Rare ALK Fusion Lung Cancer Shows Durable Response to First-Line Lorlatinib

A 45-year-old man who had never smoked walked into a Japanese hospital in July 2024 complaining of weeks of progressive dizziness and repeated falls. Neurological examination revealed right-sided dysmetria, a loss of coordination detected during finger-to-nose and heel-to-shin testing, but his consciousness was intact and his performance status remained good. What imaging would soon uncover was far more ominous than a balance disorder: a cystic mass in his right cerebellum, four additional brain lesions, and a large tumor buried in the lower lobe of his left lung. That patient would become only the sixteenth person with his rare molecular subtype of lung cancer ever reported to receive an ALK-targeted drug, and one of just two known to receive the newest generation of that drug as initial therapy.

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