The tertiary-care study initially covered 6,078 cancer cases, including 670 lung cancers and 560 cases of non-small cell lung cancer. All 560 non-small cell lung cancer cases underwent immunohistochemistry-based screening for ALK and ROS1. Among the 51 selected positive cases, the median age was 53 years, with a range of 26–82 years, and 53% were male. Eighty percent were non-smokers, 71% had stage IV disease, and adenocarcinoma was the predominant histological subtype, accounting for 65% of cases. Exploratory comparisons between the ALK and ROS1 subgroups showed no statistically significant differences in the evaluated clinicopathological characteristics.

All 51 patients had documented initiation of first-line crizotinib. The median time from diagnosis to tyrosine kinase inhibitor initiation was 0.82 months, with an interquartile range of 1.25 months, and the median observed duration of first-line treatment was 17.9 months, with an interquartile range of 22.6 months. Twelve patients, representing 23.5% of the cohort, subsequently received lorlatinib. Based on available clinical follow-up, the estimated median time to first-line treatment discontinuation was 36.4 months, with a 95% confidence interval of 27.0 months to not reached. Median progression-free survival was 41.7 months, with the same confidence interval, while median overall survival was not reached.

These treatment timelines and survival estimates are descriptive findings for the observed cohort, rather than evidence of comparative treatment efficacy. Interpretation is constrained by the retrospective design, single-centre scope, selected population of 51 immunohistochemistry-positive patients with complete data, and outcomes calculated from available follow-up. The exploratory ALK–ROS1 comparison was also limited by small subgroup sizes, particularly the nine ROS1-positive cases. The mixed cohort included two inflammatory myofibroblastic tumors, so the results were not drawn exclusively from patients with non-small cell lung cancer. The abstract states that the findings support improved access to confirmatory molecular testing and broader genomic profiling in Nepal’s resource-limited setting.

Subject of Research: Clinicopathological and treatment profile of ALK- and ROS1-positive tumors in a Nepalese retrospective cohort

Article Title: Clinicopathological profile of ALK and ROS1-positive lung tumors: a single-centre retrospective study from Nepal

Article References: Shahi, A., Poudel, B., Adhikari, S., Lama, M., & Mukherjee, A. K. (2026). Clinicopathological profile of ALK and ROS1-positive lung tumors: a single-centre retrospective study from Nepal. BMC Cancer. https://doi.org/10.1186/s12885-026-17002-1

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17002-1

Keywords: ALK-positive tumors, ROS1-positive tumors, non-small cell lung cancer, Nepal, immunohistochemistry, crizotinib, lorlatinib, progression-free survival, retrospective cohort, Clinicopathological, profile, ROS1-positive

Contrast-enhanced magnetic resonance imaging of the brain showed a 28 by 24 millimeter cystic lesion in the right cerebellum along with four supratentorial metastases, each no larger than 30 millimeters. A chest computed tomography scan revealed a 51 by 22 millimeter mass in the left lower lobe, highly suggestive of a primary lung malignancy. Because the cerebellar lesion sat in the posterior fossa and caused severe dizziness, clinicians placed an Ommaya reservoir to help manage intracranial pressure, then treated all five intracranial metastases with stereotactic radiosurgery delivered as 35 Gy in five fractions. The interventions produced marked symptomatic improvement. Bronchoscopic biopsy of the lung lesion confirmed adenocarinoma of the lung, and positron emission tomography-computed tomography revealed metastatic spread to the left hilar and subcarinal lymph nodes, the left second rib, and the left iliac bone, staging the disease as IVB, the most advanced category.

The decisive step came from molecular testing. Using the Oncomine Dx Target Test Multi-CDx System, an amplicon-based next-generation sequencing panel that screens tumor DNA for hotspot variants across 46 genes and tumor RNA for fusion transcripts involving 21 genes, the team identified an unusual rearrangement: a fusion joining exon 3 of the STRN gene to exon 20 of ALK, the anaplastic lymphoma kinase gene. ALK rearrangements are established oncogenic drivers in non-small-cell lung cancer, occurring in roughly 4 to 8 percent of cases, but the overwhelming majority involve EML4 as the fusion partner. STRN, which encodes striatin, a non-catalytic scaffold protein, is among the rare alternative partners uncovered as next-generation sequencing has entered routine practice. The resulting STRN-ALK fusion protein is believed to drive tumorigenesis by activating oncogenic signaling pathways, yet how it responds to targeted drugs has remained deeply uncertain.

Based on the fusion finding, clinicians initiated lorlatinib at 100 mg once daily as first-line systemic therapy. Lorlatinib is a third-generation ALK tyrosine kinase inhibitor engineered specifically to overcome resistance mutations in the kinase domain and to penetrate the blood-brain barrier, the fortress of lipids and tight junctions that excludes most drugs from the central nervous system. Its credentials come from the phase III CROWN trial, where it outperformed crizotinib in treatment-naive ALK-positive lung cancer, and from the recent seven-year update showing that median progression-free survival remained unreached with lorlatinib compared with 9.1 months for crizotinib. Strikingly, no new intracranial progression events occurred after the first 30 months of lorlatinib treatment in that study.

The patient’s course was not entirely smooth. Approximately one month into therapy he developed sudden neuropsychiatric adverse events, including mood changes and speech disturbances, graded as Grade 2 on the Common Terminology Criteria for Adverse Events version 5.0 scale. Lorlatinib was interrupted for about 21 days and resumed at a reduced dose of 75 mg. Four weeks later, recurrent neuropsychiatric symptoms forced a further reduction to 50 mg. A Grade 1 elevation in low-density lipoprotein cholesterol also appeared and was managed with a statin. These neuropsychiatric and metabolic effects are recognized class effects of lorlatinib, and the stepwise dose reductions illustrate a practical reality of targeted therapy: potency must be balanced against tolerability, particularly when treatment is intended to continue for years.

What happened next is the reason this case matters. Despite the reduced dose, a contrast-enhanced brain MRI at two months showed significant regression of the metastases, with the largest cerebellar lesion shrinking to 9 by 8 millimeters and all other intracranial lesions stable. At three months, chest CT demonstrated a partial response of the primary lung tumor, now measuring 23 by 12 millimeters. A follow-up MRI at 14 months confirmed sustained intracranial control without progression, and a chest CT at 17 months showed continued shrinkage of the primary lesion. The bone metastases, tracked by serial non-contrast CT, showed no radiographic progression. Dose adjustment had improved tolerability without sacrificing antitumor activity, and disease control persisted well beyond a year.

To understand why this single case carries weight, it helps to survey the other fifteen published cases of STRN-ALK-positive lung cancer treated with ALK inhibitors. The outcomes have been strikingly heterogeneous. Crizotinib-containing regimens, used in five patients, produced objective responses including one complete response and four partial responses, though durability varied. Second-generation inhibitors, most commonly alectinib, showed inconsistent efficacy, with progression-free survival ranging from mere weeks to more than a year. In one previously reported patient, alectinib failed after roughly six months and subsequent lorlatinib given second-line yielded limited benefit, prompting speculation that structural features of the STRN-ALK fusion protein might reduce sensitivity to certain inhibitors and confer intrinsic resistance. Against that backdrop, the new case, in which lorlatinib was used first and produced durable systemic and intracranial control, challenges the notion that this fusion is uniformly resistant to modern ALK inhibitors.

The heterogeneity likely reflects more than the fusion partner alone. Short-lived responses in the published cases were frequently associated with co-mutations implicated in ALK-independent resistance, including ABCB1 overexpression, which mediates drug efflux, STK11/LKB1 mutations, and PIK3CA mutations. Similar mechanisms have been described across ALK-rearranged lung cancer more broadly. Notably, in both the present case and the only other reported first-line lorlatinib case, no known resistance-associated co-mutations were identified, which may partly explain the favorable responses. There is also an intriguing biological thread: non-EML4 fusion partners appear enriched among secondary ALK rearrangements that emerge during EGFR-targeted therapy in EGFR-mutant lung cancer, accounting for roughly one-third of such acquired fusions, a far higher proportion than in de novo ALK-positive disease where EML4-ALK predominates. This suggests STRN-ALK and related fusions can arise through distinct biological routes that may shape drug sensitivity.

Central nervous system involvement looms over all of this. Up to 40 percent of patients with ALK-positive lung cancer ultimately develop brain metastases, and several of the reported STRN-ALK cases involved intracranial disease either at diagnosis or later in the course. Because the blood-brain barrier excludes many therapies, selecting an ALK inhibitor with strong CNS penetration is a critical strategic decision in this subset. Lorlatinib’s macrocyclic chemistry was designed precisely for that purpose, and the seven-year CROWN data showing no new intracranial progression events after 30 months represent some of the most durable intracranial control ever documented in oncology. However, a caveat deserves emphasis: CROWN enrolled patients based on ALK positivity detected by a Ventana immunohistochemistry assay that does not identify the specific fusion partner, so outcomes for STRN-ALK patients specifically were never separately reported, leaving the trial’s applicability to this rare subgroup formally unproven.

The authors of the report acknowledge the limitations inherent in their evidence. Molecular profiling used a limited gene panel, so additional genomic alterations could have escaped detection. Stereotactic radiosurgery was delivered before lorlatinib began, meaning the excellent intracranial control cannot be attributed to the drug alone. And as a single case report, generalizability is inherently constrained. Even so, the case extends a thin but growing evidence base suggesting that lorlatinib can deliver sustained systemic and intracranial disease control with manageable toxicity in selected patients with STRN-ALK-positive lung adenocarcinoma, particularly when deployed early. For a molecular subset so rare that each published patient constitutes a meaningful data point, that is a finding worth watching as sequencing-driven oncology continues to fragment lung cancer into ever smaller, and increasingly treatable, molecular niches.

Subject of Research: First-line lorlatinib treatment of rare STRN-ALK fusion-positive lung adenocarcinoma with brain metastases

Article Title: First‐Line Lorlatinib in Striatin–Anaplastic Lymphoma Kinase‐Positive Lung Adenocarcinoma: A Case Report and Literature Review

Article References: Maebeya, M., Tamura, S., Shono, T., Hoso, T., & Tatsuta, H. (2026). First‐Line Lorlatinib in Striatin–Anaplastic Lymphoma Kinase‐Positive Lung Adenocarcinoma: A Case Report and Literature Review. Respirology Case Reports, 14(9), Article e70750. https://doi.org/10.1002/rcr2.70750

Image Credits: AI Generated

DOI: 10.1002/rcr2.70750

Keywords: lorlatinib, STRN-ALK fusion, lung adenocarcinoma, ALK tyrosine kinase inhibitor, non-small-cell lung cancer, brain metastases, next-generation sequencing, CROWN trial, stereotactic radiosurgery, targeted therapy, rare fusion partner, drug resistance

ALK-positive NSCLC arises when a chromosomal rearrangement fuses the ALK kinase gene to a partner gene, most commonly EML4, producing a constitutively active signaling protein that drives uncontrolled proliferation. Since the first ALK inhibitor, crizotinib, entered the clinic, a succession of increasingly potent tyrosine kinase inhibitors (TKIs) has transformed outcomes for these patients. The latest generation agent, lorlatinib, demonstrated durable benefit in the phase III CROWN study. Yet resistance remains an inevitability for many patients. ALK’s kinase domain is a mutable target, and sequential treatment with TKIs selects for compound mutations that no drug approved to date can fully suppress. Patients who progress on available TKIs have limited options, a gap the authors identify as the central motivation for an orthogonal therapeutic approach.

Targeted protein degradation offers such an approach. Rather than blocking an enzyme’s active site, degraders eliminate the target protein altogether, harnessing the ubiquitin-proteasome system that cells use for routine protein turnover. Two broad strategies exist. Proteolysis-targeting chimeras, or PROTACs, are large bifunctional molecules that physically tether a target protein to an E3 ubiquitin ligase. Molecular glue degraders, by contrast, are typically smaller, more drug-like compounds that bind the E3 ligase substrate receptor and remodel its surface to recognize a neosubstrate. Their smaller size confers potential advantages in oral bioavailability and tissue penetration, but discovering glues for a chosen target has historically been a matter of luck rather than design, because the interaction is not obvious from sequence alone.

The Triana team found TRI-611 through a deliberate engineering effort. Using a time-resolved fluorescence resonance energy transfer screen that reports when ALK and cereblon (CRBN), the substrate adaptor of the CRL4 ubiquitin ligase complex, are brought into proximity, the researchers identified an initial hit compound and then optimized it for potency, selectivity and drug-like properties. Structural and biophysical work, including cryo-electron microscopy of the ternary complex, revealed that TRI-611 operates through a distinctive mechanism. The glue promotes contact between the ALK kinase domain and CRBN through a degron interface positioned distal to the kinase active site. This arrangement matters for two reasons: the drug does not need to compete with ATP at a mutation-prone catalytic pocket, and its binding surface tolerates mutations that disable orthosteric inhibitors.

That structural feature translates directly into resistance coverage. In engineered cell lines and patient-derived models, TRI-611 degraded not only wild-type EML4-ALK but also versions carrying clinically important TKI-resistance mutations, including the gatekeeper mutation L1196M and the solvent-front mutation G1202R, individually and in combination. Biochemical assays demonstrated that the drug supported ubiquitin transfer onto the mutant kinase domain by the CRBN-containing ligase complex, and degradation potency correlated tightly with anti-proliferative activity across a panel of resistant lines. Proteomic profiling after TRI-611 treatment showed a remarkably clean footprint: among thousands of quantified proteins, ALK fusion proteins were selectively depleted, with minimal effects on known CRBN neosubstrates or other kinases. In an era when glue degraders are often criticized for promiscuous neosubstrate recruitment, that selectivity is a notable technical achievement.

The pharmacology was engineered with the brain in mind. ALK-positive NSCLC has a notorious tendency to metastasize to the central nervous system, and the blood-brain barrier excludes many otherwise effective drugs, making brain metastases a frequent site of progression. Guided by central nervous system multiparameter optimization principles, the team tuned the compound’s permeability and efflux properties. In mice, TRI-611 achieved brain-to-plasma exposure ratios comparable to lorlatinib, a benchmark for brain penetration, and unbound brain concentrations exceeded the levels needed for target degradation. Once-daily oral dosing produced regressions of subcutaneous xenografts derived from both cell lines and patients, including the DFCI-669 model and the MGH953-7 patient-derived model, the latter harboring TKI-resistance mutations. Critically, intracranial xenograft models, including one driven by the doubly resistant L1196M/G1202R mutant, also responded, with luminescence-based tumor measurements showing marked shrinkage in treated animals.

Perhaps the most clinically provocative finding concerns combination therapy. Because TRI-611 binds the kinase domain at a surface remote from the ATP pocket, it does not interfere with orthosteric TKIs, and the two modalities can be used together. In vitro, the combination of TRI-611 with alectinib or lorlatinib produced greater-than-additive killing of ALK-dependent cells, quantified by Bliss synergy analysis. In vivo, pairing the degrader with lorlatinib yielded synergistic and durable tumor regressions in subcutaneous and intracranial models, outperforming either agent alone. The logic is compelling: the TKI suppresses signaling immediately while the glue removes the protein irreversibly, and degrading the target may suppress the evolutionary escape routes that kinase inhibition alone leaves open. The combination also addresses a second resistance mechanism, MET amplification, which can bypass ALK entirely; pairing TRI-611 with a MET inhibitor such as capmatinib restored growth control in MET-overexpressing models.

The study is thorough on the mechanistic details that regulators and clinicians will want. Degradation required the proteasome, as shown by rescue experiments with bortezomib, and was enhanced by CRBN overexpression, confirming the ligase dependence of the effect. Treated tumors showed loss of phosphorylated STAT3, a downstream readout of ALK signaling, within hours of dosing, linking pharmacokinetics to pharmacodynamics. Structural biology pinned the molecular determinants: mutation of a key ALK residue in the degron interface, D1389W, abolished both degradation and the compound’s anti-proliferative effect, demonstrating that the observed binding mode is causally responsible for the biology. Cryo-EM maps and a deposited crystal structure provide a template that other groups can mine for the emerging rules of glue-induced neosubstrate recognition.

Caveats remain, as they always do at the preclinical-to-clinical boundary. The efficacy data come from xenograft and cell-line models rather than patients, and the long-term consequences of chronically eliminating ALK, which has physiological roles outside cancer, will need careful toxicological evaluation. The authors note that their work was conducted by employees of Triana Biomedicines, with a patent covering TRI-611 filed by the company, and the compound’s clinical profile will ultimately be decided in human trials. Still, the bar this molecule clears is high: potent, selective, orally bioavailable, brain-penetrant degradation of a validated oncogenic driver, active against the resistance mutations that defeat today’s best drugs, and compatible with rational combinations. If the clinical experience mirrors the preclinical one, TRI-611 could mark the moment molecular glue degraders graduated from the lab bench to a front-line role against gene-fusion-driven cancers, and the strategy of degrading rather than inhibiting oncogenic kinases may rapidly expand beyond ALK.

Subject of Research: A selective, brain-penetrant molecular glue degrader of ALK fusion proteins for ALK-positive non-small-cell lung cancer

Article Title: TRI-611, a selective, brain-penetrant molecular glue degrader of ALK

Article References: Conery, A. R., La, D. S., Alekseyenko, A. A., Marcoux, D., Bart, A. G., Harlow, M. L., Arsenault, P. R., Cantone, N. R., Casaubon, R. L., Constan, A., Kamadurai, H. B., Medikonda, A. P., Nunes, D. E., Szeto, H., Wigle, T. J., Yu, M., Zagulyaeva, A., Zarate, C. M., Highfield, L., … Palombella, V. J. (2026). TRI-611, a selective, brain-penetrant molecular glue degrader of ALK. Nature. https://doi.org/10.1038/s41586-026-10998-3

Image Credits: AI Generated

DOI: 10.1038/s41586-026-10998-3

Keywords: ALK, TRI-611, molecular glue degrader, non-small-cell lung cancer, targeted protein degradation, cereblon, EML4-ALK, TKI resistance, brain penetration, lorlatinib, oncogenic fusion, drug discovery