^
    14h
    Lorlatinib Continuation Study (clinicaltrials.gov)
    P4, N=200, Recruiting, Pfizer | Trial completion date: Jun 2027 --> Dec 2026 | Trial primary completion date: Jun 2027 --> Dec 2026
    Trial completion date • Trial primary completion date
    |
    Lorbrena (lorlatinib)
    11d
    ALK-PPL: A Study to Evaluate the Combination of Platinum-pemetrexed Based Chemotherapy Plus Lorlatinib in ALK Positive Non-Small Cell Lung Cancer (NSCLC) With Exclusively Extracranial Disease Progression on Lorlatinib (clinicaltrials.gov)
    P2, N=45, Recruiting, Centro di Riferimento Oncologico - Aviano
    New P2 trial
    |
    cisplatin • carboplatin • Lorbrena (lorlatinib) • pemetrexed
    16d
    Navigating resistance to ALK inhibitors in the Lorlatinib Era: a comprehensive perspective on NSCLC. (PubMed, Expert Rev Anticancer Ther)
    Our expert opinion encapsulates the critical importance of understanding resistance mechanisms in the context of ALK inhibitors for shaping successful treatment approaches. With a focus on molecular testing and comprehensive assessment, this review contributes valuable insights to the evolving landscape of NSCLC therapy.
    Review • Journal
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK rearrangement
    |
    Lorbrena (lorlatinib)
    18d
    Response to lorlatinib rechallenge in a case of ALK-rearranged metastatic NSCLC with a resistance mutation to second generation TKIs. (PubMed, Tumori)
    Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have been developed for the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged non-small cell lung cancer (NSCLC), with the newer generation agents brigatinib, alectinib and lorlatinib showing prolonged responses. The second ALK resistance mutation detected after a chemotherapy interval, the G1202R, is the most common resistance mutation after second generation ALK TKIs and has been associated with sensitivity to third generation TKIs, such as lorlatinib. This case of a patient with EML4-ALK-rearranged NSCLC shows that sequential treatment with next-generation ALK TKIs, including rechallenge, can induce profound remissions, even in heavily pretreated patients, and that ALK-targeted strategies may be personalized by considering the presence of distinct ALK resistance mutations.
    Journal • Metastases
    |
    ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
    |
    ALK rearrangement • ALK mutation • ALK G1202R • ALK I1171N • ALK I1171 • EML4-ALK G1202R
    |
    Alecensa (alectinib) • Lorbrena (lorlatinib) • Alunbrig (brigatinib)
    25d
    LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion. (PubMed, Commun Biol)
    In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.
    Journal
    |
    CLIP1 (CAP-Gly Domain Containing Linker Protein 1)
    |
    ALK mutation
    |
    Lorbrena (lorlatinib) • Xospata (gilteritinib)
    29d
    Lorlatinib Continuation Study (clinicaltrials.gov)
    P4, N=200, Recruiting, Pfizer | Trial completion date: Dec 2026 --> Jun 2027 | Trial primary completion date: Dec 2026 --> Jun 2027
    Trial completion date • Trial primary completion date
    |
    Lorbrena (lorlatinib)
    29d
    PF-07284892 in Participants With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=53, Active, not recruiting, Pfizer | N=36 --> 53
    Enrollment change • Combination therapy • Metastases
    |
    ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NF1 (Neurofibromin 1)
    |
    BRAF V600E • EGFR mutation • BRAF V600 • ALK positive • NF1 mutation • RAS mutation • ROS1 positive
    |
    Erbitux (cetuximab) • Lorbrena (lorlatinib) • Mektovi (binimetinib) • Braftovi (encorafenib) • PF-07284892
    1m
    Lung adenocarcinoma patients with ROS1-rearranged tumors by sex and smoking intensity. (PubMed, Heliyon)
    Among patients who exhibited resistance to crizotinib, follow-up treatment of entrectinib and lorlatinib showed remarkable survival benefits. Newer-generation ALK/ROS1-targeted drugs showed efficacy in a cohort of crizotinib resistant ROS1 + patients. These results, when validated, could assist efficiently accruing ROS1 + patients.
    Journal
    |
    ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
    |
    ROS1 rearrangement
    |
    Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib)
    1m
    A pragmatic guide for management of adverse events associated with lorlatinib. (PubMed, Lung Cancer)
    We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.
    Review • Journal • Adverse events
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK positive
    |
    Lorbrena (lorlatinib)
    1m
    Lorlatinib for Newly-Diagnosed High-Grade Glioma With ROS or ALK Fusion (clinicaltrials.gov)
    P1, N=15, Not yet recruiting, Nationwide Children's Hospital
    New P1 trial
    |
    ALK fusion • ROS1 fusion
    |
    carboplatin • Lorbrena (lorlatinib) • cyclophosphamide
    1m
    Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition) (PubMed, Zhonghua Zhong Liu Za Zhi)
    Seven different ALK-TKIs have been approved by the National Medical Products Administration (NMPA) of China, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib. On January 16, 2024, the NMPA approved iruplinalkib for the first-line treatment of locally advanced or metastatic ALK-positive NSCLC patients. In order to better understand the efficacy and safety of iruplinalkib, and facilitate more rationally clinical application of iruplinalkib, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists co-organized experts to compile the "Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)".
    Journal • Metastases
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK positive • ALK fusion
    |
    Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib) • Ensacove (ensartinib) • Qi Xinke (iruplinalkib)
    2ms
    HER3 overexpression: a predictive marker for poor prognosis in advanced ALK-positive non-small cell lung cancer treated with ALK inhibitors. (PubMed, Transl Lung Cancer Res)
    Combination treatment with lorlatinib and erlotinib significantly reduced HRG1-induced activation of RTK signaling in ALK-positive NSCLC cells. HER3 overexpression has potential as a prognostic marker in ALK-positive NSCLCs, including ALK-TKI naïve and treated cases, especially those with EML4-ALK V1/V2. Assessing HER3 expression may be crucial for treatment planning and outcome prediction in these patients.
    Journal • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • EML4 (EMAP Like 4) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3)
    |
    HER-2 expression • ALK positive • EGFR overexpression • MET overexpression • EML4-ALK fusion • ALK fusion • ERBB3 expression • MET expression • ERBB3 overexpression • EML4-ALK fusion + ALK positive • EML4-ALK variant 1
    |
    erlotinib • Lorbrena (lorlatinib)
    2ms
    Cost-effectiveness of first-line versus second-line use of brigatinib followed by lorlatinib in patients with ALK-positive non-small cell lung cancer. (PubMed, Front Public Health)
    Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.
    Journal • HEOR • Cost-effectiveness • Cost effectiveness
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK positive
    |
    Lorbrena (lorlatinib) • Alunbrig (brigatinib)
    2ms
    CRISPR/Cas9-edited ROS1 + non-small cell lung cancer cell lines highlight differential drug sensitivity in 2D vs 3D cultures while reflecting established resistance profiles. (PubMed, J Transl Med)
    In this study we knock-in for the first time in a ROS1 + patient-derived cell line, three different known resistance-causing mutations using CRISPR/Cas9 in the endogenous translocated ROS1 alleles. Pharmacological assays performed in 2D and 3D cell culture revealed that spheroids are more sensitive to TKIs than cells cultured as a monolayer. This direct comparison between two culture systems could be done thanks to the implementation of normalized growth rates (NGR) to uniformly quantify drug response between 2D and 3D cell culture. Overall, this study presents the added value of using spheroids and positions lorlatinib and repotrectinib as the most effective TKIs against the studied ROS1 resistance point mutations.
    Preclinical • Journal
    |
    ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • SLC34A2 (Solute carrier family 34 member 2)
    |
    ROS1 rearrangement • ROS1 G2032R • ROS1 S1986Y
    |
    Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Augtyro (repotrectinib)
    2ms
    ORAKLE: Lorlatinib After Failure of First-line Second-generation ALK Kinase Inhibitor in Patients With Advanced ALK-positive Non-small Cell Lung Cancer (clinicaltrials.gov)
    P2, N=23, Active, not recruiting, Intergroupe Francophone de Cancerologie Thoracique | Trial primary completion date: Jan 2024 --> Jan 2025
    Trial primary completion date • Metastases
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK rearrangement
    |
    Lorbrena (lorlatinib)
    2ms
    Real world study of safety and efficacy of lorlatinib as second line and beyond in ALK-rearranged advanced non-small cell lung cancer patients in India - a multicentre chart review study (ROSELAND). (PubMed, Ecancermedicalscience)
    Thirty-three (87%) patients experienced treatment-related toxicity and six (16%) patients required dose modification. Lorlatinib was highly efficacious in terms of overall response rate, median PFS and median OS in this small real-world cohort of advanced ALK+ve NSCLC with a manageable safety profile.
    Review • Journal • Real-world evidence • Real-world • Metastases
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK rearrangement
    |
    Lorbrena (lorlatinib)
    2ms
    Long-Term Efficacy and Safety of Lorlatinib in Japanese Patients With ALK-Positive Advanced NSCLC-A Brief Report From the CROWN Study. (PubMed, JTO Clin Res Rep)
    The safety profile was consistent with that reported previously, with no new safety signals. This updated analysis in the Japanese population revealed prolonged benefits of lorlatinib over crizotinib in patients with treatment-naive advanced ALK-positive NSCLC with and those without brain metastases.
    Journal • Metastases
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK positive
    |
    Xalkori (crizotinib) • Lorbrena (lorlatinib)
    2ms
    Overcoming Central β-Sheet #6 (Cβ6) ALK Mutation (L1256F), TP53 Mutations and Short Forms of EML4-ALK v3/b and v5a/b Splice Variants are the Unmet Need That a Re-Imagined 5th-Generation (5G) ALK TKI Must Deliver. (PubMed, Lung Cancer (Auckl))
    Currently, a fourth-generation (4G) ALK TKI, NVL-655, is being developed to attack some of the unmet needs such as compound resistance mutations in cis...Potentially, in the shifting landscape where lorlatinib should be the first-line ALK TKI of choice based on the CROWN trial, the central β-sheet #6 (Cβ6) mutation ALK L1256F will be the potential acquired resistance mutation to lorlatinib which may be resistant to current ALK TKIs. Here we opine on what additional capacities a putative fifth-generation (5G) ALK TKI will need to possess if it can be achieved in one single molecule. We propose randomized trial schemas targeting some of the intrinsic resistance mechanisms that will lead to approval of a prototypic fifth-generation (5G) ALK TKI and actually be beneficial to ALK+ NSCLC patients rather than just design a positive pivotal superiority trial for the sole purpose of drug approval.
    Journal
    |
    ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • EML4 (EMAP Like 4)
    |
    TP53 mutation • ALK positive • ALK fusion • ALK mutation • EML4-ALK variant 3 • EML4-ALK variant 3 + TP53 mutation
    |
    Lorbrena (lorlatinib) • NVL-655
    2ms
    Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART) PRIME Trial (clinicaltrials.gov)
    P1, N=2, Terminated, OHSU Knight Cancer Institute | Active, not recruiting --> Terminated; Low accrual
    Trial termination
    |
    Keytruda (pembrolizumab) • Opdivo (nivolumab) • Avastin (bevacizumab) • Venclexta (venetoclax) • Lynparza (olaparib) • Mekinist (trametinib) • erlotinib • Gilotrif (afatinib) • Yervoy (ipilimumab) • Ibrance (palbociclib) • dasatinib • Zelboraf (vemurafenib) • Tafinlar (dabrafenib) • carboplatin • Imfinzi (durvalumab) • sorafenib • Rozlytrek (entrectinib) • imatinib • Sutent (sunitinib) • everolimus • Nerlynx (neratinib) • Iclusig (ponatinib) • Kadcyla (ado-trastuzumab emtansine) • Cotellic (cobimetinib) • Lorbrena (lorlatinib) • Lenvima (lenvatinib) • bortezomib • doxorubicin hydrochloride • capecitabine • Verzenio (abemaciclib) • Xtandi (enzalutamide capsule) • Cabometyx (cabozantinib tablet) • albumin-bound paclitaxel • Stivarga (regorafenib) • abiraterone acetate • oxaliplatin • Aliqopa (copanlisib) • Vizimpro (dacomitinib) • Zydelig (idelalisib) • daunorubicin • Zolinza (vorinostat) • Idhifa (enasidenib) • Farydak (panobinostat) • Erivedge (vismodegib) • Nubeqa (darolutamide) • bicalutamide • leucovorin calcium • cabazitaxel • Vesanoid (tretinoin) • fluorouracil topical
    2ms
    Mechanisms of Resistance to Tyrosine Kinase Inhibitors in ROS1 Fusion-Positive Nonsmall Cell Lung Cancer. (PubMed, Clin Chem)
    This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.
    Journal
    |
    MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CD74 (CD74 Molecule) • SLC34A2 (Solute carrier family 34 member 2)
    |
    MET amplification • ROS1 fusion • ROS1 positive • ROS1 G2032R • ROS1 mutation
    |
    Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib)
    2ms
    An Infant-Type Hemispheric Glioma With SOX5::ALK: A Novel Fusion. (PubMed, J Natl Compr Canc Netw)
    After initial chemotherapy with cyclophosphamide, carboplatin, and etoposide for 2 cycles, the tumor size progressed markedly and the patient underwent a subtotal resection of brain tumor followed by treatment with lorlatinib, an ALK tyrosine kinase inhibitor with central nervous system (CNS) activity. After 14 months of treatment, partial response was achieved, and the infant had normal growth and development. In conclusion, we identified a case of congenital IHG with a novel SOX5::ALK fusion that had progressed after chemotherapy and showed partial response and clinical benefit after treatment with the CNS-active ALK inhibitor lorlatinib.
    Journal
    |
    FAP (Fibroblast activation protein, alpha) • GFAP (Glial Fibrillary Acidic Protein)
    |
    ALK fusion
    |
    carboplatin • Lorbrena (lorlatinib) • cyclophosphamide • etoposide IV
    2ms
    A Study to Learn About Lorlatinib in Patients With Non-Small Cell Lung Cancer Which Could Not Be Controlled (clinicaltrials.gov)
    P=N/A, N=73, Completed, Pfizer
    New trial
    |
    ALK (Anaplastic lymphoma kinase)
    |
    Lorbrena (lorlatinib)
    2ms
    Anaplastic Lymphoma Kinase (ALK) Inhibitors Show Activity in Colorectal Cancer With ALK Rearrangements: Case Series and Literature Review. (PubMed, Oncologist)
    Both fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and bevacizumab combined with 5-fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) proved ineffective against the disease...The patient was initially treated with ensartinib monotherapy for 9 months, then with ensartinib combined with local radiotherapy and fruquintinib for another 4 months for isolated hilar hepatic lymph node metastasis. The patient experienced disease progression with an acquired ALK G1202R resistance mutation that responded well to lorlatinib...However, the patient responded remarkably well to alectinib. Our report emphasizes the importance of gene detection in the treatment of malignant tumors, and the significance of ALK mutations in CRC.
    Review • Journal
    |
    ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
    |
    ALK positive • ALK rearrangement • EML4-ALK fusion • ALK fusion • ALK G1202R • CAD-ALK fusion • EML4-ALK G1202R
    |
    Avastin (bevacizumab) • 5-fluorouracil • Alecensa (alectinib) • Lorbrena (lorlatinib) • oxaliplatin • irinotecan • Ensacove (ensartinib) • Fruzaqla (fruquintinib) • leucovorin calcium
    3ms
    ALKALINE: Activity of Lorlatinib Based on ALK Resistance Mutations Detected on Blood in ALK Positive NSCLC Patients (clinicaltrials.gov)
    P2, N=68, Active, not recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Trial completion date: Jul 2024 --> Nov 2024 | Trial primary completion date: Dec 2023 --> Jul 2024
    Trial completion date • Trial primary completion date
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK rearrangement
    |
    Lorbrena (lorlatinib)
    3ms
    A Study to Learn About the Study Medicine (Called Lorlatinib) in People With Liver Dysfunction (clinicaltrials.gov)
    P1, N=24, Recruiting, Pfizer | Trial completion date: Dec 2023 --> Aug 2024 | Trial primary completion date: Dec 2023 --> Aug 2024
    Trial completion date • Trial primary completion date
    |
    Lorbrena (lorlatinib)
    3ms
    NANT 2015-02: A Phase 1 Study of Lorlatinib (PF-06463922) (clinicaltrials.gov)
    P1, N=65, Active, not recruiting, New Approaches to Neuroblastoma Therapy Consortium | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024
    Trial completion date • Trial primary completion date
    |
    ALK fusion • ALK mutation • ALK translocation • ALK amplification
    |
    Lorbrena (lorlatinib) • cyclophosphamide • topotecan • Neulasta (pegfilgrastim) • Neupogen (filgrastim)
    3ms
    Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient. (PubMed, Acta Pharmacol Sin)
    In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.
    Journal
    |
    EML4 (EMAP Like 4) • IL6 (Interleukin 6) • CXCL5 (Chemokine (C-X-C motif) ligand 5) • CXCL1 (Chemokine (C-X-C motif) ligand 1)
    |
    ALK positive • EML4-ALK fusion • ALK fusion • ALK G1269A • EML4-ALK G1269A • IL6 expression
    |
    Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib)
    3ms
    China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition) (PubMed, Zhonghua Yi Xue Za Zhi)
    As of June 27, 2023, seven ALK-TKI, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib, have garnered approval from the China National Medical Products Administration (NMPA)(ranking according to the approval time for marketing by NMPA), providing individualized treatment modalities for ALK-positive NSCLC patients. To standardize the application of ALK-TKI, the Chinese Association for Clinical Oncologists and the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care has organized experts to compile the " China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)". This treatment expert recommendation provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese advanced ALK fusion-positive NSCLC.
    Journal • Metastases
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK positive • ALK fusion
    |
    Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib) • Ensacove (ensartinib) • Qi Xinke (iruplinalkib)
    3ms
    Prospective observational study to explore genes and proteins predicting efficacy and safety of brigatinib for ALK-gene rearranged non-small-cell lung cancer: study protocol for ABRAID study (WJOG11919L). (PubMed, Ther Adv Med Oncol)
    Cohorts A, B, and 0 will enroll patients receiving alectinib as the first ALK-TKI, receiving alectinib as the first ALK-TKI and subsequently cytotoxic agents and/or lorlatinib after alectinib, and without a history of ALK-TKI, respectively. The results will provide crucial information for establishing treatment strategies, discovering novel biomarkers, and developing new therapeutic agents. UMIN000042439.
    Journal • Observational data
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK rearrangement
    |
    PGDx elio™ plasma resolve assay
    |
    Alecensa (alectinib) • Lorbrena (lorlatinib) • Alunbrig (brigatinib)
    3ms
    Treatment Advances in Lung Cancer with Leptomeningeal Metastasis. (PubMed, Curr Cancer Drug Targets)
    Exciting progress has been made by focusing on specific mutations within lung cancer, including the use of EGFR tyrosine kinase inhibitors or inhibitors for anaplastic lymphoma kinase gene rearrangement, such as osimertinib, alectinib, and lorlatinib. However, the sample size of prospective clinical trials investigating LM for lung cancer is still limited, with most reports being retrospective. Developing more effective management protocols for metastatic LM in lung cancer remains an ongoing challenge for the future.
    Journal • IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase)
    |
    EGFR mutation • ALK rearrangement
    |
    Tagrisso (osimertinib) • Alecensa (alectinib) • Lorbrena (lorlatinib)
    3ms
    A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations. (PubMed, Front Mol Biosci)
    This comparative study of the potential binding effects of fourth-generation inhibitors TPX-0131 and repotrectinib and third-generation inhibitor LOR for ALK F1174C/L/V mutations revealed the atomistic insights of the binding mechanism. These computational findings enable us to carry out further research for the clinical implementation of fourth-generation ALK inhibitors on ALK-positive NSCLC.
    Journal
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK positive • ALK rearrangement • ALK mutation • ALK F1174C • ALK F1174V
    |
    Lorbrena (lorlatinib) • Augtyro (repotrectinib) • TPX-0131
    3ms
    ALK F1174S mutation impairs ALK kinase activity in EML4-ALK variant 1 and sensitizes EML4-ALK variant 3 to crizotinib. (PubMed, Front Oncol)
    These findings highlight the complexity of drug selection when treating patients harboring resistance mutations and suggest that the F1174S mutation in EML4-ALK variant 1 is likely not a potent oncogenic driver. Additional oncogenic driver or other resistance mechanisms should be considered in the case of EML4-ALK variant 1 with F1174S mutation.
    Journal
    |
    ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
    |
    EML4-ALK fusion • ALK fusion • ALK mutation • EML4-ALK variant 3 • ALK F1174C • EML4-ALK variant 1 • EML4-ALK F1174C
    |
    Xalkori (crizotinib) • Lorbrena (lorlatinib)
    3ms
    The lack of head-to-head randomised trials and the consequences for patients and national health service: The case of non-small cell lung cancer. (PubMed, Eur J Clin Pharmacol)
    There are few head-to-head studies comparing treatments for NSCLC; there are no such studies between the latest generation of drugs. Consequently, ambiguous areas exist due to the lack of comparative studies among the available evidence, preventing the clinician's choice of the most effective treatment and risking the patient receiving suboptimal therapy. Simultaneously, the price of the drug cannot be determined correctly, relying only on indirect evaluations from different trials. To dispel this uncertainty, it would be desirable to initiate a process that brings together the demands derived from clinical practice and clinical research to provide clinicians and patients with the best possible evidence.
    Journal • Head-to-Head
    |
    ALK (Anaplastic lymphoma kinase)
    |
    Keytruda (pembrolizumab) • Opdivo (nivolumab) • Xalkori (crizotinib) • Tagrisso (osimertinib) • Tecentriq (atezolizumab) • Gilotrif (afatinib) • Yervoy (ipilimumab) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Alunbrig (brigatinib)
    4ms
    Comparing efficacy and safety of upfront treatment strategies for anaplastic lymphoma kinase-positive non-small cell lung cancer: a network meta-analysis. (PubMed, Explor Target Antitumor Ther)
    The analysis included 9 RCTs with 2,443 patients receiving eight different treatments: alectinib (at two different dosages), brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Based on the network meta-analysis, alectinib and lorlatinib emerged as the most promising upfront treatment options. These treatments provide prolonged disease control while maintaining an acceptable safety profile.
    Retrospective data • Review
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK positive
    |
    Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib) • Ensacove (ensartinib)
    4ms
    From Development to Place in Therapy of Lorlatinib for the Treatment of ALK and ROS1 Rearranged Non-Small Cell Lung Cancer (NSCLC). (PubMed, Diagnostics (Basel))
    The ability to overcome acquired resistance to prior generation TKIs (alectinib, brigatinib, ceritinib, and crizotinib) and the high intracranial activity in brain metastatic disease thanks to increased blood-brain barrier penetration are the reasons for the growing popularity and interest in this molecule. So, when prescribing lorlatinib, clinicians must face two diametrically opposed characteristics: a great therapeutic potential without the intrinsic limitations of its precursor TKIs, a cytotoxic activity threatened by suboptimal tolerability, and the unavoidable onset of resistance mechanisms we cannot properly manage yet. In this paper, we give a critical point of view on the stepwise introduction of this promising drug into clinical practice, starting from its innovative molecular and biochemical properties to intriguing future developments, without forgetting its weaknesses.
    Review • Journal
    |
    ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
    |
    ALK rearrangement • ROS1 positive • ROS1 rearrangement
    |
    Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib)
    4ms
    Real-world evidence of lorlatinib therapy in Taiwanese patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. (PubMed, J Formos Med Assoc)
    Lorlatinib exhibits substantial activity and tolerability when used clinically in a later-line setting in a Taiwanese population with ALK-positive advanced NSCLC.
    Journal • HEOR • Real-world evidence • Real-world • Metastases
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK positive
    |
    Lorbrena (lorlatinib)
    4ms
    ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition. (PubMed, Proc Natl Acad Sci U S A)
    Finally, we show that the remarkable response to the 14-d combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.
    Journal
    |
    ALK (Anaplastic lymphoma kinase) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • CHEK1 (Checkpoint kinase 1)
    |
    Lorbrena (lorlatinib) • elimusertib (BAY 1895344)
    4ms
    In-depth Analysis of Lorlatinib-related neurocognitive Adverse Events in Patients With Non-small-cell Lung Cancer. (PubMed, Clin Lung Cancer)
    Lorlatinib treatment did not result in a sustained and significant decline within any of the specified neurocognitive domains.
    Journal • Adverse events
    |
    ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
    |
    ALK rearrangement • ROS1 rearrangement
    |
    Lorbrena (lorlatinib)
    4ms
    Treatment sequencing after failure to alectinib in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer. (PubMed, Cancer Sci)
    The times to treatment discontinuation of the regimen between patients treated with lorlatinib and brigatinib were similar, with a hazard ratio of 1.02 (95% confidence interval, 0.64-1.64) in the period after marketing brigatinib. This study provides insights into the evolving treatment landscape for patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer who experience failed alectinib treatment and highlights the need for further studies and data accumulation to determine the optimal treatment strategy.
    Journal
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK positive
    |
    Alecensa (alectinib) • Lorbrena (lorlatinib) • Alunbrig (brigatinib)
    4ms
    Safety and Efficacy of Lorbrena (clinicaltrials.gov)
    P=N/A, N=683, Recruiting, Pfizer | Trial completion date: Jun 2025 --> Dec 2025 | Trial primary completion date: Jun 2025 --> Dec 2025
    Trial completion date • Trial primary completion date
    |
    Lorbrena (lorlatinib)
    4ms
    Dissecting the role of ALK double mutations in drug resistance to lorlatinib with in-depth theoretical modeling and analysis. (PubMed, Comput Biol Med)
    Furthermore, the US simulation results elucidate that the pathways through which lorlatinib dissociates vary across mutant systems, and the distinct environments during the dissociation process culminate in diverse resistance mechanisms. Collectively, these insights provide important clues for the design of novel inhibitors to combat resistance.
    Journal
    |
    ALK (Anaplastic lymphoma kinase)
    |
    ALK positive • ALK mutation • ALK I1171
    |
    Lorbrena (lorlatinib)
    5ms
    Transformation of NSCLC to SCLC harboring EML4-ALK fusion with V1180L mutation after alectinib resistance and response to lorlatinib: A case report and literature review. (PubMed, Lung Cancer)
    This study affirms the efficacy of lorlatinib in patients with ALK-positive SCLC transformation harboring the V1180L mutation. Furthermore, it underscores the imperative of conducting genetic testing in patients who transition to SCLC following ALK-TKI resistance, as targeted therapies may remain efficacious if a genetic driver is identified.
    Clinical • Retrospective data • Review • Clinical Trial,Phase II • Journal
    |
    ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
    |
    ALK positive • EML4-ALK fusion • ALK fusion • ALK mutation • ALK V1180L • ALK fusion + ALK V1180L
    |
    Alecensa (alectinib) • Lorbrena (lorlatinib)