorlatinib-induced hyperlipidemic effects in hepatic cells, we also explored the capacity of silibinin to interact with and block CYP3A4 activity using in silico computational descriptions and in vitro biochemical assays. A semi-targeted ultrahigh pressure liquid chromatography accurate mass quadrupole time-of-flight mass spectrometry with electrospray ionization (UHPLC-ESI-QTOF-MS/MS)-based lipidomic approach revealed that short-term treatment of hepatic cells with lorlatinib promotes the accumulation of numerous molecular species of cholesteryl esters and triglycerides. Silibinin treatment significantly protected the steady-state lipidome of hepatocytes against the hyperlipidemic actions of lorlatinib. Lipid staining confirmed the ability of lorlatinib to promote neutral lipid overload in hepatocytes upon long-term exposure, which was prevented by co-treatment with silibinin. Computational analyses and cell-free biochemical assays predicted a weak to moderate inhibitory activity of clinically relevant concentrations of silibinin against CYP3A4 when compared with recommended (rosuvastatin) and non-recommended (simvastatin) statins for lorlatinib-associated dyslipidemia. The elevated plasma cholesterol and triglyceride levels in lorlatinib-treated lung cancer patients might involve primary alterations in the hepatic accumulation of lipid intermediates. Silibinin could be clinically explored to reduce the undesirable hyperlipidemic activity of lorlatinib in lung cancer patients.

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Hochmair, Maximilian J., Hannah Fabikan, Oliver Illini, Christoph Weinlinger, Ulrike Setinek, Dagmar Krenbek, Helmut Prosch et al. « Later-Line Treatment with Lorlatinib in ALK- and ROS1-Rearrangement-Positive NSCLC : A Retrospective, Multicenter Analysis ». Pharmaceuticals 13, n^o 11 (7 novembre 2020) : 371. http://dx.doi.org/10.3390/ph13110371.

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In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement–positive non–small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced ALK- or ROS1-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the ALK- and ROS1-positive groups, respectively. In the ALK-positive group, lorlatinib proved efficacy after both brigatinib and alectinib. Lorlatinib treatment was well tolerated. Later-line lorlatinib treatment can induce sustained responses in patients with advanced ALK- and ROS1-positive lung cancer.

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Solomon, Benjamin J., Todd Michael Bauer, Enriqueta Felip, Geoffrey Liu, Julien Mazieres, Filippo de Marinis, Yasushi Goto et al. « Progression-free survival with subsequent anticancer therapies from a phase 3 trial of lorlatinib in treatment-naive patients (pts) with ALK+ advanced non–small cell lung cancer (NSCLC). » Journal of Clinical Oncology 40, n^o 16_suppl (1 juin 2022) : 9069. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9069.

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9069 Background: Lorlatinib, a brain-penetrant, third generation ALK tyrosine kinase inhibitor (TKI), demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs crizotinib in a phase 3 study in pts with previously untreated ALK+ advanced NSCLC (CROWN; NCT03052608). This study investigated the efficacy of treatments following progression on lorlatinib or crizotinib from the CROWN trial. Methods: Pts were randomized 1:1 to receive oral lorlatinib 100 mg daily or crizotinib 250 mg twice daily. The primary endpoint was PFS assessed per blinded independent central review, and secondary endpoints included time from randomization to the date of progression of disease on first subsequent systemic anticancer therapy or death (PFS2). Results: As of September 20, 2021, 91 of 149 patients (61.1%) vs 12 of 147 patients (8.2%) were still receiving lorlatinib vs crizotinib, respectively. In the lorlatinib arm, 33 of 149 patients (22.1%) received ≥1 subsequent systemic anticancer therapy vs 103 of 147 patients (70.1%) in the crizotinib arm. Among the patients who received subsequent systemic anticancer therapy, most patients in both treatment arms received ALK TKIs as first subsequent treatment: 63.6% and 93.2% in the lorlatinib and crizotinib arms. Chemotherapy was administered as first subsequent therapy to 36.3% and 2.9% of the patients, respectively. Median duration of treatment on first subsequent anticancer therapy was 9.6 months (IQR, 2.9-18.1 months) for lorlatinib arm and 13.3 months (IQR, 4.8-21.2 months) for crizotinib arm. Median PFS2 was not reached (NR; 95% CI, NR-NR) in the lorlatinib arm and was 39.6 months (95% CI, 27.4-NR) in the crizotinib arm, with a hazard ratio for lorlatinib vs crizotinib of 0.45 (95% CI, 0.30-0.67). Conclusions: While subsequent anticancer therapies offered clinical benefit in both treatment arms, PFS2 results indicated that clinical benefit was prolonged with lorlatinib vs crizotinib. Clinical trial information: NCT03052608.

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Mori, Shunta, Hiroki Izumi, Jie Liu, Kosuke Tanaka, Shogo Kumagai, Takuma Hayashida, Yosuke Kagawa et al. « Abstract 5351 : LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 5351. http://dx.doi.org/10.1158/1538-7445.am2022-5351.

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Abstract Background: CLIP1-LTK was recently discovered as a novel oncogenic gene fusion in non-small cell lung cancer (NSCLC). Lorlatinib, an ALK/ROS1 inhibitor, can inhibit CLIP1-LTK constitutive kinase activity, and showed dramatic and promising efficacy in a patient with NSCLC harboring CLIP1-LTK fusion. However, acquired resistance to lorlatinib will be inevitably developed, especially by mutations in LTK gene, as 50-60% of oncogenic driver-positive NSCLC develop resistance to kinase inhibitors by acquired mutations in the target gene. The aim of this study is to identify the LTK mutations responsible for resistance to lorlatinib in CLIP1-LTK fusion positive NSCLC, and to explore compounds that can overcome resistance. Methods: As LTK and ALK share nearly 80% protein sequence identity in their respective kinase domains, we established Ba/F3 cells expressing CLIP1-LTK (Ba/F3-CLIP1-LTK) with six different LTK mutations (I565N, F568C, L590M, L592F, G596R, and G663A), all of which are analogous to reported ALK mutations responsible for resistance to lorlatinib. Ba/F3 cells expressing CLIP1-LTK with these different LTK mutations, as well as CLIP1-LTK-wild type (WT) were treated with several concentrations of lorlatinib. Then, the efficacy of other compounds including crizotinib, alectinib, ceritinib, brigatinib, entrectinib, giltertinib, repotorectinib was assessed to detect which compounds can overcome lorlatinib resistance. Results: All LTK mutations tested showed resistance to lorlatinib, with IC50s of lorlatinib ranging 2.7 to 31.3 nM, which were higher than that in Ba/F3-CLIP-LTK-WT (1.0 nM) in cell viability assay. An IC50 of giltertinib in Ba/F3-CLIP1-LTK-F568C was lower than that of lorlatinib (0.9 vs 2.7 nM). Moreover, an IC50 of giltertinib in Ba/F3-CLIP1-LTK-G663A was lower than that of lorlatinib (2.7 vs 19.4 nM). Ba/F3-CLIP1-LTK-L592F was rather sensitive to crizotinib compared with Ba/F3-CLIP1-LTK-WT (IC50, <0.1 vs 16.5 nM). Similarly, Ba/F3-CLIP1-LTK-G596R was similar to repotorectinib compared with WT (IC50, 10.4 vs 11.3 nM). The results of western blotting assay evaluating phosphorylation of CLIP1-LTK were in accordance with that obtained cell viability assay. Conclusion: We identified that several LTK mutations, analogous to ALK resistant mutations, were responsible for lorlatinib resistance, some of which can be overcome by existing compounds. Further validation and exploration are warranted to establish resistance mechanism-based precision medicine following lorlatinib treatment in CLIP1-LTK fusion-positive NSCLC. Citation Format: Shunta Mori, Hiroki Izumi, Jie Liu, Kosuke Tanaka, Shogo Kumagai, Takuma Hayashida, Yosuke Kagawa, Yuji Shibata, Shingo Matumoto, Koichi Goto, Susumu Kobayashi. LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5351.

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Ando, Koichi, Ryo Manabe, Yasunari Kishino, Sojiro Kusumoto, Toshimitsu Yamaoka, Akihiko Tanaka, Tohru Ohmori et Hironori Sagara. « Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK-Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non-Asian Patients : A Systematic Review and Network Meta-Analysis ». Cancers 13, n^o 15 (23 juillet 2021) : 3704. http://dx.doi.org/10.3390/cancers13153704.

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To date, there have been no head-to-head randomized controlled trials (RCTs) comparing the safety and efficacy of lorlatinib and alectinib in anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) ALK-inhibitor‒naïve advanced non-small cell lung cancer (NSCLC). We performed a network meta-analysis comparing six treatment arms (lorlatinib, brigatinib, alectinib, ceritinib, crizotinib, and platinum-based chemotherapy) in overall participants and in Asian and non-Asian subgroups. Primary endpoints were progression-free survival (PFS), overall survival (OS), and grade 3 or higher adverse events (G3-AEs). There were no significant differences between lorlatinib and alectinib in overall participants for both PFS (hazard ratio [HR], 0.742; 95% credible interval [CrI], 0.466–1.180) and OS (HR, 1.180; 95% CrI, 0.590–2.354). In the Asian subgroup, there were no significant differences in PFS between lorlatinib and alectinib (HR, 1.423; 95% CrI, 0.748–2.708); however, in the non-Asian subgroup, PFS was significantly better with lorlatinib than with alectinib (HR, 0.388; 95% CrI, 0.195–0.769). The incidence of G3-AEs in overall participants was significantly higher with lorlatinib than with alectinib (risk ratio, 1.918; 95% CrI, 1.486–2.475). These results provide valuable information regarding the safety and efficacy of lorlatinib in ALK-p ALK-inhibitor‒naïve advanced NSCLC. Larger head-to-head RCTs are needed to validate the study results.

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Goldsmith, Kelly C., Yael P. Mosse, Kimberly Kayser, Yueh-Yun Chi, Marc Chioda, Holger C. Thurm, Joseph Chen et al. « Phase I trial of lorlatinib in combination with topotecan/cyclophosphamide in children with ALK-driven refractory or relapsed neuroblastoma : A new approaches to neuroblastoma therapy consortium study. » Journal of Clinical Oncology 40, n^o 16_suppl (1 juin 2022) : 10041. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10041.

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10041 Background: Lorlatinib, a macrocyclic ATP-competitive ALK inhibitor, exerts potent activity against neuroblastoma (NB) xenograftsharboring the most common ALK mutations. We performed a first-in-child phase 1 study of lorlatinib for patients with refractory/relapsed (R/R) ALK aberrant high-risk NB. We previously reported on Part A of the study, where safety of single agent lorlatinib was determined, showing complete responses (CR) to lorlatinib at the recommended phase 2 dose (RP2D) of 115 mg/m2 in pts < 18 years and 150 mg in pts > 18 yrs. Part B of the study aimed to determine the safety, pharmacokinetics (PK), RP2D, and explore the anti-tumor activity of lorlatinib in combination with topotecan and cyclophosphamide in pts with R/R ALK-driven NB. Methods: Patients with R/R NB ages 1-17 years with ALK mutations or amplification were eligible; prior ALK inhibitor (ALKi) treatment was allowed. Lorlatinib was orally administered once daily on days 1-28 with topotecan (0.75 mg/m2/day) and cyclophosphamide (250 mg/m2/day) administered intravenously days 1-5 and GCSF starting day 6. Two lorlatinib dose levels (DL) of 95 mg/m2/day (DL4B) and 115 mg/m2/day (DL5B) were assessed using a 3+3 dose escalation design with the primary endpoint of dose limiting toxicity (DLT) in Course 1. We report lorlatinib safety, PK, and objective response rate (ORR) for patients enrolled on Part B. Results: Between 10FEB2020 and 03DEC2021,9 eligible pts enrolled on Part B with a median age of 6.7 years (3.7-12.7). Three pts were enrolled onto DL4B and six onto DL5B (2/3 pts on DL4B and 4/6 pts on DL5B had received prior ALKi therapy) with no DLT’s observed in course 1. One patient on DL5B experienced a neuropsychological DLT in Course 3. Most common treatment-related adverse events were hematological, febrile neutropenia, high cholesterol, hypertriglyceridemia, and neuropsychological effects. The median number of courses received was 6 with a range of 1-8 on DL4B and 1-7 on DL5B. Of the 8 patients evaluable for response, ORR was 50%: 2/3 pts on DL4B and 2/5 pts on DL5B. Preliminary PK data demonstrate comparable dose level-associated lorlatinib steady state exposure between Part B chemotherapy combination and Part A monotherapy cohorts, supporting that chemotherapy had no effect on lorlatinib exposure that there are no overlapping toxicities. Conclusions: Lorlatinib in combination with topotecan and cyclophosphamide is well tolerated, and early data suggest encouraging objective anti-tumor activity. These data support the current integration of lorlatinib into up-front high risk neuroblastoma therapy for patients with ALK-driven neuroblastoma. Clinical trial information: NCT03107988.

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Thèses sur le sujet "Lorlatinib"

GEETA, GEETA. « In vitro and in vivo characterization of resistance to lorlatinib treatment in ALK mutated cancers ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241123.

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La terapia personalizzata ha cambiato lo scenario clinico dei tumori ALK-positivi. Tuttavia, la resistenza farmacologica rimane un ostacolo importante cui far fronte. Lorlatinib è un farmaco di terza generazione che inibisce la maggior parte dei mutanti di ALK resistenti agli attuali inibitori. In questo studio sono state utilizzate in vitro e in vivo linee cellulari resistenti a lorlatinib derivanti da linfoma anaplastico a grandi cellule (ALCL), carcinoma polmonare non a piccole cellule (NSCLC) e neuroblastoma, allo scopo di studiare i meccanismi che guidano l'acquisizione della resistenza. In vitro, cellule di ALCL trattate con alte concentrazioni di lorlatinib hanno acquisito le seguenti mutazioni composte di ALK: G1202R/G1269A e C1156F/L1198F. In vivo, Le cellule di ALCL xenotrapiantate in topi immunocompromessi hanno acquisito le seguenti mutazioni ricorrenti: N1178H (5 topi su 10) e G1269A (4 topi su 10). È interessante notare che nelle cellule umane, dove l’espressione di NPM/ALK è tipicamente nucleare, la presenza della mutazione induce la localizzazione citoplasmatica di NPM/ALKN1178H, probabilmente mimandone l’overespressione. Nelle cellule resistenti si è osservata una significativa alterazione dei pathway di PI3K/AKT e RAS/MAPK, come dimostrato dall’analisi dell’espressione genica tramite RNA-seq. Il coinvolgimento di questi pathway nella resistenza a lorlatinib è stato confermato dalla validazione funzionale con inibitori. Le cellule di NSCLC trattate in vitro con lorlatinib hanno acquisito iperattivazione di EGFR. Il trattamento con un inibitore di EGFR, erlotinib, , è stato in grado di ripristinare la sensibilità a lorlatinib. In cellule di neuroblastoma resistenti a lorlatinib, il sequenziamento dell'intero esoma e l’analisi proteomica hanno rivelato una forma tronca di NF1 e l’iperattivazione di EGFR e ErbB4. Questi dati forniscono un'ampia caratterizzazione dei meccanismi di resistenza che possono insorgere in diversi tumori ALK-positivi dopo il trattamento con lorlatinib.
Targeted therapy changed the standard of care in ALK-dependent tumors. However, resistance remains a major challenge. Lorlatinib is a third-generation ALK inhibitor that inhibits most ALK mutants resistant to current ALK inhibitors. In this study, we utilize lorlatinib-resistant anaplastic large cell lymphoma (ALCL), non–small cell lung cancer (NSCLC), and neuroblastoma cell lines in vitro and in vivo to investigate the acquisition of resistance and its underlying mechanisms. ALCL cells acquired compound ALK mutations G1202R/G1269A and C1156F/L1198F in vitro at high drug concentrations. ALCL xenografts selected in vivo showed recurrent N1178H (5/10 mice) and G1269A (4/10 mice) mutations. Interestingly, intracellular localization of NPM/ALKN1178H skewed toward the cytoplasm in human cells, possibly mimicking overexpression. RNA sequencing of resistant cells showed signiﬁcant alteration of PI3K/AKT and RAS/MAPK pathways. Functional validation by small-molecule inhibitors conﬁrmed the involvement of these pathways in resistance to lorlatinib. NSCLC cells exposed in vitro to lorlatinib acquired hyperactivation of EGFR, which was blocked by erlotinib to restore sensitivity to lorlatinib. In neuroblastoma, whole-exome sequencing and proteomic proﬁling of lorlatinib-resistant cells revealed a truncating NF1 mutation and hyperactivation of EGFR and ErbB4. These data provide an extensive characterization of resistance mechanisms that may arise in different ALK-positive cancers following lorlatinib treatment.

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Livres sur le sujet "Lorlatinib"

Junod, Jake. Coloring Book - You Will Get Better - Lorlatinib. Independently Published, 2021.

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Chapitres de livres sur le sujet "Lorlatinib"

Richardson, Paul F. « Discovery and Early Development of the Next-Generation ALK Inhibitor, Lorlatinib (18) ». Dans Drug Discovery and Development, 185–218. Third edition. | Boca Raton, Florida : CRC Press, 2019. | : CRC Press, 2019. http://dx.doi.org/10.1201/9781315113470-12.

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Dugger, Robert, Bryan Li et Paul Richardson. « Discovery and Development of Lorlatinib : A Macrocyclic Inhibitor of EML4-ALK for the Treatment of NSCLC ». Dans ACS Symposium Series, 27–59. Washington, DC : American Chemical Society, 2019. http://dx.doi.org/10.1021/bk-2019-1332.ch002.

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Cairns, John Alexander. « Assessing the Cost-Effectiveness of Molecular Targeted Therapies and Immune Checkpoint Inhibitors ». Dans Human Perspectives in Health Sciences and Technology, 175–85. Cham : Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-92612-0_11.

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AbstractMolecular targeted therapies and immune checkpoint inhibitors have in recent years been transforming the care of many cancer patients. This chapter compares twenty-one appraisals of molecular targeted therapies in non-small-cell lung cancer, comprising six EGFR-TK inhibitors (gefitinib, erlotinib, afatinib, necitumumab, osimertinib and dacomitinib), five ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib and lorlatinib) and two ROS1 inhibitors (crizotinib and entrectinib), with fifteen appraisals of checkpoint inhibitors used in the treatment of non-small-cell lung cancer comprising the anti-PD-1 agents nivolumab and pembrolizumab, and the anti-PD-L1 agents atezolizumab and durvalumab. Differences with respect to economic evaluation, such as, in terms of the clinical evidence underlying the modelling of cost-effectiveness, and differences observed with respect to life-extending end-of-life status and with respect to inclusion in the Cancer Drugs Fund, are highlighted. The differences observed between the appraisal of the two types of therapy derive from the more limited clinical data and the more restricted application of the targeted medicines. This study of decision making with respect to oncology drugs is likely to be increasingly relevant to a much wider range of medicines, as differential weighting of QALYs and the use of managed access schemes are extended beyond oncology drugs.

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Yamazaki, Shinji. « Translational Modeling and Simulation for Molecularly Targeted Small Molecule Anticancer Agents : Case Studies of Multiple Tyrosine Kinase Inhibitors, Crizotinib and Lorlatinib ». Dans Early Drug Development, 433–66. Weinheim, Germany : Wiley-VCH Verlag GmbH & Co. KGaA, 2018. http://dx.doi.org/10.1002/9783527801756.ch16.

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Richardson, Paul F., et Ted W. Johnson. « Discovery of the ALK/ROS1 Inhibitor, Lorlatinib (PF-06463922) ». Dans 2017 Medicinal Chemistry Reviews, 45–66. Medicinal Chemistry Division of the American Chemical Society, 2017. http://dx.doi.org/10.29200/acsmedchemrev-v52.ch3.

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Actes de conférences sur le sujet "Lorlatinib"

Yoda, Satoshi, Leila Dardaei, Manrose Singh, Jeffrey A. Engelman, Alice T. Shaw et Aaron N. Hata. « Abstract 3144 : Prediction of ALK mutations associated with acquired resistance to lorlatinib ». Dans Proceedings : AACR Annual Meeting 2017 ; April 1-5, 2017 ; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-3144.

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Recondo, Gonzalo, Laura Mezquita, David Planchard, Anas Gazzah, Francesco Facchinetti, Ludovic Bigot, Ahsan Z. Rizvi et al. « Abstract 311 : Diverse biological mechanisms drive resistance to Lorlatinib in ALK-rearranged Lung Cancer ». Dans Proceedings : AACR Annual Meeting 2019 ; March 29-April 3, 2019 ; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-311.

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Sharma, Geeta G., Sara Redaelli, Monica Ceccon, Marina Zappa, Carlo Gambacorti-Passerini et Luca Mologni. « Abstract 902 : In vitro and in vivo characterization of resistance to lorlatinib treatment in ALK mutated cancers ». Dans Proceedings : AACR Annual Meeting 2018 ; April 14-18, 2018 ; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-902.

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Tangpeerachaikul, Anupong, Amit Deshpande, Nancy E. Kohl, Joshua C. Horan et Henry E. Pelish. « Abstract P244 : NVL-655 exhibits antitumor activity in lorlatinib-resistant and intracranial models of ALK-rearranged NSCLC ». Dans Abstracts : AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics ; October 7-10, 2021. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1535-7163.targ-21-p244.

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Shaw, Alice T., Jean-François Martini, Benjamin Besse, Todd M. Bauer, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely et al. « Abstract CT044 : Efficacy of lorlatinib in patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC) andALKkinase domain mutations ». Dans Proceedings : AACR Annual Meeting 2018 ; April 14-18, 2018 ; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-ct044.

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Okada, Koutaroh, Mitsugu Araki, Tomoko Oh-hara, Makoto Nishio, Yasushi Okuno, Naoya Fujita et Ryohei Katayama. « Abstract A125 : Predication of lorlatinib resistance mechanisms and therapeutic strategies to overcome the resistance in ALK rearranged non-small cell lung cancer ». Dans Abstracts : AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics ; October 26-30, 2019 ; Boston, MA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1535-7163.targ-19-a125.

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Pelish, Henry E., Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair et Joshua C. Horan. « Abstract 1468 : NUV-655 (NVL-655) is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation ». Dans Proceedings : AACR Annual Meeting 2021 ; April 10-15, 2021 and May 17-21, 2021 ; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1468.

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Bauer, Todd M., Jean-François Martini, Benjamin Besse, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, Sai-Hong Ignatius Ou et al. « Abstract CT025 : Impact of the EML4-ALK fusion variant on the efficacy of lorlatinib in patients (pts) with ALK-positive advanced non-small cell lung cancer (NSCLC) ». Dans Proceedings : AACR Annual Meeting 2020 ; April 27-28, 2020 and June 22-24, 2020 ; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-ct025.

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Bearz, Alessandra, Jean-François Martini, Jacek Jassem, Sang-We Kim, Gee-Chen Chang, Alice Shaw, Deborah Shepard et al. « Abstract LB043 : Efficacy of Lorlatinib in Treatment-Naïve Patients (pts) With ALK-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) in Relation to EML4-ALK Variant Type and ALK Mutations ». Dans Proceedings : AACR Annual Meeting 2021 ; April 10-15, 2021 and May 17-21, 2021 ; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-lb043.

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