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

Case Report: Lorlatinib for the treatment of ALK-rearranged poorly differentiated thyroid carcinoma after progression to prior ALK-specific tyrosine-kinase inhibitor. (PubMed, Front Oncol) - "We report a 19-year-old male with ALK-rearranged, radioiodine-refractory PDTC who started systemic therapy with ceritinib, achieving a complete metabolic response. Treatment with the third-generation ALK inhibitor led to a deep and durable complete metabolic response, sustained for more than four years, including persistence of remission after treatment discontinuation, with minimal toxicity. This case highlights the potential role of sequential ALK inhibition to overcome acquired resistance in ALK-rearranged TC and underscores the importance of comprehensive molecular profiling to guide personalized treatment strategies in rare aggressive thyroid cancers."

Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma • ALK

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

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

Case Report: TPR-ALK fusion-positive inflammatory myofibroblastic tumour treated with sequential ALK inhibitors. (PubMed, Front Oncol) - "This TPR-ALK fusion-driven IMT demonstrates that disease progression after an initial response to crizotinib can be effectively overcome with lorlatinib, resulting in rapid and durable clinical benefit. These findings add to emerging evidence supporting next-generation ALK inhibitors as effective treatment options for ALK-rearranged IMT after crizotinib failure."

Journal • Oncology • 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

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

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

Characterization of TKI-induced drug-tolerant persister cells from patient-derived cell lines (AACR 2026) - "The two main models used were MR57, harboring EML4-ALK fusion and ALK C1156Y/G1269A mutation and sensitive to the 3rd generation ALK inhibitor lorlatinib, and ST6566, carrying an EGFR L858R mutation and highly sensitive to osimertinib.Results and DTP cells are characterized by marked phenotypic plasticity...These experiments revealed that targeting EMT-associated transcriptional control with the BRD4 inhibitor JQ1, inhibiting FGFR-driven signaling with erdafitinib, or blocking DNA-damage repair via the ATM inhibitor AZD-0156 each significantly delayed DTP regrowth. Overall, our results demonstrate that DTP cells regrowth can be delayed in vitro, suggesting exploitable vulnerabilities. While further validation is required, they provide a rational for testing these strategies in vivo, with an ultimate goal of informing patient therapeutic approach."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRD4 • EGFR • EML4 • STING

OB-001 boost the brain penetration of multiple TKIs (AACR 2026) - "OB-001 selectively boosts brain exposure without substantially increasing systemic exposure. These data demonstrate that theoretically a pharmacokinetic window can be achevied with OB-001 whereby enhanced brain metatsases efficacy could be acheived for numerous kinase inhibitors without effecting systemic toxicity. These findings support OB-001 as a first-in-class CNS-targeted efflux modulating adjunct capable of elevating brain drug exposure beyond what is achievable by existing kinase inhibitors alone."

Oncology • Solid Tumor • ABCB1 • ABCG2

Intragenic fusion architecture dictates resistance: UGT1A1 links CD74-ROS1 breakpoint heterogeneity to TKI response (ELCC 2026) - "The molecular mechanism underlying this variant-specific intrinsic resistance remains completely unknown, representing a major gap in knowledge that impedes personalized therapeutic strategies.Methods To elucidate the mechanism, we established isogenic NSCLC cell models expressing CR-L or CR-S and systematically evaluated their in vitro sensitivity (IC50) to multiple ROS1 TKIs (crizotinib, entrectinib, and lorlatinib). We identify UGT1A1-mediated metabolism as a novel, variant-specific resistance mechanism in CR-L NSCLC-a new paradigm distinct from acquired mutations. Our findings nominate UGT1A1 as a predictive biomarker and establish a directly translatable combinatorial strategy (atazanavir + lorlatinib) to overcome this primary resistance."

Heterogeneity • Lung Cancer • Non Small Cell Lung Cancer • CD74 • ROS1 • UGT1A1

Real-world safety of ALK inhibitors in non-small cell lung cancer patients: A FAERS disproportionality analysis (ELCC 2026) - "In the cardiac cluster, crizotinib showed marked bradycardia (ROR 12.52, CI 9.57–16.37), with lower but similar signals for alectinib. Gastrointestinal signals were most frequent with ceritinib, while pulmonary disproportionality was observed primarily with lorlatinib, brigatinib, and crizotinib.Conclusions Relative to other NSCLC therapies, ALKis are associated with higher reporting signals across the eye, nervous system, cardiac, musculoskeletal, gastrointestinal, and pulmonary adverse event clusters, with agent-specific disproportionalities being noted. The findings are consistent with ALKi's known safety profiles, emphasizing the importance of corroborating clinical trials with real-world data and the value of pharmacovigilance findings in treatment selection."

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

Skeletal muscle, subcutaneous and intramuscular fat as prognostic biomarkers in TKI-treated fusion-positive NSCLC (ELCC 2026) - "BC parameters were correlated to progression-free survival (PFS) using a Cox model.Results Among 17 pts, 10 ALK positive pts were treated with alectinib and 4 with lorlatinib, while 2 ROS1-positive and 1 NTRK1-positive with entrectinib. Notably, SAT was also related to worse PFS at all time points: T0 (HR 1.02; p=0.046), T1 (HR 1.02; p=0.040), T2 (HR 1.02; p=0.023), and T3 (HR 1.02; p=0.043). No statistically significant changes in BC parameters were observed across time-points (T0-T3), possibly due to the nutritional intervention and limited sample size.Conclusions Despite the preliminary nature of these findings, SMA, SAT and IMAT emerged as potential prognostic biomarkers in fusion-positive NSCLC pts treated with TKIs, highlighting the clinical relevance of body composition assessment and suggesting a pivotal role of targeted interventions, including nutritional support and physical exercise."

Biomarker • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • ALK • NTRK1 • ROS1

Treatment sequencing after alectinib failure in ALK-positive NSCLC: A Canadian multicentre real-world analysis (ELCC 2026) - "We evaluated treatment sequencing, durability and clinical outcomes of lorlatinib (L) or brigatinib (B) treatments immediately after A progression.Methods In a Canada-wide multicentre retrospective cohort study of advanced ALK-positive NSCLC treated with either L or B following A progression, endpoints included overall survival (OS), progression-free survival (PFS), time to treatment discontinuation (TTD), and subsequent treatment lines. This clinically relevant data informs real-world sequencing decisions beyond PFS alone. Durability of benefit, not only response duration, should guide post-A treatment decisions in ALK-positive NSCLC."

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

Real-world tolerability and long-term toxicity of lorlatinib in ALK+/ROS1+ advanced NSCLC (ELCC 2026) - "Only 15% of AEs resolved before discontinuation.Conclusions In this real-world cohort, focusing on long-term toxicity, lorlatinib showed a manageable safety profile with low discontinuation rate. Although AEs were frequent, persistent, and often co-existing, they were predominantly low grade and did not compromise efficacy, supporting proactive toxicity monitoring and individualized dose adjustments to optimize tolerability."

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

Lorlatinib-related toxicity and its association with systemic drug exposure in non-small cell lung cancer (ELCC 2026) - P=N/A | "TDM would suggest an early dose reduction in 40% of patients with lorlatinib Ctrough above the 181 ng/mL threshold.Conclusions Lorlatinib exposure correlates strongly with severe toxicity, supporting the clinical potential of TDM. A Ctrough threshold of 181 ng/mL may identify patients at risk of toxicity and guide dose adjustment to improve tolerability."

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

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) - "The risk of CNS progression was lower with 1L lorlatinib (HR=0.32; 95% CI 0.15–0.67; P=0.003).Conclusions In this NGS-confirmed real-world cohort, 1L lorlatinib was associated with longer PFS and a lower risk of CNS progression compared with lorlatinib after a 2G ALK TKI, while OS was similar between strategies within current follow-up. These findings support preferential use of upfront lorlatinib in advanced ALK-positive NSCLC in everyday practice."

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

Rare and non-canonical ALK fusion in advanced NSCLC: Heterogeneous clinical outcomes with ALK inhibitors (ELCC 2026) - "A 22-year-old patient with HIP1–ALK and concomitant TP53 mutation experienced rapid disease progression, with limited benefit from sequential ALK TKIs (PFS 8 months with alectinib and 4 months with lorlatinib) and fatal outcome. In contrast, the patient harboring NCOA1–ALK is experiencing durable disease control with first-line alectinib since February 2023.Conclusions In a real-world setting, NGS identifies a non-negligible proportion of rare and non-canonical ALK fusions associated with markedly heterogeneous clinical outcomes. These findings suggest that rare ALK rearrangements may represent biologically distinct entities with variable sensitivity to ALK TKIs and support comprehensive molecular profiling and cautious interpretation beyond the canonical EML4–ALK paradigm."

Clinical • Clinical data • Heterogeneity • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • ALK • CAPN1 • EML4 • HIP1 • NCOA1 • TP53

TRI-611, a development stage molecular glue degrader of ALK, promotes the degradation of TKI-resistant ALK fusion proteins and leads to regression of ALK TKI-refractory tumors (AACR 2026) - "Finally, we show that TRI-611 leads to the regression of an EML4-ALK mutant primary patient-derived xenograft isolated from a patient that had progressed on prior alectinib and lorlatinib. These data demonstrate the potential of TRI-611 to address a key liability of ALK TKIs that all target the same site on ALK and support the development of TRI-611 in all ALK+ NSCLC patients, including patients with wild-type ALK kinase domain and those with acquired TKI resistance mutations."

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

Clinical Manifestations of Primary CNS T-Cell Lymphoma: A Retrospective Study of Histopathologic, Molecular, and Neuroimaging Features. (PubMed, Neurology) - "Although PCNSTL is exceptionally rare, we identified distinct neuroimaging patterns showing highly aggressive features on MRI but hypometabolic PET imaging, which may assist in identifying future PCNSTL cases. Despite the limited cohort size, our findings suggest that MTX-based chemotherapy with ASCT may translate into favorable outcome. We report on an ALK1-positive PCNSTL case with sustained complete remission after targeted therapy with lorlatinib."

Journal • Retrospective data • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Transplantation • ALK1

A patient with advanced ALK-positive NSCLC at diagnosis with a follow up of >7 years and multiple lines of systemic therapy and local ablative therapy (DKK 2026) - "He was initially treated with bevacizumab, carboplatin and pemetrexed outside our institution. Due to multiple side effects the therapy was switched to pembrolizumab after the 1st cycle...The patient started alectinib in 11/2018 with rapid clinical improvement and a partial response after 6 weeks...Side effects were hypercholesterinemia (>600 gm/dl) and hypertriglyceridemia (>400 mg/dl) requiring therapy with rosuvastatin and ezetrol...NGS again showed no new on/off-target resistance pattern and he continued lorlatinib...The patient was included in the Early Access Program of NVL-655 currently available at 6 European sites. He started therapy in 06/2025 in Paris and responded in PET-CT after six weeks. He had no side effects CTC >1° and is continuing the therapy."

Clinical • IO biomarker • Metastases • Dyslipidemia • Hypertriglyceridemia • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • ALK • EML4 • NKX2-1 • PD-L1 • TP53

Missense mutant p53 regulates DNA replication and damage response to promote resistance to targeted therapies in ALK fusion lung adenocarcinoma (AACR 2026) - "Carfilzomib synergized with lorlatinib in resistant ALK+ p53 mutant cells and induced robust tumor response in TP53 mutant ALK+ PDX models resistant to lorlatinib, demonstrating therapeutic potential. In summary, missense mutp53 promotes ALK TKI resistance by enhancing DNA replication and repair."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRCA1 • CDKN2A • CHEK1 • EGFR • MSH6 • MYC • TGFB1 • TP53

Differential sensitivity of paired FUS-TFCP2+ RMS PDX models developed from tumor specimens obtained prior to and after ALK inhibitor therapy (AACR 2026) - "ALKi-sensitive PDX174 was derived from a patient tumor sample obtained prior to an 11-month ALKi (lorlatinib) regimen...Global kinome analysis using multiplexed inhibitor beads also showed an increase in CDK4/6 activation in ALKi-resistant PDX199 versus ALKi-sensitive PDX174. Pre-clinical models such as these provide a platform to connect molecular signatures with targeted therapy, increase our mechanistic understanding of tumor adaptive responses and design therapies that will mitigate the emergence of therapeutic resistance."

Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • ALK • CDK1 • CDK4 • FUS • TFCP2

Unbiased discovery of novel macrophage-activating immunotherapies for ALK+ non-small cell lung cancer (AACR 2026) - "Importantly, combining the CD47×TROP2 bsAb with lorlatinib produced synergistic anti-tumor effects, offering a promising strategy to overcome or delay resistance. Overall, our study has identified novel bispecific antibodies that may be highly active for ALK+ lung cancer and our findings could be translated to the clinic to benefit patients in the future."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • EML4 • FOLR1 • HER-2 • NECTIN1 • NECTIN4 • PD-L1 • SIRPA • TFRC

Targeting BCL2 pathway to enhance immunogenicity in ALK+ NSCLC (AACR 2026) - "However, this has not been studied in the context of ALK+ NSCLC.We hypothesized that ALK-directed therapy in combination with BH3 mimetics would initiate ICD through the release of DAMPs and increase sensitivity to ALK TKIs. We evaluated the efficacy of ALK TKIs (Lorlatinib, Alectinib) alone and in combination with the BH3 mimetics navitoclax (BCL-2/BCL-xL inhibitor), venetoclax (BCL-2 inhibitor) and s63845 (MCL-1 inhibitor) to induce damage-associated molecular patterns (DAMPs) in ALK+ NSCLC cell lines. ALK+ cancer cell lines exhibited high expression of MCL-1 and BCL-xL proteins, indicating their dependency on BCL-2 family proteins for survival. ALK-directed therapy has the potential to induce immunogenic cell death (ICD) and elicit antitumor immune responses. Combining BH3 mimetics with ALK TKIs can be a promising therapeutic strategy to enhance anti-tumor immunity and overcome ALK TKI resistance in ALK+ NSCLC"

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BCL2L1 • CXCL10 • IFNB1

Quantifying evolutionary dynamics and tumor heterogeneity in oncogene-addicted advanced non-small cell lung cancer (AACR 2026) - "In pt992, 3 ALK double-mutant subclones shared an original mutation F1193Y, and independently acquired secondary hits G1269A, E1210K, and G1210R, driving differential resistance to Crizotinib and Lorlatinib. RNA-seq immune deconvolution via CIBERSORT showed variable immune cell infiltration patterns without correlation to clinical outcome. These results demonstrate that TKIs drive clonal diversification and evolution of resistance in oncogene-addicted NSCLC, and offer a quantitative framework for lineage-informed therapeutic strategies."

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