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

Neuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer. (PubMed, Proc Natl Acad Sci U S A) - "In vivo, mice treated with the ALK inhibitor lorlatinib at the onset of colitis exhibited a remarkable 90% reduction in tumor burden without significantly affecting overall inflammation. Moreover, activating TRPV1+ neurons using DREADD technology exacerbated tumor growth, whereas silencing these neurons significantly reduced it. These findings reveal that TRPV1+ nociceptors drive CAC progression via the ALKAL2/ALK pathway."

Journal • Colorectal Cancer • Gastroenterology • Gastrointestinal Disorder • Immunology • Oncology • Pain • Solid Tumor • ALK • ALKAL2 • TRPV1

Old Wine in New Bottles? Deuterium Switch (Replacing Hydrogen With Deuterium) Comes to Thoracic Oncology as Deuterated Lorlatinib (Deulorlatinib, TGRX-326) and Deuterated Osimertinib (Asandeutertinib, TY-9591) in ALK+ NSCLC and EGFR+ NSCLC, Respectively. (PubMed, J Thorac Oncol) - No abstract available

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

Discovery of an ALK degrader for lorlatinib-resistant compound mutations. (PubMed, Eur J Med Chem) - "By using WZH-15-125 as the warhead, we designed an ALK PROTAC molecule WZH-17-002 that can efficiently degrade ALK proteins with half maximal degradation concentration (DC50) values of 25 nM. Furthermore, WZH-17-002 suppresses the emergence of drug resistance and exhibits superior in vivo pharmacological efficacy than lorlatinib in ALK G1202R/L1196M xenograft mouse models. These findings suggest a potential strategy for overcoming resistance to ALK TKI therapies."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ALK

Lung Adenocarcinoma With Extensive Vascular Invasion and Retinal Metastasis: A Case Report. (PubMed, Respirol Case Rep) - "This case underscores LUAD's potential for atypical metastasis, such as to the retina, necessitating comprehensive assessment and personalised management strategies. The shift from Crizotinib to Lorlatinib highlights the importance of targeted therapy in managing advanced NSCLC with rare metastatic involvement."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ophthalmology • Pain • Pulmonary Disease • Small Cell Lung Cancer • Solid Tumor • PD-L1 • ROS1

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

Postmarketing safety of loratinib: An analysis of the FDA Adverse Event Reporting System (FAERS). (ASCO 2025) - "The overall adverse effects of lorlatinib are manageable, but the risk of hyperlipidaemia, particularly very low-density lipoprotein elevation, is strong, in addition to adverse effects including death, progressive tumours, impaired consciousness and psychiatric disorders. These signals require further regulatory investigation to determine their significance."

Adverse events • Clinical • P4 data • CNS Disorders • Dyslipidemia • Lung Cancer • Mental Retardation • Oncology • Psychiatry • Solid Tumor • ALK

Hyperlipidemia as adverse event of lorlatinib, a multicenter cohort study. (ASCO 2025) - P4 | "Among them, statins were most frequently used in 64 cases (85.3%) when resuvastatin was most frequently used (40/64, 62.5%), followed by ezetimibe (13/75, 17.3%), fenofibrate (12/75, 16%), and PCSK9 inhibitors (3/75, 4%). Hyperlipidemia had high incidence in real world use of lorlatinib, predominantly grade 1-2 hypercholesterolemia and hypertriglyceridemia, while no grade 5 cardiovascular events had been observed. Different lipid-lowering drugs did not significantly affect the lipid-lowering effect. No association was observed between treatment outcomes and blood lipid levels."

Adverse events • Clinical • Dyslipidemia • Hypertriglyceridemia • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Pancreatitis • Solid Tumor • ALK

Impact of a molecular tumor board on treatment decisions for advanced solid tumors: Experience from a Portuguese cancer center. (ASCO 2025) - "Clinical benefit was observed in 10 (6%) patients, with 1 complete response (CR) (porocarcinoma TMB-high under pembrolizumab), 3 partial responses (PR) (myofibroblastic tumor, mROS1, under lorlatinib; neuroblastoma, mALK, under lorlatinib; melanoma, mBRAF V600E not detected by PCR, under encorafenib/binimetibib), and 6 stable diseases (SD). These findings indicate that MTB-guided therapy may enhance clinical outcomes with manageable toxicity in a subset of patients with advanced, refractory malignancies. The study highlights the necessity of further investigation into resistance mechanisms and the incorporation of molecularly guided decisions in earlier treatment lines."

Metastases • Lung Cancer • Melanoma • Neuroblastoma • Oncology • Solid Tumor • BRAF • KRAS • NRAS • PIK3CA • TMB • TP53

The prognostic impact of TP53 mutation on survival outcomes in ALK fusion–positive lung cancer. (ASCO 2025) - "Crizotinib was the most commonly used ALKi (58.1%, n=50), while ceritinib, alectinib, and lorlatinib were used in 9.3% (n=8), 17.4% (n=15), and 15.1% (n=13) patients respectively. TP53 co-mutation has a negative prognostic impact in patients with ALK rearranged lung cancer. Studies evaluating fourth generation ALKi, or the addition of chemotherapy in these patients are warranted."

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

Lorlatinib in TKI-naïve patients with advanced ALK-positive non-small cell lung cancer (NSCLC) from India. (ASCO 2025) - "Consistent with CROWN trial data, the preliminary results from this real-world study with 1L Lorlatinib in ALK positive advanced NSCLC in the Indian population supports its effectiveness as well as tolerability profile."

Clinical • Metastases • Dyslipidemia • Hypertriglyceridemia • Lung Cancer • Metabolic Disorders • 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-life efficacy and safety data of lorlatinib treatment in ROS-1–positive advanced non-small cell lung cancer: Turkish Oncology Group (TOG) study. (ASCO 2025) - "In summary, lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC. Lorlatinib has side effects and these side effects are manageable. There are few treatment options for patients who progress under crizotinib therapy, lorlatinib can be used safely and effectively as a next-line targeted agent."

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

Co-mutations in non small cell lung cancer: Real-world data and clinical insights from a tertiary care centre in western India. (ASCO 2025) - "ALK and ROS1 co-mutation patients received either chemotherapy or Lorlatinib. With the evolving diagnostic and therapeutic paradigm of lung cancer, multiple coexisting mutations present a new therapeutic challenge, highlighting the emergent need for improved strategies to address these clinical issues. Distribution of pathogenic mutations in NSCLC patients (N = 72).* 2 (25%) had triple mutations; ** Escape mutations."

Clinical • IO biomarker • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • EGFR • PD-L1 • ROS1

Evaluating activation of MAPK signaling as a potential mechanism of acquired resistance to lorlatinib in ALK-rearranged lung cancer.. (ASCO 2025) - " WES analysis from an ALK-rearranged NSCLC patient who sequentially received crizotinib, ceritinib, and lorlatinib, but eventually developed resistance, identified a MAP2K2P298L mutation associated with lorlatinib resistance. Activation of the MAPK signaling pathway contributes to acquired resistance to lorlatinib in ALK-rearranged NSCLC. Combining lorlatinib with trametinib represents a promising therapeutic strategy to overcome this resistance and improve clinical outcomes for patients who no longer respond to lorlatinib."

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

Lorlatinib therapy in relapsed/refractory ALK+ lymphomas previously treated with tyrosine kinase inhibitors. (ASCO 2025) - "Funded by No funding sources reported Clinical Trial Registration Number: EudraCT2016-003970-41 Background: ALK+ Lymphomas are aggressive diseases with poor prognosis when chemoimmunotherapy (CIT) and Crizotinib fail...2 pts also received other TKIs (Alectinib and Ceritinib)... Our analysis confirms Lorlatinib's efficacy and safety as salvage therapy. Achieving a CR at M1 was found to be the most important prognostic factor for survival. Adverse events are manageable with dose adjustments."

IO biomarker • Alzheimer's Disease • B Cell Lymphoma • CNS Disorders • Dyslipidemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • ALK • CLTC • EML4

Shifting landscape of resistance to next-generation ALK inhibitors with evolving treatment paradigm in ALK+ lung cancer. (ASCO 2025) - "Funded by No funding sources reported 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..."

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

Depth of response and progression-free survival in patients with advanced ALK-positive non–small-cell lung cancer treated with lorlatinib. (ASCO 2025) - P3 | " The CROWN study is an ongoing, international, open-label, randomized, phase 3 trial comparing lorlatinib vs crizotinib in patients with previously untreated ALK-positive advanced NSCLC. Greater DepOR was associated with PFS benefit in patients with advanced ALK-positive NSCLC treated with lorlatinib. ClinicalTrials.gov: NCT03052608. PFS in patients evaluable for DepOR (n=142).NE, not evaluable."

Clinical • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EML4

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 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

Impact of lorlatinib dose modifications on adverse event outcomes in the phase 3 CROWN study. (ASCO 2025) - P3 | "Funded by Pfizer Clinical Trial Registration Number: NCT03052608 Background: In an updated analysis of the CROWN study (NCT03052608), after 5 years of follow-up, lorlatinib continued to show superior efficacy over crizotinib in patients with previously untreated advanced ALK+ non-small cell lung cancer (NSCLC), with median progression-free survival (PFS) still not reached. This post hoc analysis of the CROWN study showed that dose reductions were effective in managing AEs associated with lorlatinib. These findings show the importance of dose modifications to mitigate toxicity and continue lorlatinib treatment for prolonged periods of time in patients with advanced ALK+ NSCLC."

Adverse events • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Real-world data on the efficacy and safety of iruplinalkib (WX-0593) in ALK-positive advanced lung adenocarcinoma patients previously treated with lorlatinib. (ASCO 2025) - "Iruplinalkib exhibited promising efficacy and acceptable toxicity in patients with ALK-positive advanced LUAD patients who were previously treated with lorlatinib."

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

Caught in the Lung Crossfire: Fatal Case of Lorlatinib-induced Pneumonitis and ARDS in a Patient With ALK-positive NSCLC (ATS 2025) - "Lorlatinib-induced pneumonitis is infrequently reported, but early recognition is crucial as it can progress to life-threatening respiratory failure.Case Description: We present a case of a 63-year-old non-smoker man who was initially diagnosed with stage IIIA NSCLC, underwent left upper lobectomy, followed by adjuvant chemotherapy with four cycles of Alimta and Cisplatin, followed by adjuvant Alectinib. Early drug discontinuation and corticosteroid therapy are critical, but even with aggressive management, outcomes may be poor. This case highlights the need for further research into the pathophysiology and risk factors associated with TKI-induced pneumonitis to improve outcomes and guide future therapy."

Clinical • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • 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

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

Unmasking Malignancy in the Pleura: A Case of Dyspnea and Effusion Unveiling Adenocarcinoma (ATS 2025) - "Patient was subsequently referred to oncology and initiated on cemiplimab and lorlatinib as targeted therapy.This case highlights an atypical diagnostic pathway to stage IV NSCLC and the importance of evaluating pleural effusions thoroughly. In cases like this, repeat imaging after drainage can uncover previously hidden pathology. This approach underscores the value of a comprehensive, multi-modal diagnostic strategy for precise staging and tailored treatment planning in advanced NSCLC."

Clinical • Cardiovascular • Diabetes • Hypertension • Immunology • Lung Adenocarcinoma • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Solid Tumor • Type 2 Diabetes Mellitus