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Hibma, Jennifer E., Melissa O’Gorman, Sunil Nepal, Sylvester Pawlak, Katherine Ginman, and 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, no. 1 (October 26, 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, no. 1 (February 26, 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, and Alice Tsang Shaw. "Resistance to lorlatinib in ROS1 fusion-positive non-small cell lung cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 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, no. 1 (December 1, 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, and Javier A. Menendez. "Silibinin Suppresses the Hyperlipidemic Effects of the ALK-Tyrosine Kinase Inhibitor Lorlatinib in Hepatic Cells." International Journal of Molecular Sciences 23, no. 17 (September 1, 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, no. 11 (November 7, 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, no. 16_suppl (June 1, 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, no. 12_Supplement (June 15, 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, and 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, no. 15 (July 23, 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, no. 16_suppl (June 1, 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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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, no. 16_suppl (June 1, 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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Baldacci, Simon, Virginie Avrillon, Benjamin Besse, Bertrand Mennecier, Michael Duruisseaux, Julien Mazieres, Renaud Descourt, et al. "Lorlatinib for advanced ALK and ROS1+ non-small cell lung cancer (NSCLC): Efficacy and treatment sequences in the IFCT-1803 LORLATU expanded access program (EAP) cohort." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 9615. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.9615.
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9615 Background: Lorlatinib, a third-generation tyrosine kinase inhibitor targeting ALK and ROS1, has been made available in France starting October 2015 through an EAP for advanced, refractory, ALK+ NSCLC after the failure of chemotherapy and TKIs. Besides the landmark, multi-cohort phase II trial that assessed lorlatinib in ALK+ NSCLC, real-life evidence regarding the efficacy and safety, as well as treatment sequences including lorlatinib, is lacking. Methods: We report the cohort of consecutive patients with advanced, refractory, ALK or ROS1+ NSCLC enrolled in the French EAP of lorlatinib from October 2015 to October 2019. Data were collected from medical records by French Cooperative Thoracic Intergroup (IFCT) research study assistants on site. Primary endpoint was progression-free survival. Results: 200 patients were included: 143 (71.5%) ALK+, 57 (28.5%) ROS1+, 87 (44%) men, 127 (66%) never-smokers, and 167 (85%) stage IV disease. Mean age was 59 years. At the time of initiation of lorlatinib, 146 (74%) patients had Central Nervous System (CNS) disease (78 % for ALK+, 63% for ROS1+), 131 (76%) were PS 0/1. Lorlatinib was delivered as 2nd/3rd/4th/5th+ line in 3%/17%/27%/53%of ALK+ patients and in 30%/30%/16%/24%of ROS1+ patients, respectively. 150 (75%), 185 (93%), 138 (69%), and 80 (40%) patients had received prior chemotherapy, crizotinib, 2nd generation TKIs, and brain radiotherapy, respectively. Median PFS and OS from the initiation of lorlatinib were 11.8 (95% CI 7.3-14.6) months and NR (95% CI 18.6-NR) months, respectively for ALK+ patients and 7.6 (95% CI 6.2-10.2) months and 20.9 (95% CI 10.0-NR) months, respectively for ROS1+ patients. ORR and DCR were 46.2% (95% CI 37.6-54.7) and 86.2% (95% CI 80.2-92.1), respectively for ALK+ patients and 47.1% (95% CI 33.4-60.8) and 88.2% (95% CI 79.4-97.1), respectively for ROS1+ patients. CNS ORR was 41.7% (95% CI 33.3-50.1) and 37.7% (95% CI 24.7-50.8), respectively. With a median follow-up of 15.6 (95% CI 14.0-17.6) months, progression under lorlatinib treatment was observed in 71 (50%) ALK+ patients and 35 (61%) ROS1+ patients, and CNS progression in 24 (34%) and 8 (23%) patients, respectively. The safety profile of lorlatinib was consistent with published data. Conclusions: These real-life results confirmed lorlatinib as a major treatment option for patients with advanced refractory ALK or ROS1+ NSCLC.
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Mann, Janelle E. "Lorlatinib (Lorbrena®)." Oncology Times 41, no. 6 (March 2019): 5. http://dx.doi.org/10.1097/01.cot.0000554513.89621.63.
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Bearz, Alessandra, Jean-Francois Martini, Jacek Jassem, Sang-We Kim, Gee-Chen Chang, Alice Tsang Shaw, Deborah Shepard, et al. "Phase 3 trial of lorlatinib in treatment-naive patients (Pts) with ALK-positive advanced non–small cell lung cancer (NSCLC): Comprehensive plasma and tumor genomic analyses." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 9070. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9070.
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9070 Background: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, has shown overall and intracranial activity in ALK+ advanced NSCLC. In the randomized, multicenter, phase 3 study in pts with previously untreated ALK+ advanced NSCLC (CROWN; NCT03052608), lorlatinib showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs crizotinib (Shaw AT, et al. N Engl J Med. 2020;383:2018-2029). Comprehensive molecular profiling of circulating tumor DNA (ctDNA) and tumor tissue was performed to identify molecular correlates of response. Methods: At baseline (BL), plasma samples were available from 134 and 129 pts in the lorlatinib and crizotinib arms, respectively. Analyses returned results for tumor tissue (archived or new biopsy) from 147 pts across both arms. Plasma and tumor DNA were analyzed by next-generation sequencing (NGS; Guardant360 and TissueNext, respectively, Guardant Health, Inc.). Objective response rate (ORR), duration of response, and PFS based on the September 20, 2021, cutoff, all assessed by blinded independent central review, were summarized according to mutation and tumor mutation burden (TMB) status. Results: At BL, 22% of pts had no detectable ctDNA. ALK missense mutations (n=19) or deletion (n=1) were detected in plasma of 12 pts (n=5 and 7 in the lorlatinib and crizotinib arms, respectively). Most pts harbored 1 mutation, but 3 pts harbored ≥3 mutations. In tumor samples, no somatic ALK mutation was detected. ALK fusions were detected in plasma of 48% of pts and in tumor of 80%. EML4-ALK variant (v) subtypes were highly concordant between ctDNA and tumor tissue. Based on ctDNA, ORRs were generally higher in the lorlatinib vs crizotinib arm, reaching 80% and 72% for EML4-ALK v1 and v3, respectively, in the lorlatinib arm, and 50% and 74% in the crizotinib arm. Median PFS was not reached for v1 in the lorlatinib arm and was 7.4 mo in the crizotinib arm; for v3, mPFS was 33.3 and 5.5 mo, respectively. TP53 mutations were found in 42% of pts with detectable ctDNA, and their presence did not seem to influence lorlatinib activity. In the crizotinib arm, absence of TP53 mutations led to longer PFS. These findings are being verified in tumor tissue. A pt treated with lorlatinib with an ongoing partial response in tumor lesions at the data cutoff date was found to have a KRAS G12V mutation and the presence of ALK fusion in tumor tissue but had no ctDNA detected at BL. Conclusions: Pts with untreated ALK+ advanced NSCLC had higher ORRs and potentially longer PFS across predefined biomarker subgroups when treated with lorlatinib compared with crizotinib in the phase 3 CROWN study. Based on pretreatment ctDNA and tumor tissue analyses, lorlatinib led to strong clinical benefit regardless of the type of ALK rearrangement or presence of potential driver co-mutation. Clinical trial information: NCT03052608.
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Solomon, Benjamin J., Todd M. Bauer, Filippo de Marinis, Enriqueta Felip, Yasushi Goto, Geoffrey Liu, Julien Mazieres, et al. "Plain language summary of the CROWN study comparing lorlatinib with crizotinib for people with untreated non-small cell lung cancer." Future Oncology 17, no. 34 (December 1, 2021): 4649–56. http://dx.doi.org/10.2217/fon-2021-0904.
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This is a summary of a research study (known as a clinical trial) called CROWN. The study tested two medicines called lorlatinib and crizotinib in participants with untreated non-small cell lung cancer that had spread to other parts of their body. All those who took part had changes in a gene called ALK, which is involved in cell growth. In total, 296 participants from 23 countries took part. Half the participants took lorlatinib and half took crizotinib. After participants started taking lorlatinib or crizotinib, they were checked regularly to see if their tumors had grown or spread to other parts of their body (known as tumor progression) and to monitor any side effects. After 1 year of treatment, the participants who took lorlatinib were twice as likely to be alive with no tumor growth as the participants who took crizotinib. More participants who took lorlatinib had cancer that shrank (76%) compared with the participants who took crizotinib (58%). This was also true of the participants whose cancer had spread to their brain. The most common side effects in participants who took lorlatinib were increases in the amount of cholesterol and triglycerides (a type of fat) in their blood, swelling, weight gain, nerve damage, unclear thoughts, and diarrhea. Among the participants who took crizotinib, the most common side effects were diarrhea, feeling like you want to throw up, sight problems, swelling, vomiting, changes in liver function, and feeling tired. Overall, the CROWN study showed that fewer participants with advanced ALK+ non-small cell lung cancer died or had tumor growth with lorlatinib compared with crizotinib treatment. ClinicalTrials.gov NCT number: NCT03052608 .
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Jóri, Balázs, Markus Falk, Iris Hövel, Peggy Weist, Markus Tiemann, Lukas C. Heukamp, and Frank Griesinger. "Acquired G2032R Resistance Mutation in ROS1 to Lorlatinib Therapy Detected with Liquid Biopsy." Current Oncology 29, no. 9 (September 16, 2022): 6628–34. http://dx.doi.org/10.3390/curroncol29090520.
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Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)/receptor tyrosine kinase inhibitor (ROS1), demonstrated efficacy in ROS1 positive (ROS1+) non-small cell lung cancer (NSCLC), although approval is currently limited to the treatment of ALK+ patients. However, lorlatinib-induced resistance mechanisms, and its efficacy against the resistance mutation G2032R in ROS1, respectively, have not yet been fully understood. Furthermore, concomitant tumor suppressor gene p53 (TP53) mutations occur in driver alteration positive NSCLC, but their prognostic contribution in the context of ROS1 inhibition remains unclear. Here we report a ROS1+ NSCLC patient who developed an on target G2032R resistance mutation during second-line lorlatinib treatment, indicating the lack of activity of lorlatinib against ROS1 G2032R. The resistance mutation was detected in plasma-derived ctDNA, signifying the clinical utility of liquid biopsies.
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Laktionov, K. K., E. V. Reutova, S. Yu Kruteleva, and E. Yu Antonova. "Efficacy of lorlatinib in the treatment of ALK-positive non-small cell lung cancer patients with progression on crizotinib: personal experience." Meditsinskiy sovet = Medical Council, no. 20 (December 10, 2021): 62–67. http://dx.doi.org/10.21518/2079-701x-2021-20-62-67.
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Introduction. Lorlatinib is a third generation ALK tyrosine kinase inhibitor. Back in 2018, the drug underwent accelerated FDA approval and was recommended for the treatment of patients with ALK-positive non-small cell lung cancer after progression on crizotinib and another ALK inhibitor. For a long time, the use of the drug in Russia was possible only in clinical trials or expanded access program. However, now this drug is becoming available in our country.Purpose. To analyze the overall and intracranial response during lorlatinib therapy, as well as the tolerability of lorlatinib therapy in patients with ALK-positive non-small cell lung cancer who previously received crizotinib and one or more lines of cytostatic therapy.Materials and methods. The study included 39 patients aged 28 to 76 years, diagnosed with non-small cell lung cancer. In 36 cases, a translocation in the ALK gene was detected, in three, a ROS1 translocation. All patients received targeted therapy with crizotinib and one or more lines of chemotherapy before starting lorlatinib therapy. All patients received 100 mg lorlatinib therapy until disease progression or intolerable toxicity.Results. During the observation period for the moment of September 2021, an objective response was achieved in 28 patients (71.7%), in 10 patients (25.6%) – stabilization of the disease, in one patient (2.6%) – progression. The median duration of the drug was just over 40 months. The drug intake was characterized by a predictable and manageable toxicity profile.Conclusions. These data indicate a high direct efficacy of lorlatinib in patients with ALK/ROS1 translocations. The data obtained do not contradict the results obtained in the course of clinical trials. The drug lorlatinib has currently received registration in Russia for the treatment of non-small cell lung cancer in cases of the development of progression while taking secondgeneration ALK inhibitors or several lines of therapy with ALK inhibitors.
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Chen, Wei, Yafei Shi, Shuya Qi, Haiyan Zhou, Chunyu Li, Dujia Jin, and Guohui Li. "Pharmacokinetic Study and Tissue Distribution of Lorlatinib in Mouse Serum and Tissue Samples by Liquid Chromatography-Mass Spectrometry." Journal of Analytical Methods in Chemistry 2019 (March 4, 2019): 1–10. http://dx.doi.org/10.1155/2019/7574369.
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In the present study, we developed and validated a rapid and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of lorlatinib in mouse serum and tissue samples, and such a method was successfully applied to investigate the pharmacokinetic study and tissue distribution of lorlatinib after oral administration. Samples were processed with methanol to precipitate protein and extract drugs, and Afatinib-d6 was used as the internal standard (IS). For LC-MS/MS analysis, compounds were separated on a C18 column by gradient elution (0.1% of formic acid and methanol) at 0.5 mL/min in the positive-ion mode with m/z 407.28 [M + H]+ for lorlatinib and m/z 492.10 [M + H]+ for IS. Good linearity was observed within the calibration ranges. Selectivity, accuracy (−6.42% to 8.84%), precision (1.69% to 10.98%), recoveries (91.4% to 115.0%), and matrix effect (84.2% to 110.6%) were all within the acceptable ranges. After oral administration, serum concentration of lorlatinib quickly achieved the maximal concentration (2,705.683 ± 539.779 μg/L) at 0.625 ± 0.231 h. The highest concentration was detected in the liver (3,153.93 ng/100 mg), followed by the stomach (2,159.92 ng/100 mg) and the kidney (548.83 ng/100 mg). In conclusion, a simple and rapid detection method was established and validated for determination of lorlatinib in blood and tissue samples of mouse. The pharmacokinetic study and tissue distribution of lorlatinib were successfully investigated using this method.
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Dagogo-Jack, Ibiayi, Geoffrey R. Oxnard, Jessica Fink, Gianluca Diubaldi, Caitlyn Helms, Justin F. Gainor, Michael S. Rabin, et al. "A phase II study of lorlatinib in patients (pts) with ALK-positive (ALK+) lung cancer with brain-only progression." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 9595. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.9595.
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9595 Background: Lorlatinib is a 3rd-generation ALK tyrosine kinase inhibitor (TKI) developed to penetrate the central nervous system (CNS) and overcome resistance to 2nd-generation (2nd-gen) ALK TKIs. In a phase II study, lorlatinib demonstrated significant intracranial (IC) activity after failure of 2nd-gen TKIs. As treatment discontinuation for extracranial (EC) progression can confound assessment of durability of IC response, we performed a phase II study (NCT02927340) to selectively evaluate lorlatinib activity in ALK+ pts with CNS-only disease. Methods: Between 11/2016 and 1/2019, 22 pts with IC progression on an ALK TKI with no other sites of measurable disease were enrolled at 2 institutions. Pts received lorlatinib at a starting dose of 100 mg QD. The primary endpoint was the IC disease control rate (DCR) at 12 weeks per modified RECIST v1.1. Secondary endpoints were IC objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Results: Of the 22 pts enrolled, 21 (95%) had progressed on a 2nd-gen ALK TKI and 14 (64%) had previously received CNS radiation (median 21.1 months between radiation and lorlatinib). Median number of prior ALK TKIs was 2 (range 1-4). As of the data cutoff of 12/15/19, median follow-up was 14 months. At 12 weeks, the IC-DCR was 95%, including 8 pts with stable disease. Best IC ORR was 59% with 6 complete and 7 partial responses. Nine (41%) pts relapsed on study, including 3 IC-only, 5 EC-only, and 1 combined relapse. Four pts continued treatment beyond EC-only progression. Although median IC DOR and PFS were not estimable due to few progression events, the IC progression-free rate at 12 months was 81% (95% CI: 53%-94%). Twelve pts have discontinued study treatment due to progression (n = 6), edema (n = 1), pulmonary hypertension (n = 1), or transition to commercial lorlatinib (n = 4). Conclusions: Lorlatinib induces durable intracranial responses in pts with CNS-only progression on 2nd-gen ALK TKIs, suggesting that CNS-specific relapses are primarily driven by ALK-dependent mechanisms. Further studies are needed to characterize the molecular basis of sensitivity to lorlatinib in this unique subgroup of pts with ALK+ lung cancer. Clinical trial information: NCT02927340 .
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Solomon, Benjamin, Todd Bauer, Tony Mok, Geoffrey Liu, Julien Mazieres, Filippo de Marinis, Yasushi Goto, et al. "Abstract CT223: Updated efficacy and safety from the phase 3 CROWN study of first-line lorlatinib vs crizotinib in advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC)." Cancer Research 82, no. 12_Supplement (June 15, 2022): CT223. http://dx.doi.org/10.1158/1538-7445.am2022-ct223.
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Abstract Background: Lorlatinib improved progression-free survival (PFS) and demonstrated intracranial (IC) activity in patients (pts) with untreated advanced ALK+ NSCLC in the interim analysis of the randomized, Phase 3, CROWN study of lorlatinib vs crizotinib. We report updated 36-month follow-up data. Methods: 296 pts with previously untreated advanced ALK+ NSCLC were randomized 1:1 to oral lorlatinib (100 mg QD; n=149) or crizotinib (250 mg BID; n=147), stratified by presence of CNS metastases (mets) and ethnicity. Primary endpoint: PFS by blinded independent central review (BICR). Secondary endpoints included overall survival, PFS by investigator, and objective response (OR), IC-OR, IC time to progression (IC-TTP), duration of response (DR), IC-DR (all by BICR), and safety. Results: At data cutoff (Sep 20, 2021), median duration of follow-up for PFS was 36.7 months for lorlatinib and 29.3 months for crizotinib. Median PFS by BICR was NR (95% CI, NR-NR) for lorlatinib and 9.3 months (95% CI, 7.6-11.1) for crizotinib (HR, 0.27; 95% CI, 0.18-0.39). PFS by investigator results were similar (Table). For pts with brain mets at baseline (n=37 lorlatinib/n=39 crizotinib), the HR for IC-TTP for lorlatinib vs crizotinib was 0.10 (95% CI, 0.04-0.27), and for pts without brain mets (n=112/n=108) was 0.02 (95% CI, 0.002-0.14). OR, IC-OR, DR, and IC-DR were all improved with lorlatinib vs crizotinib (Table). All-cause grade 3-4 adverse events (AEs) and AEs leading to treatment discontinuation were reported in 76% and 7% of pts with lorlatinib and 57% and 10% of pts with crizotinib, respectively. No new safety signals emerged. Conclusions: These updated long-term data from CROWN confirm the efficacy of lorlatinib over crizotinib in pts with treatment-naïve ALK+ NSCLC, with no new safety signals detected, and support the use of lorlatinib in pts with untreated ALK+ NSCLC with and without brain mets. Summary of other efficacy resultsa Clinical trial information: NCT03052608 Funding: Pfizer Inc. ITT population Lorlatinib(n=149) Crizotinib(n=147) % alive without progression at:12 mo (95% CI) 78 (70–84) 38 (29–47) 24 68 (60–75) 22 (14–30) 36 64 (55–71) 19 (12–27) Median PFS by investigator, mo (95% CI) NR (NR–NR) 9.1 (7.4–10.9) HR (95% CI) 0.19 (0.13–0.27) Confirmed OR, n (%) [95% CI] 115 (77) [70–84] 86 (59) [50–67] Median DR,b mo (95% CI) NR (NR–NR) 9.6 (9.0–12.9) Patients with measurable or nonmeasurable brain metastases at baseline (n=37) (n=39) Median PFS, mo (95% CI) NR (18.2–NR) 7.2 (3.7–9.2) HR (95% CI) 0.21 (0.10–0.44) Confirmed IC-OR, n (%) [95% CI] 24 (65) [48–80] 7 (18) [8–34] Complete response, n (%) 22 (60) 5 (13) Median IC-DR,b mo (95% CI) NR (NR–NR) 9.4 (6.0–11.1) Patients without brain metastases at baseline (n=112) (n=108) Median PFS, mo (95% CI) NR (NR–NR) 11.0 (9.0–14.6) HR (95% CI) 0.29 (0.19–0.44) aBy blinded independent central review unless stated otherwise. bIn patients with a confirmed complete or partial response. CI, confidence interval; DR, duration of response; HR, hazard ratio; ITT, intention- to-treat; NR, not reached; IC, intracranial; OR, objective response; PFS, progression-free survival. Citation Format: Benjamin Solomon, Todd Bauer, Tony Mok, Geoffrey Liu, Julien Mazieres, Filippo de Marinis, Yasushi Goto, Dong-Wan Kim, Yi-Long Wu, Mikhail Dvorkin, Jacek Jassem, Froylán López-López, Ross Soo, Anna Polli, Elisa Dall'O, Laura Iadeluca, Francesca Toffalorio, Enriqueta Felip. Updated efficacy and safety from the phase 3 CROWN study of first-line lorlatinib vs crizotinib in advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) [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 CT223.
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Gafer, Huda, Quincy de Waard, Annette Compter, and Michel van den Heuvel. "Rapid regression of neurological symptoms in patients with metastasised ALK+ lung cancer who are treated with lorlatinib: a report of two cases." BMJ Case Reports 12, no. 7 (July 2019): e227299. http://dx.doi.org/10.1136/bcr-2018-227299.
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Oral anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) have shown significant benefit in the management of ALK-rearranged non-small cell lung cancer (NSCLC). However, almost all patients will experience disease progression after front-line ALK-TKIs such as crizotinib. Treatment with third generation ALK-TKI lorlatinib can have a significant clinical impact following disease progression, even in patients with a very poor performance status. Here, we review two clinical cases with metastatic ALK-rearranged NSCLC who had pulmonary disease control with first-generation ALK inhibitor. However, disease progressed rapidly in the central nervous system with severe neurological symptoms. Treatment with lorlatinib, a third-generation ALK-TKI, led to a rapid radiological and clinical cerebral response in both patients. Lorlatinib can overcome ALK resistance to crizotinib, and the presented cases suggest a potential role for lorlatinib in patients with rapidly progressive cerebral and leptomeningeal metastases.
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Aydemirli, Mehtap Derya, Jaap D. H. van Eendenburg, Tom van Wezel, Jan Oosting, Willem E. Corver, Ellen Kapiteijn, and Hans Morreau. "Targeting EML4-ALK gene fusion variant 3 in thyroid cancer." Endocrine-Related Cancer 28, no. 6 (June 1, 2021): 377–89. http://dx.doi.org/10.1530/erc-20-0436.
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Finding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line ‘JVE404’ derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient’s treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining signal intensities of a half and a third of control, respectively, with crizotinib. The patient had a 6-month lasting stable disease on crizotinib, but progressive disease occurred, including the finding of cerebral metastases, at 8 months. With lorlatinib, partial response, including clinical cerebral activity, was already achieved at 11 weeks’ use and ongoing partial response at 7 months. To our best knowledge, this is the first reported case describing a patient-specific targeted treatment with lorlatinib based on an EML4-ALK gene fusion v3 in a thyroid cancer patient, and own cancer cell line. Tumor-agnostic targeted therapy may provide valuable treatment options in personalized medicine.
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Gourzoulidis, George, Oresteia Zisimopoulou, Nadia Boubouchairopoulou, Christina Michailidi, Chrissy Lowry, Charalampos Tzanetakos, and Georgia Kourlaba. "Cost-effectiveness Analysis of Lorlatinib in Patients Previously Treated with Anaplastic Lymphoma Kinase Inhibitors for Non-small Cell Lung Cancer in Greece." Journal of Health Economics and Outcomes Research 9, no. 1 (February 17, 2022): 50–57. http://dx.doi.org/10.36469/jheor.2022.32983.
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Background: Non-small cell lung cancer (NSCLC), which accounts for about 80%-85% of lung cancer cases, is a leading cause of cancer-related death worldwide. Lorlatinib is a potent third-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with advanced, ALK-positive NSCLC previously treated with at least one second-generation ALK tyrosine kinase inhibitor. Objective: The present study assessed the cost-effectiveness of lorlatinib vs pemetrexed with platinum combination of carboplatin or cisplatin (P-ChT) in Greece. Methods: A partitioned survival model with 3 health states, referring to pre-progression, progressed disease, and death, was locally adapted from a Greek payer perspective over a lifetime horizon. Clinical and safety data and utility values applied in the model were extracted from the literature. A matching-adjusted indirect comparison of lorlatinib and P-ChT was performed. Only direct medical costs (€) from 2020 were included in the analysis. Primary outcomes were patient life years (LYs), quality-adjusted life years (QALYs), total costs, and incremental cost-effectiveness ratios per QALY and LY gained. All future outcomes were discounted at 3.5% per annum. A probabilistic sensitivity analysis was conducted to account for model uncertainty. Results: The analysis showed that, over a lifetime horizon, the estimated total costs of lorlatinib and P-ChT were €81 754 and €12 343, respectively. Lorlatinib was more effective than P-ChT with 2.4 and 1.5 more LYs and QALYs gained, respectively. The generated incremental cost-effectiveness ratios of lorlatinib compared with P-ChT were €28 613 per LY gained and €46 102 per QALY gained. Probabilistic sensitivity analysis confirmed the deterministic results. Conclusion: The present analysis suggests that lorlatinib may be considered as a cost-effective option compared with P-ChT in Greece for the treatment of patients with advanced, ALK-positive NSCLC whose disease has progressed after at least one second-generation ALK tyrosine kinase inhibitor. In addition, this option addresses a significant unmet medical need.
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Matsuda, Hironari, Munechika Hara, Shin-Ichiro Iwakami, and Kazuhisa Takahashi. "EML4-ALK positive lung adenocarcinoma with skeletal muscle metastasis in the right calf which was treatable with lorlatinib after resistance to treatment with alectinib." BMJ Case Reports 14, no. 4 (April 2021): e240295. http://dx.doi.org/10.1136/bcr-2020-240295.
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This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.
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Hu, Wenyue, Daniel Lettiere, Susanna Tse, Theodore R. Johnson, Kathleen E. Biddle, Stephane Thibault, Xavier Palazzi, Joseph Chen, Yazdi K. Pithavala, and Martin Finkelstein. "Liver Toxicity Observed With Lorlatinib When Combined With Strong CYP3A Inducers: Evaluation of Cynomolgus Monkey as a Nonclinical Model for Assessing the Mechanism of Combinational Toxicity." Toxicological Sciences 182, no. 2 (May 21, 2021): 183–94. http://dx.doi.org/10.1093/toxsci/kfab056.
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Abstract Lorlatinib is a potent small-molecule anaplastic lymphoma kinase inhibitor approved for the treatment of patients with nonsmall cell lung cancer. In a drug-drug interaction study in healthy human participants, liver enzyme elevations were observed when a single 100 mg dose of lorlatinib was administered after multiple doses of rifampin, a strong cytochrome P450 (CYP) 3A inducer and a pregnane X receptor (PXR) agonist. A series of in vitro and in vivo studies were conducted to evaluate potential mechanisms for the observed clinical toxicity. To investigate the involvement of CYP3A and/or PXR in the observed liver toxicity, studies were conducted in cynomolgus monkeys administered lorlatinib alone or with coadministration of multiple doses of known CYP3A inducers that are predominantly PXR agonists (rifampin, St. John’s wort) or predominantly constitutive androstane receptor agonists (carbamazepine, phenytoin) and a net CYP3A inhibitory PXR agonist (ritonavir). Results from the investigative studies identified cynomolgus monkeys as a pharmacologically relevant nonclinical model, which recapitulated the elevated liver function test results observed in humans. Furthermore, liver toxicity was only observed in this model when lorlatinib was coadministered with strong CYP3A inducers, and the effects were not restricted to, or exclusively dependent upon, a PXR activation mechanism. These results generated mechanistic insights on the liver enzyme elevations observed in the clinical drug-drug interaction study and provided guidance on appropriate product safety label for lorlatinib.
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Hu, Jia, Baoshi Zhang, Fangfang Yao, Yan Fu, Dianjun Chen, Donghui Li, Nan Du, et al. "Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report." Therapeutic Advances in Respiratory Disease 14 (January 2020): 175346662093577. http://dx.doi.org/10.1177/1753466620935770.
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EML4-ALK rearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored. In this case report, we describe a patient with EML4-ALK-rearranged stage IIIB MPM who was administered with alectinib and lorlatinib as first-line and fourth-line therapy, respectively. He had remarkable response evaluated as partial response on both regimens lasting approximately 3.5 months on each regimen. His plasma samples were collected during the treatment course and submitted for targeted sequencing to understand the molecular mechanisms of his therapeutic resistance. Sequencing analysis revealed the emergence of ALK I1171N and L1196M at alectinib progression. Meanwhile, ALK I1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be in cis to G1202R. We speculate that these multiple mutations synergistically mediated his resistance to both alectinib and lorlatinib. Our report describes the detection of EML4-ALK rearrangement in a patient with MPM who had remarkable therapeutic response with ALK inhibitors. Moreover, our case also revealed acquired mechanisms of lorlatinib resistance mediated by multiple mutations ALK I1171N, L1196M, and G1202R, contributing an incremental step to our understanding of the complexity of acquired resistance mechanisms in sequential ALK inhibitor therapy. The reviews of this paper are available via the supplemental material section.
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Mengya Liao, Mengya Liao, Xin Wang Xin Wang, and Qin Wang and Yiwen Zhang Qin Wang and Yiwen Zhang. "Direct Enantioseparation of Lorlatinib Enantiomers by Liquid Chromatography on a Chiralpak IB Column." Journal of the chemical society of pakistan 45, no. 1 (2023): 53. http://dx.doi.org/10.52568/001195/jcsp/45.01.2023.
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Enantiomeric forms of many drugs are known to have different physiological and therapeutic effects. Previous studies indicated that the inhibitory activity of an enantiomer of Lorlatinib on L1196M kinase was 300 times lower than that of Lorlatinib. In this study, an analytical method for the enantioseparation of Lorlatinib was established on a Chiralpak IB column. Baseline separation was obtained within 10 min using v(n-hexane): v(2-propanol): v(diethylamine) = 85:15:0.1 as mobile phase, and a resolution higher than 2.2. Various factors of HPLC such as the effect of chiral columns, the contents of mobile phase and column temperature were thoroughly investigated. Calibration curves were plotted within the concentration range between 10 and 1000 μg mL-1 (n = 8), and recoveries between 97.86% and 100.99% were obtained, with a relative standard deviation (RSD) lower than 1.6%. The LOD and LOQ for Lorlatinib were 10.34 and 34.49 μg mL-1, respectively, and those for its enantiomer were 11.76 and 39.21 μg mL-1, respectively. Validating factors such as the accuracy, precision, linear relationship, and LOD/LOQ confirmed that the method has the advantages of high efficiency, accuracy and stability and can be used to detect the enantiomeric purity of Lorlatinib. In addition, the chiral recognition mechanisms were discussed according to the thermodynamic parameters and simulation studies between racemates and CSPs.
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Shaw, Alice T., Benjamin J. Solomon, Benjamin Besse, Todd M. Bauer, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, et al. "ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 37, no. 16 (June 1, 2019): 1370–79. http://dx.doi.org/10.1200/jco.18.02236.
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PURPOSE Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non–small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that ALK resistance mutations may represent a biomarker of response in previously treated patients. PATIENTS AND METHODS Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non–small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK mutation–focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to ALK mutation status. RESULTS Approximately one quarter of patients had ALK mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, the efficacy of lorlatinib was comparable among patients with and without ALK mutations using plasma or tissue genotyping. In contrast, in patients who had failed 1 or more second-generation ALK TKIs, objective response rate was higher among patients with ALK mutations (62% v 32% [plasma]; 69% v 27% [tissue]). Progression-free survival was similar in patients with and without ALK mutations on the basis of plasma genotyping (median, 7.3 months v 5.5 months; hazard ratio, 0.81) but significantly longer in patients with ALK mutations identified by tissue genotyping (median, 11.0 months v 5.4 months; hazard ratio, 0.47). CONCLUSION In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib.
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Syed, Yahiya Y. "Lorlatinib: First Global Approval." Drugs 79, no. 1 (January 2019): 93–98. http://dx.doi.org/10.1007/s40265-018-1041-0.
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Choudhury, Noura J., Robert J. Young, Matthew Sellitti, Alexandra Miller, and Alexander Drilon. "Lorlatinib and Bevacizumab Activity in ALK-Rearranged Lung Cancers After Lorlatinib Progression." JCO Precision Oncology, no. 4 (November 2020): 1333–38. http://dx.doi.org/10.1200/po.20.00271.
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Soo, Ross A., Jean-Francois Martini, Anthonie J. van der Wekken, Shunsuke Teraoka, Alice T. Shaw, Deborah Shepard, Anna Maria Calella, et al. "Early circulating tumor (ct) DNA dynamics and efficacy of lorlatinib: Analysis from the CROWN study." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9011. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9011.
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9011 Background: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, significantly improved progression-free survival (PFS) and overall/intracranial responses vs crizotinib in patients (pts) with previously untreated ALK-positive advanced non-small cell lung cancer (NSCLC) in the ongoing randomized Phase 3 CROWN study (NCT03052608). To identify whether additional molecular biomarker analysis correlated with efficacy, we evaluated early ctDNA dynamics compared with clinical outcomes. Methods: Plasma samples were prospectively collected at screening (SC), week 4 (cycle 2, day 1 [C2D1]), week 24 (C7D1), and end of treatment for ctDNA analysis. ctDNA was analyzed using Guardant360CDx (Guardant Health, Inc., Redwood City, CA, USA). Mean variant allele fraction (VAF) of ALK alterations (fusions and/or mutations) and overall detected alterations at each time point and longitudinal mean change (dVAF) as (VAFC2D1) – (VAFSC) were calculated; dVAF <0 indicated decreased ctDNA at week 4. Objective tumor response and PFS were evaluated according to dVAF. These analyses were repeated vs ctDNA results at week 24. Additional correlation analyses between depth of molecular response and/or ctDNA clearance and clinical outcomes are ongoing. Results: Paired samples were available at SC and week 4 from 232 of 255 pts included in the ctDNA analysis: 118/130 (90.8%) in the lorlatinib arm and 114/125 (91.2%) in the crizotinib arm. ALK alterations were detected in 122/232 (52.6%) pts at SC (62/118 [52.5%] from the lorlatinib arm) but only 19/232 (8.2%) at week 4 (8/118 [6.8%] from the lorlatinib arm). Mean VAF of ALK alterations at week 4 was significantly decreased compared with SC in both treatment arms (lorlatinib -1.54, crizotinib -1.25; both P<0.0001; P=0.4239 between arms). In the lorlatinib arm, mean VAF at week 4 was significantly decreased compared with SC in pts with a complete or partial response (dVAF -1.53; n=47; P<0.0001), or stable disease (dVAF -1.37; n=12; P=0.0304). Similar results were observed in the crizotinib arm. In pts with dVAF <0 for ALK alterations, mean percent change from screening in tumor size was -40.8% with lorlatinib (n=59) and -38.7% with crizotinib (n=58). Only 2 pts had dVAF ≥0, both from the crizotinib arm. Median PFS for pts with dVAF <0 for ALK alterations was not reached in the lorlatinib arm (n=62), and was 7.4 months (95% CI, 7.2–9.3) in the crizotinib arm (n=58). Similar response and PFS data were observed in the analysis of dVAF for ALK alterations at week 24. Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in pts with previously untreated ALK-positive NSCLC. The magnitude of reduction in ctDNA at 4 weeks may be associated with better responses and potentially longer PFS. These findings further support the utility of dynamic ctDNA monitoring in ALK-positive NSCLC. Reference: Shaw AT, et al. N Engl J Med. 2020;383:2018-2029. Clinical trial information: NCT03052608.
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Tao, Jiahao, Chuangjie Zheng, Cuifen Zhang, Ling Zhou, Zeyu Liu, Yanqun Zhou, Xuewu Huang, Lizhu Lin, and Linzhu Zhai. "First-line treatments for patients with advanced ALK gene rearrangements in NSCLC: a systematic review and network meta-analysis." Journal of International Medical Research 50, no. 11 (November 2022): 030006052211327. http://dx.doi.org/10.1177/03000605221132703.
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Objective To conduct a network meta-analysis of randomised controlled trials to determine the optimal clinical choice of first-line therapy for patients with ALK receptor tyrosine kinase ( ALK) gene rearrangement non-small cell lung cancer (NSCLC). Methods Clinical trials in patients with histologically confirmed ALK gene rearrangement NSCLC, that included ALK inhibitors as first-line therapy, were identified using database searches. A Bayesian network meta-analysis was conducted to calculate the efficacy and safety of the included first-line treatments. Results Nine trials with 2,407 patients were included for analyses. Lorlatinib was better than brigatinib for progression-free survival (PFS) (hazard ratio 0.79, 95% confidence interval 0.63, 0.98). In subgroup analyses, lorlatinib exhibited the highest probability of best PFS ranking in patients with or without baseline brain metastases (38% and 80%, respectively); brigatinib had the highest probability of best PFS ranking among Asian patients (47%). Alectinib offered the highest survival advantage (57% probability), while lorlatinib was likely to be the best treatment for an objective response (41% probability). Alectinib displayed the highest probability of being ranked lowest for grade ≥3 adverse events (86%). Conclusions Lorlatinib was associated with the best PFS overall, and was suitable for patients with or without brain metastases. Brigatinib was associated with the best PFS in Asian patients.
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Makimoto, Go, Keita Kawakado, Masamoto Nakanishi, Tomoki Tamura, and Shoichi Kuyama. "Successful Treatment with Lorlatinib after the Development of Alectinib-Induced Liver Damage in ALK-Positive Non-Small-Cell Lung Cancer: A Case Report." Case Reports in Oncology 14, no. 1 (March 1, 2021): 197–201. http://dx.doi.org/10.1159/000513624.
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Alectinib is a key drug for treating <i>anaplastic lymphoma kinase</i> (<i>ALK</i>)-positive non-small-cell lung cancer (NSCLC). Alectinib-induced hepatotoxicity is less common than that through other ALK inhibitors, such as crizotinib or ceritinib. Herein, we describe a case of <i>ALK</i>-positive adenocarcinoma successfully treated with lorlatinib after developing alectinib-induced hepatotoxicity. A 57-year-old Japanese man received alectinib as first-line therapy for <i>ALK</i>-positive NSCLC. After 79 days, alectinib was discontinued because of hepatotoxicity and later restarted at 150 mg/day, inducing hepatotoxicity again after 64 days. Switching to lorlatinib treatment (continued for >4 months) caused no severe adverse effects. Hence, lorlatinib may be useful for patients experiencing alectinib-induced hepatotoxicity.
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Descourt, Renaud, Maurice Pérol, Gaëlle Rousseau-Bussac, David Planchard, Bertrand Mennecier, Marie Wislez, Jacques Cadranel, et al. "Brigatinib for Pretreated, ALK-Positive, Advanced Non-Small-Cell Lung Cancers: Long-Term Follow-Up and Focus on Post-Brigatinib Lorlatinib Efficacy in the Multicenter, Real-World BrigALK2 Study." Cancers 14, no. 7 (March 30, 2022): 1751. http://dx.doi.org/10.3390/cancers14071751.
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Brigatinib is a next-generation ALK inhibitor (ALKi) that shows efficacy in ALK inhibitor naïve and post-crizotinib ALK+ advanced NSCLCs (aNSCLCs). The efficacy of brigatinib was retrospectively assessed in patients with aNSCLCs included in the brigatinib French Early-Access Program (1 August 2016–21 January 2019). The primary endpoint was investigator-assessed progression-free survival (invPFS) and the primary analysis was updated in 2021 with a longer follow-up, focused on post-brigatinib lorlatinib efficacy. Sixty-six centers included 183 patients: median age 60 ± 12.7 years; 78.3% never/former smokers; median of 3 ± 1 previous lines and 2 ± 0.5 ALKis; 37.1% ECOG PS 2 and 55.6% >3 metastatic sites. The median follow-up from brigatinib initiation was 40.4 months (95% CI 38.4–42.4). InvPFS was 7.4 months (95% CI 5.9–9.6), median duration of treatment (mDOT) was 7.3 months (95% CI 5.8–9.4) and median overall survival (mOS) was 20.3 months (95% CI 15.6–27.6). The median DOT and OS from brigatinib initiation tend to decrease with the number of ALK inhibitors used in previous lines of therapy. Based on the data collected, 92 (50.3%) patients received ≥1 agent(s) post-brigatinib and 68 (73.9%) of them received lorlatinib, with 51 (75%) immediately receiving it post-brigatinib, 12 (17.6%) receiving it after one and 5 (7.4%) after ≥2 subsequent treatments. The median follow-up was 29.9 (95% CI 25.7–33.1) months. Lorlatinib mDOT was 5.3 (95% CI 3.6–7.6) months with a median OS from lorlatinib initiation of 14.1 (95% CI 10.3–19.2) months. The results of the brigALK2 study confirm the efficacy of brigatinib in a population of heavily pretreated ALK+ aNSCLC patients and provide new data on the activity of lorlatinib after brigatinib.
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Parate, Shraddha, Vikas Kumar, Jong Chan Hong, and Keun Woo Lee. "Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics." Molecules 26, no. 8 (April 7, 2021): 2114. http://dx.doi.org/10.3390/molecules26082114.
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Non-small cell lung cancer (NSCLC) is a lethal non-immunogenic malignancy and proto-oncogene ROS-1 tyrosine kinase is one of its clinically relevant oncogenic markers. The ROS-1 inhibitor, crizotinib, demonstrated resistance due to the Gly2032Arg mutation. To curtail this resistance, researchers developed lorlatinib against the mutated kinase. In the present study, a receptor-ligand pharmacophore model exploiting the key features of lorlatinib binding with ROS-1 was exploited to identify inhibitors against the wild-type (WT) and the mutant (MT) kinase domain. The developed model was utilized to virtually screen the TimTec flavonoids database and the retrieved drug-like hits were subjected for docking with the WT and MT ROS-1 kinase. A total of 10 flavonoids displayed higher docking scores than lorlatinib. Subsequent molecular dynamics simulations of the acquired flavonoids with WT and MT ROS-1 revealed no steric clashes with the Arg2032 (MT ROS-1). The binding free energy calculations computed via molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) demonstrated one flavonoid (Hit) with better energy than lorlatinib in binding with WT and MT ROS-1. The Hit compound was observed to bind in the ROS-1 selectivity pocket comprised of residues from the β-3 sheet and DFG-motif. The identified Hit from this investigation could act as a potent WT and MT ROS-1 inhibitor.
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Blais, Normand, Jean-Philippe Adam, John Nguyen, and Jean C. Grégoire. "Evaluation and Management of Dyslipidemia in Patients Treated with Lorlatinib." Current Oncology 28, no. 1 (January 4, 2021): 265–72. http://dx.doi.org/10.3390/curroncol28010029.
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The use of lorlatinib, an anaplastic lymphoma kinase (ALK) inhibitor for the treatment of ALK-positive metastatic non-small cell lung cancer, is associated with dyslipidemia in over 80% of patients. Clinical trial protocols for the management of lorlatinib-associated dyslipidemia differ from clinical practice guidelines for the management of dyslipidemia to prevent cardiovascular disease, in that they are based on total cholesterol and triglyceride levels rather than on the low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol levels that form the basis of current cardiovascular guideline recommendations. In order to simplify and harmonize the management of cardiovascular risk in patients with lorlatinib, an advisory committee consisting of a medical oncologist, a cardiologist, and two pharmacists with expertise in cardiology and oncology aimed to develop a simplified algorithm, adapted from the Canadian Cardiovascular Society dyslipidemia recommendations. Recommendations for the evaluation and management of hypercholesterolemia and isolated hypertriglyceridemia in patients treated with lorlatinib are outlined. These recommendations are based on data collected in a large number of lipid-lowering therapy trials applicable to individuals with and without cancer. Considering the relatively long life expectancy and improving prognosis of patients with ALK translocations, this specific patient population should be treated as are patients without cancer and are likely to derive the same benefits from lipid-lowering therapy.
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Krome, Susanne. "Lorlatinib mit hoher intrakranieller Ansprechrate." Onkologische Welt 12, no. 02 (April 2021): 106. http://dx.doi.org/10.1055/a-1404-8725.
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Translokationen des Gens für die anaplastische Lymphomkinase (ALK) gehören zu den wichtigsten Treibermutationen für nicht-kleinzellige Bronchialkarzinome (NSCLC). Tyrosinkinase-Inhibitoren (TKI) sind als Standardtherapie für fortgeschrittene, ALK-positive NSCLC etabliert. In der CROWN-Studie empfahl sich der Drittgenerations-TKI Lorlatinib als Erstlinientherapie. Die Überlegenheit gegenüber Crizotinib galt auch für die Rückbildung von Gehirnmetastasen.
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Sidaway, Peter. "Lorlatinib effective in multiple settings." Nature Reviews Clinical Oncology 16, no. 2 (November 26, 2018): 66. http://dx.doi.org/10.1038/s41571-018-0141-9.
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Killock, David. "Lorlatinib in ROS1-positive NSCLC." Nature Reviews Clinical Oncology 17, no. 1 (November 8, 2019): 7. http://dx.doi.org/10.1038/s41571-019-0301-6.
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Chabrol, Alexandre, Marie Mayenga, Abdul Momen Hamid, Sylvie Friard, Hélène Salvator, Hélèe Doubre, Séverine Fraboulet, et al. "Lorlatinib – Induced pulmonary arterial hypertension." Lung Cancer 120 (June 2018): 60–61. http://dx.doi.org/10.1016/j.lungcan.2018.03.023.
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Li, Bryan, Richard W. Barnhart, Jacqui E. Hoffman, Asaad Nematalla, Jeffrey Raggon, Paul Richardson, Neal Sach, and John Weaver. "Exploratory Process Development of Lorlatinib." Organic Process Research & Development 22, no. 9 (August 2018): 1289–93. http://dx.doi.org/10.1021/acs.oprd.8b00210.
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"Lorlatinib." Reactions Weekly 1840, no. 1 (January 2021): 244. http://dx.doi.org/10.1007/s40278-021-90387-y.
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"Lorlatinib." Reactions Weekly 1851, no. 1 (April 2021): 213. http://dx.doi.org/10.1007/s40278-021-94303-7.
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"Lorlatinib." Reactions Weekly 1877, no. 1 (October 2021): 236. http://dx.doi.org/10.1007/s40278-021-03806-x.
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"Lorlatinib." Reactions Weekly 1865, no. 1 (July 2021): 262. http://dx.doi.org/10.1007/s40278-021-99550-9.
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"Lorlatinib." Reactions Weekly 1896, no. 1 (March 2022): 276. http://dx.doi.org/10.1007/s40278-022-11067-4.
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"Lorlatinib." Reactions Weekly 1896, no. 1 (March 2022): 277. http://dx.doi.org/10.1007/s40278-022-11068-4.
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"Lorlatinib." Reactions Weekly 1926, no. 1 (October 1, 2022): 292. http://dx.doi.org/10.1007/s40278-022-24570-6.
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"Lorlatinib." Reactions Weekly 1926, no. 1 (October 1, 2022): 291. http://dx.doi.org/10.1007/s40278-022-24569-7.
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"Lorlatinib." Reactions Weekly 1715, no. 1 (August 2018): 163. http://dx.doi.org/10.1007/s40278-018-50711-x.
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