Alunbrig (brigatinib) / Takeda - LARVOL DELTA

Shifting landscape of resistance to next-generation ALK inhibitors with evolving treatment paradigm in ALK+ lung cancer. (ASCO 2025) - "Background: Next-generation (gen) ALK tyrosine kinase inhibitors (TKIs) are standard first-line (1L) therapy for patients (pts) with ALK-rearranged (ALK+) metastatic non-small cell lung cancer (mNSCLC), having supplanted crizotinib (criz)... This retrospective study included pts with ALK+ mNSCLC who received 2G ALK TKIs (alectinib, brigatinib, ceritinib, ensartinib) or 3G TKI lorlatinib (lorl) and had post-progression tissue (TBx) or liquid bx (LBx) assessed by next-generation sequencing (NGS)... In this largest analysis of post-2G/3G ALK TKI TBx/LBx to date, on-target resistance was less freq after 2G/3G TKIs in pts treated with the current paradigm (upfront 2G/3G ALK TKIs) than the past approach (2G/3G TKI after 1L criz). These findings crystallize a shifting resistance landscape and indicate an increasing role for off-target resistance with upfront 2G/3G TKIs, highlighting a need to uncover and therapeutically address off-target resistance."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EML4 • MET

Real-world treatment patterns and time-to-treatment discontinuation among advanced ALK-positive non-small cell lung cancer patients. (ASCO 2025) - " Among 680 patients, 1L therapy distribution was as follows: crizotinib (n=366, 53.8%), alectinib (n=267, 39.3%), brigatinib (n=22, 3.2%), and ceritinib (n=25, 3.7%). This study provides real-world evidence on TTD and treatment patterns among advanced ALK+ NSCLC patients. Transition rates to 2L ALK TKIs were lower than expected based on clinical trials, with high rates of discontinuation without transition. With alectinib, brigatinib, and lorlatinib equally recommended as 1L options in US clinical guidelines, these findings provide real-world evidence to help clinicians differentiate among therapies and guide treatment sequencing decisions."

Clinical • HEOR • Metastases • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Real-World Creatinine-Based Estimates of Acute and Chronic Kidney Dysfunction in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer Receiving Tyrosine Kinase Inhibitors. (PubMed, Clin Lung Cancer) - "AKI/CKD events were frequent post-ALKi initiation (using creatinine-based eGFR), with a minority resulting in treatment change. Mean eGFR declined in the 90-days post-ALKi start. Most patients had mild CKD, with eGFR recovering postdrug cessation. AKI did not impact OS. Our findings suggest that most patients may continue ALKi therapy despite creatinine-based eGFR changes."

Journal • Real-world evidence • Acute Kidney Injury • Cardiovascular • Chronic Kidney Disease • Hypertension • Lung Cancer • Nephrology • Non Small Cell Lung Cancer • Oncology • Renal Disease • Solid Tumor • ALK • CST3

Progression-Free Survival and Objective Response Rates As Surrogate Endpoints for Overall Survival Among Patients With ROS1+ Locally Advanced or Metastatic Non-Small Cell Lung Cancer Receiving ROS1 Tyrosine Kinase Inhibitors (ISPOR 2025) - " Twelve cohorts from non-randomized clinical trials involving treatment with crizotinib, entrectinib, lorlatinib, brigatinib or ceritinib were identified; repotrectinib cohorts were excluded. The current analysis demonstrated a strong association between OS and PFS among TKI-treated patients with ROS1+ aNSCLC, lending support to previous real world evidence evaluating surrogacy of PFS. However, OS and ORR demonstrated a weak association with substantial uncertainty. The lack of head-to-head evidence precluded assessment of the correlation between treatment effects."

Clinical • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Combination of Osimertinib and Brigatinib in the Treatment of EGFR Triple-Mutated Lung Adenocarcinoma: A Case Report. (PubMed, Curr Oncol) - "The combined treatment of osimertinib and brigatinib offers a promising new approach. Nonetheless, it is important to consider the potential risk of off-target toxicities."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

Treatment of metastatic ALK-positive non-small cell lung cancer: indirect comparison of different ALK inhibitors using reconstructed patient data. (PubMed, Front Oncol) - "Second- and third-generation ALKi, including alectinib, brigatinib, ensartinib, envonalkib, and lorlatinib, have shown better efficacy than crizotinib. In this indirect comparison using reconstructed patient data, lorlatinib emerged as the most effective ALKi, showed the most favorable HR for PFS compared to the other ALKi, although it did not reach statistical significance versus alectinib and ensartinib. Additionally, lorlatinib showed the highest efficacy in the control of CNS progression."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Molecular profiling using NGS in lung cancer patients: Revolutionizing targeted therapy and personalized treatment. (ASCO 2025) - "The hotspot KRAS mutation G12C was detected in 10,3% of cases and it is associated with response to the FDA approved drugs Sotorasib and Adagrasib...Additionally, ALK fusion was detected in 2,2% of patients offering response to on label therapies like Brigatinib and Lorlatinib... The findings described above underline the necessity of a multigene analysis for patients with NSCLC, in order to benefit from the available targeted therapies. PDL-1 testing increases this benefit as it is a positive predictive biomarker for immunotherapy, even for patients harboring no driver mutations."

Clinical • IO biomarker • Next-generation sequencing • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • HER-2 • KRAS • MET • NTRK1 • NTRK2 • NTRK3 • RET • ROS1 • STK11

Real-world baseline characteristics and diagnostic path of Polish patients with ALK-positive NSCLC eligible for brigatinib treatment: Interim results from the ENTIRETY study. (ASCO 2025) - P | "These findings enhance our understanding of the characteristics and diagnostic path of Polish patients with ALK+ NSCLC receiving brigatinib treatment. Patient flow*.*Data based on patient-reported questionnaire unless noted otherwise. # Based on patients' medical history (with no missing values)."

Clinical • Real-world • Real-world evidence • CNS Disorders • Fatigue • Insomnia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Sleep Disorder • Solid Tumor • ALK

Real-world comparative outcomes of alectinib and brigatinib in ALK-positive non–small cell lung cancer: A retrospective cohort analysis using HIRA data. (ASCO 2025) - "Both alectinib- and brigatinib-treated patients who transitioned to lorlatinib demonstrated notably prolonged survival. In this real-world study, both alectinib and brigatinib provided favorable survival outcomes in patients with ALK-positive NSCLC. While brigatinib showed a trend toward reduced mortality in univariable analysis, this was not maintained in adjusted models. Alectinib conferred a longer duration of disease control (PFS) in both first- and second-line settings."

Real-world • Real-world evidence • Retrospective data • Diabetes • Hypertension • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

A window of opportunity study for preoperative brigatinib in resectable anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC): WILDERNESS trial. (ASCO 2025) - P2 | "Neoadjuvant brigatinib was effective and safe in patients with resectable ALK-positive NSCLC. Single-cell transcriptomic analysis highlights the balance between effector and regulatory T cell programs as a critical determinant of pathologic response and the clearance of drug-tolerant and persister cancer cells."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • CD4 • CD8 • FOXP3 • PRDM1

Challenges in Projecting Treatment Journeys for ALK-mutated NSCLC: Addressing Uncertainty in PPS and Immature Overall Survival Data (ISPOR 2025) - " We analyzed RCTs and RWE for patients with ALK-mutated stage IV NSCLC treated with third-generation TKIs: lorlatinib, alectinib, and brigatinib. The lack of a defined PPS standard and immature OS data increases uncertainty in treatment projections. While RWE mitigates gaps, robust sensitivity analyses remain critical to account for variability in post-progression outcomes."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Optimized Treatment Sequences for ALK+ Stage IV NSCLC: Cost-Effectiveness Analysis From RCT data and Real-World Evidence (ISPOR 2025) - " An analytical decision model was developed, considering transitions between six health states: first-line progression-free survival (PFS) with tyrosine kinase inhibitors (TKIs; lorlatinib, alectinib, brigatinib), first-line post-progression survival (PPS), second-line PFS with TKIs, third-line PFS with chemotherapy, PPS, and death. RWE clarified some uncertainties in the model, but the cost-effectiveness ratio remains unfavorable across both models, likely due to the high costs of the evaluated technologies."

Clinical • Cost effectiveness • HEOR • Metastases • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Cost-Utility Analysis of Lorlatinib in First-Line Treatment of adult patients with ALK-Positive Advanced Non-Small Cell Lung Cancer (aNSCLC) in Colombia (ISPOR 2025) - "In the Colombian health care system setting, lorlatinib is a cost-effective alternative against alectinib, brigatinib and crizotinib for the first-line treatment of adult patients ALK-positive aNSCLC."

Clinical • HEOR • Metastases • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

A Simple and Practical Guide to Implementing Generalized Risk-Adjusted Cost-Effectiveness (GRACE): A Case Study in Non-Small Cell Lung Cancer (ISPOR 2025) - " A traditional CEA model evaluating alectinib, brigatinib, and lorlatinib in advanced anaplastic lymphoma kinase (ALK)-positive NSCLC was extended into GRACE. GRACE analyses can significantly shift cost-effectiveness conclusions and accommodate both societal and patient-centered risk preferences. This study provides a step-by-step guide to extending traditional CEA models into GRACE, demonstrating its feasibility and flexibility in advancing more accurate, comprehensive, and equitable value assessments."

Case study • Clinical • Cost effectiveness • HEOR • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Case Report: Severe brigatinib-induced pneumonitis in a patient with EML4-ALK+ metastatic non-small cell lung adenocarcinoma. (PubMed, Front Oncol) - "The workup for alternative etiologies of respiratory distress was unrevealing, and the patient was treated for presumed brigatinib-induced pneumonitis with high-dose methylprednisolone. This case demonstrates high-grade, rapidly progressive brigatinib-induced pneumonitis with prompt clinical improvement after steroids and a marked disease response without recurring toxicity after treatment with an alternative ALK TKI, alectinib."

Journal • Inflammation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Solid Tumor • ALK • EML4

Progression and expansion of ALK inhibitors against NSCLC: A dual target approach. (PubMed, Eur J Med Chem) - "Since the ALK inhibitors such as Crizotinib, Ceritinib, Brigatinib, Alectinib and Lorlatinib, was endorsed for the treatment of advanced NSCLC linked to ALK gene rearrangement. The aim of this review is to summarize the introduction to ALK and the synergy between ALK and other anti-tumor targets, recent developments in the synthesis of various dual inhibitors of the ALK. We also thoroughly discussed their design concepts, structure-activity relationships (SARs), preclinical and clinical data as well as in silico studies to provide ideas for further development of novel ALK based dual inhibitors."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MET • ROS1

Successful Treatment of Osimertinib Resistance in an EGFR-Mutant Lung Cancer Patient With a Rare STRN3-ALK Fusion Using Brigatinib and Osimertinib. (PubMed, Kaohsiung J Med Sci) - No abstract available

Journal • Lung Cancer • Oncology • Solid Tumor • EGFR • STRN3

ALK-driven NSCLC and radiotherapy - pro (ESTRO 2025) - "LAURA selected patients with common mutations in EGFR due to the availability of a well-tolerated and efficacious agent (osimertinib), but the findings of this study are likely to be transferable to other such settings...eg. brigatinib, alectinib. A small retrospective series published recently suggests that consolidation ALK-targeted therapy may be more beneficial than durvalumab and no treatment in the scenario where an ALK rearrangement has been identified in the tumour. Prospective evidence is awaited from the ongoing phase 2 BOUNCE trial and phase 3 HORIZON-1 trials, although some patients may ask about off-license use of ALK-targeted therapies in the interim. This presentation will discuss the completed and ongoing studies in the 'ALK-positive' NSCLC chemoradiation setting and explore the implications of these data."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • EML4

Disproportionality Analysis of ALK Inhibitor-Induced Hemolytic Adverse Events: A Pharmacovigilance Study Using the FDA Adverse Event Reporting System Database. (PubMed, Can J Physiol Pharmacol) - "The findings highlight alectinibs potential hemolytic risk, necessitating hematologic monitoring. Proposed mechanisms include immune-mediated hemolysis, direct cytotoxicity, and metabolic variability. Routine hemoglobin and bilirubin assessments, along with clinical vigilance, are essential. Further studies are needed to elucidate mechanisms of causality and optimize patient safety."

Adverse events • Journal • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Inter-Ethnic Differences in the Efficacy and Safety of Tyrosine Kinase Inhibitors Used in Oncology: Insights From Phase 3 Clinical Trials. (PubMed, Clin Transl Sci) - "Twelve (16%) of the analyses investigating the efficacy of afatinib, brigatinib, dacomitinib, gilteritinib, lorlatinib, neratinib, osimertinib, or pazopanib were assessed to report population differences in PFS and/or OS...The majority of clinical trials noted no clinically remarkable differences in safety between subpopulations; however, for brigatinib, crizotinib, pazopanib, and sunitinib, distinct patterns of adverse events were reported in the Asian and non-Asian subgroups. The underrepresentation of specific subpopulations, the grouping together of results of diverse subpopulations, as well as inconsistencies in the definition and reporting of participant ethnicity/ancestry are barriers to the meaningful exploration of inter-ethnic differences in TKI response. Therefore, further insight into the associations between ethnicity/ancestry and TKI response will require an increase in the diversity of clinical trial participants and appropriate analysis and reporting of..."

Journal • P3 data • Review • Oncology

Multidisciplinary treatment of advanced or metastatic ALK-positive non-small cell lung cancer: Real-world data on Brigatinib combined with local therapy. (PubMed, Medicine (Baltimore)) - "Combining brigatinib with local therapy appears safe and potentially more effective for advanced ALK-positive NSCLC. Further studies are warranted."

Journal • Real-world evidence • Cardiovascular • Hypertension • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Solid Tumor • ALK

Clinical practice guideline on anaplastic lymphoma kinase-tyrosine kinase inhibitors for non-small cell lung cancer (2025 edition) (PubMed, Zhonghua Zhong Liu Za Zhi) - "As of December 31, 2024, eight ALK-TKIs, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, iruplinalkib, and invonalkib have garnered approval from the China National Medical Products Administration (NMPA) (Ranking according to the approval time for marketing by NMPA), providing targeted treatment agents for ALK-positive NSCLC patients. To standardize the application of ALK-TKIs, 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 "Clinical practice guideline on anaplastic lymphoma kinase-tyrosine kinase inhibitors for non-small cell lung cancer (2025 edition)". This guideline 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..."

Clinical guideline • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Short‑term efficacy assessment of brigatinib for the treatment of neurofibromatosis type 2: A retrospective study. (PubMed, Oncol Lett) - "However, no significant improvement was seen in acoustic neuroma volume or the mean hearing threshold (both P>0.05). In conclusion, brigatinib may relieve meningiomas and pain and improve emotional well-being in patients with NF2."

Journal • Retrospective data • Brain Cancer • CNS Tumor • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Pain • Solid Tumor • NF2

Identification of genes associated with drug persistence/resistance using CRISPR screening and scRNA-seq of ALK rearranged lung cancer (AACR 2025) - "Cas9 and genome-wide sgRNA-introduced cells were cultured with alectinib or lorlatinib for 9 days, and sgRNAs in surviving drug-tolerant cells were analyzed by NGS...In contrast, NF2 knockout itself induces drug resistance rather than drug persistence, and we found that brigatinib may be able to overcome the resistance induced by NF2 loss, because brigatinib inhibited ALK as well as several other kinases at single digit nM...Single-cell RNA sequencing revealed that MMP11-positive cancer-associated fibroblasts (CAFs) and a subset of tumor-associated macrophages (TAMs) were the major sources of Gas6 in the tumor microenvironment. This study uncovered some of the unidentified resistance mechanisms and potential therapeutic strategies to overcome the resistance."

Brain Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • AXL • CAFs • EGFR • ERRFI1 • GAS6 • MMP11 • NF2 • PTEN

Evaluation of lorlatinib efficacy using plasma DNA (AACR 2025) - "This study is the first to analyze lorlatinib's efficacy in such patients by integrating ctDNA analysis to explore predictive markers and resistance mechanisms. This multi-center prospective study enrolled patients with ALK-rearranged NSCLC resistant to alectinib, with no prior exposure to ALK-TKIs other than alectinib and brigatinib. This exploratory study highlights the complexity of resistance mechanisms in ALK-rearranged NSCLC treated with lorlatinib, demonstrating ctDNA's potential as a predictive biomarker for treatment outcomes. The persistence and emergence of specific mutations, such as in TP53 and ALK, underscore the need for further investigation into combination or personalized therapeutic strategies. Despite the study's limited sample size, these findings offer critical insights into the genomic landscape influencing lorlatinib efficacy following alectinib resistance."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • TP53