Lorbrena (lorlatinib) / Pfizer, CStone Pharma - LARVOL DELTA

A highly selective, brain-penetrant and overcoming G2032R resistance ROS1 inhibitor JYP0322 in NSCLC patients with ROS1 fusion (AACR 2025) - P1 | "JYP0322 had a favorable safety profile with a low incidence of neurotoxicities. It showed highly promising anti-tumor effects in patients with ROS1+NSCLC including both TKI-naïve and TKI pre-treated patients, as well as those with TKI-heavily treated, brain metastases, or harboring ROS1 G2032R mutation.Tumor response in patients with ROS1+ advanced NSCLCG2032R mutationsPrevious treatment lines≥2L and ROS1 TKI≥1ROS1 TKI naive Evaluable subjects (All dose level)All (n=7)Lorlatinib pretreated (n=3)All (n=22)CNS metastasis (n=13)All (n=14)CNS metastasis (n=1)ORR71.4%66.7%54.5%38.5%85.7%100%DCR100%100%81.8%69.2%100%100%"

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

Pivotal ARROS-1 Efficacy and Safety Data: Zidesamtinib in TKI Pre-treated Patients with Advanced/Metastatic ROS1+ NSCLC (IASLC-WCLC 2025) - P1/2 | "50% of patients received ≥2 (range 1-4) prior ROS1 TKIs, of whom 93% had prior lorlatinib, repotrectinib, and/or taletrectinib. In this pivotal ROS1 TKI pre-treated data set, zidesamtinib demonstrated clinically meaningful activity and durability, including in patients with CNS disease and/or ROS1 G2032R-mutations, and/or in patients who had exhausted available options. Encouraging preliminary activity was also observed in TKI-naïve patients. Zidesamtinib's safety profile was consistent with its highly ROS1-selective, TRK-sparing design."

Clinical • Metastases • CNS Disorders • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Pulmonary Disease • Solid Tumor • ROS1

Longitudinal methylation- vs genomic-based circulating tumor DNA molecular response analysis in patients with ALK+ advanced non-small cell lung cancer treated with lorlatinib in the CROWN study (ESMO 2025) - P3 | "Earlier analysis from CROWN showed that C2D1 circulating tumor DNA (ctDNA) reduction based on genomic variants predicted better outcomes in pts treated with lorlatinib but did not predict crizotinib response; however, ctDNA change was not quantifiable in many pts due to low shedding. Conclusions This analysis from the CROWN study showed that methylation-based TF was more sensitive in detecting ctDNA than genomic methods and can provide informative results in more pts; furthermore, methylation TF can stratify PFS in pts with undetectable ctDNA by genomics. Comparison of TF change at C2D1 and C7D1 indicates that MR at C7D1 is a better predictor of PFS than at C2D1 in pts treated with lorlatinib and adds to the body of literature supporting ctDNA as an early endpoint."

Circulating tumor DNA • Clinical • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Neurological adverse events of ROS1 inhibitors for non-small cell lung cancer: data from the FDA adverse event reporting system. (PubMed, Front Neurol) - "Although agents such as Crizotinib, Ceritinib, Lorlatinib, Entrectinib, and Repotrectinib have demonstrated strong efficacy and intracranial activity, their neurological safety profiles remain insufficiently characterized in real-world settings. This study provides real-world evidence that newer ROS1 inhibitors exhibit earlier but generally manageable neurological AEs. Clinicians should implement early neurotoxicity monitoring and individualized risk assessment to ensure safe and effective targeted therapy for ROS1-positive NSCLC."

Adverse events • Journal • CNS Disorders • Cognitive Disorders • Developmental Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Patterns of Progression with Lorlatinib and Insights into Subsequent Anticancer Therapy Efficacy in Advanced ALK+ NSCLC (IASLC-WCLC 2024) - P3 | "Best Overall Response and Objective Response Rate on First Subsequent Anticancer Therapy Study treatment Lorlatinib Crizotinib First Subsequent Therapy Any ALK TKI (n=23) a Any non-ALK TKI (n=15) b Overall (n=38) Any ALK TKI (n=101) a Any non-ALK TKI (n=8) b Overall (n=109) Objective response rate (95% CI), % c 26.1 (10.2-48.4) 20.0 (4.3-48.1) 23.7 (11.4-40.2) 17.8 (10.9-26.7) 12.5 (0.3-52.7) 17.4 (10.8-25.9) Best overall response, n (%) Complete response 2 (9) 1 (7) 3 (8) 1 (1) 0 1 (1) Partial response 4 (17) 2 (13) 6 (16) 17 (17) 1 (13) 18 (17) Stable disease 1 (4) 3 (20) 4 (11) 23 (23) 0 23 (21) Progressive disease 6 (26) 3 (20) 9 (24) 10 (10) 2 (25) 12 (11) Unknown 3 (13) 5 (33) 8 (21) 9 (9) 4 (50) 13 (12) Not reported, therapy ongoing 7 (30) 1 (7) 8 (21) 41 (41) 1 (13) 42 (39) a Includes alectinib, brigatinib, ceritinib, crizotinib, and lorlatinib. b Includes chemotherapy ± anti-angiogenic, chemotherapy/immunotherapy,..."

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

From class effects to specificity FAERS evidence and network mapping of adverse events in NSCLC targeted therapy. (PubMed, Int J Surg) - "This first NSCLC-focused FAERS comparison integrating four-method signal detection with network analysis delineates reproducible class effects superimposed by drug-specific toxicities. Findings support tailored monitoring (e.g., dermatologic care for EGFR-TKIs; ECG/electrolytes for osimertinib; lipid/CK surveillance for ALK-TKIs; blood pressure/liver testing for RET-TKIs) to inform risk-aware first-line decisions."

Adverse events • Journal • Cardiovascular • Dyslipidemia • Hypertension • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • KRAS • ROS1

First-line lorlatinib versus crizotinib in Asian patients with advanced ALK-positive NSCLC: 5-year outcomes from the CROWN study. (PubMed, J Thorac Oncol) - P3 | "After 5 years of follow-up, lorlatinib efficacy and safety in the Asian subgroup of CROWN continue to be consistent with those in the overall population, with PFS remaining unreached with lorlatinib."

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

Long-Term Risk of Radiation Necrosis Following SRS in ALK-Positive NSCLC in the Era of CNS-Penetrant TKIs (IASLC-TTLC 2026) - "Alectinib was the most frequent concomitant TKI around the time of SRS (46.2%), followed by crizotinib (23.1%) and lorlatinib (19.2%)...All five of these patients were symptomatic and required steroid treatment; one patient also received bevacizumab...Among TRC cases, treatment with a highly CNS-penetrant TKI (alectinib, brigatinib, or lorlatinib) at the time of TRC was associated with symptomatic presentation (55.6% vs 0.0%; OR 11.12, 95% CI: 0.52-236.77, p=0.096)... In this single-institution series, ALK-positive NSCLC patients on TKI frequently experienced treatment-related changes after SRS, with higher incidence than historically observed in non-ALK populations. Single-fraction treatment and highly CNS-penetrant TKI use following SRS may increase the risk of TRC. The emergence of symptomatic TRC years after SRS underscores the need for long-term surveillance and continued refinement of risk stratification and treatment sequencing within the evolving TKI–radiation..."

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

Based on the CROWN Findings, Lorlatinib Should Be the Preferred First-Line Treatment for Patients With Advanced ALK-Positive NSCLC. (PubMed, J Thorac Oncol) - No abstract available

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

Efficacy of lorlatinib after failure of a first-line ROS1 tyrosine kinase inhibitor (ROS1 TKI) in patients (pts) with advanced ROS1-positive non-small cell lung cancer (ROS1+ NSCLC) (IFCT-2003 ALBATROS) (ESMO 2025) - P2 | "Background Current ESMO guidelines recommend ROS1 TKIs crizotinib and entrectinib as preferred first-line treatments for advanced ROS1 + NSCLC. Conclusions In this phase II trial, lorlatinib demonstrated robust clinical activity in ROS1+ NSCLC pts who received one line of ROS1+ TKI, mostly crizotinib. Lorlatinib activity according to baseline molecular profile including resistance mutation to crizotinib will be presented."

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

A Study to Learn About Lorlatinib in Patients With Non-Small Cell Lung Cancer (NSCLC) Which Has Spread Out. (clinicaltrials.gov) - P=N/A | N=35 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=500 ➔ 35 | Trial completion date: Dec 2025 ➔ Jun 2026 | Trial primary completion date: Dec 2025 ➔ Jun 2026

Enrollment change • Enrollment closed • Real-world evidence • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Real-World Tolerability and Long-Term Toxicity of Lorlatinib in ALK+/ROS1+ Advanced NSCLC (ELCC 2026) - No abstract available

Clinical • Metastases • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • ROS1

Real-world experience with lorlatinib therapy in ALK-positive, pretreated non-small cell lung cancer patients in Russia (ELCC 2026) - No abstract available

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

Lorlatinib-related toxicity and its association with systemic drug exposure in non-small cell lung cancer (ELCC 2026) - No abstract available

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

First-line lorlatinib versus sequential second-generation ALK TKI followed by lorlatinib in advanced ALK-positive non-small cell lung cancer A real-world cohort study (ELCC 2026) - No abstract available

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

Cost of managing brain metastases in ALK-positive advanced NSCLC patients receiving first-line ALK TKIs in China. (PubMed, Lung Cancer Manag) - "Limited CIR beyond 12 months existed for brigatinib and ensartinib. Results from the Asian group's CIR aligned with global trials. Due to lower BM CIR, lorlatinib showed higher BM management cost savings compared to crizotinib and alectinib in Chinese 1 L patients."

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

Comparison of the efficacy based on clinicopathological characteristics and the safety of first-line treatments for patients with advanced ALK rearrangement non-small cell lung cancer: a network meta-analysis. (PubMed, Front Oncol) - "Specifically, lorlatinib demonstrated superior efficacy in the Non-Asian subgroup (86.8%), patients without brain metastasis (84.7%), those with Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1 (78.5%), males (71.2%), females (83.9%), patients aged < 65 years (74.3%), and never-smoking patients (89.7%)...Ensartinib achieved the optimal PFS in the Asian subgroup (71.8%)...Alectinib had the lowest hepatic and gastrointestinal AEs risk, while iruplinalkib had the lowest hematological AEs risk. https://www.crd.york.ac.uk/prospero/, identifier CRD42023495527."

Journal • Retrospective data • Review • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

A Phase II Trial of Stereotactic Body Radiotherapy (SBRT) in Patients with Stage IV Oncogene-Driven Non-Small Cell Lung Cancer (NSCLC) (ASTRO 2024) - "Most had EGFR driver mutations (n=22, 54.5% on osimertinib), followed by ALK (n=4, on alectinib or lorlatinib), and ROS1 fusions (n=1, on crizotinib). Consolidation SBRT to predominantly the primary lung site in pts with oncogene-driven metastatic NSCLC was not associated with decrease in frequency of DF which constituted 50% of first failures at 1 year. The lack of reduction in DF suggests that SBRT to the primary lung site only is insufficient. Consideration should be given to consolidation SBRT to not only the primary site but also additional original sites of metastasis."

Clinical • Metastases • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • ROS1

A first-in-human, phase 1 study of the SHP2 inhibitor PF-07284892 as monotherapy and in combination with different targeted therapies in oncogene-driven, treatment-resistant solid tumors. (ASCO 2023) - P1 | "In the absence of dose limiting toxicity (DLT), matched targeted therapy (lorlatinib for ALK/ROS1 fusion+ cancers, encorafenib + cetuximab for BRAFV600E colorectal cancers, and binimetinib for MAPK-mutant cancers) could be added after 6 weeks of monotherapy at the discretion of the investigator. PF-07284892 was generally well tolerated alone and in combination with rational targeted therapies. This study design enabled combination therapy rescue of disease progression on PF-07284892 monotherapy with 3 pts achieving confirmed PR. Clinical trial information: NCT04800822."

Combination therapy • Monotherapy • P1 data • Anemia • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Oncology • Solid Tumor • Thrombocytopenia • ALK • ROS1

A comprehensive functional atlas of ALK kinase domain variants reveals resistance landscape to ALK inhibitors. (PubMed, Genome Biol) - "This study provides a comprehensive functional atlas of ALK tyrosine kinase domain variants under TKI selection, offering a valuable experimental framework for interpreting resistance-associated variants. Although derived from in vitro models and therefore context dependent, this resource complements existing clinical and genomic knowledge and may aid in the functional interpretation of ALK variants observed in ALK-driven cancers."

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

Fourth-quarter 2025 operational revenue reflected higher revenues primarily for (Businesswire) - "Eliquis globally, up 8%...Lorbrena globally, up 45% operationally, driven primarily by increased patient share in the first-line ALK-positive metastatic non-small cell lung cancer (ALK+ mNSCLC) treatment setting in the U.S., China, and certain other international markets, partially offset by lower net price in the U.S. mainly due to the impact of higher manufacturer discounts resulting from the IRA Medicare Part D redesign; and Padcev globally, up 15% operationally, driven primarily by increased market share in first-line locally advanced or metastatic urothelial cancer (la/mUC)."

Commercial • Atrial Fibrillation • Non Small Cell Lung Cancer • Urothelial Cancer • Venous Thromboembolism

Hepatotoxicity of new-generation ALK inhibitors versus crizotinib in patients with non-small cell lung cancer: A systematic review and meta-analysis. (PubMed, iScience) - "Alectinib, lorlatinib, and brigatinib are associated with lower risks of hepatotoxicity when compared with crizotinib. Lorlatinib conferred a greater reduction in any grades AST than second-generation inhibitors compared to crizotinib. Our findings suggest that the selection of the ALK inhibitor should be individualized based on the specific profile of hepatotoxicity and their efficacy."

Journal • Retrospective data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Comment on "A Real-World Pharmacovigilance Analysis of Lorlatinib-Associated Metabolic Effects Using the FDA Adverse Events Reporting System (FAERS) Database From 2013 to 2024" by Frey et al. (PubMed, Endocr Pract) - No abstract available

Adverse events • Journal • Real-world evidence

SAILOR: Iruplinalkib in ALK-Positive Advanced Lung Adenocarcinoma After Lorlatinib (clinicaltrials.gov) - P=N/A | N=20 | Recruiting | Sponsor: Peking University Shenzhen Hospital

New trial • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

An Observational Study of the Efficacy and Safety of Iruplinalkib(WX-0593) in ALK-positive Advanced Lung Adenocarcinoma Following Lorlatinib Treatment (ChiCTR) - P=N/A | N=10 | Not yet recruiting | Sponsor: Peking University Shenzhen Hospital; Peking University Shenzhen Hospital

New trial • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK