After two episodes of massive intracranial hemorrhage and a period of respiratory failure, a critical condition notice lay quietly at the nurses’ station of St. Jude Children’s Research Hospital. On the brain scan of a three-year-old boy, a tumor occupying nearly the entire left hemisphere filled the screen.
In 2021, genomic analysis of the tumor revealed a rare target — a SPECC1L-ALK fusion.
This finding led to a highly uncertain therapeutic attempt: treatment with lorlatinib, a targeted agent at that time approved only for lung cancer.
Emergency Intervention:
Lorlatinib in a Child With ALK-Fusion–Positive High-Grade Glioma
The three-year-old boy was brought to the emergency department because of persistent vomiting, somnolence, and ocular deviation. Brain magnetic resonance imaging revealed a devastating reality: a massive tumor occupying nearly the entire left cerebral hemisphere.
Neurosurgeons attempted resection, but two procedures were aborted due to life-threatening intracranial bleeding. Chemotherapy was also discontinued after further hemorrhage. Conventional medical options appeared exhausted.
Given the extremely poor prognosis, the medical team and the family jointly decided to limit further resuscitative measures and gradually transition toward comfort-focused supportive care.
Genomic testing became the turning point.
RNA sequencing of the tumor identified a rare actionable alteration — the SPECC1L-ALK fusion.
This opened a therapeutic window, and the team decided to attempt treatment with lorlatinib, a third-generation ALK inhibitor specifically engineered for central nervous system penetration and originally approved for lung cancer.
With informed parental consent, therapy was initiated via nasogastric administration at a dose of 95 mg/m² once daily, derived from prior pediatric studies in ALK-driven refractory tumors.
The clinical response was clear and encouraging: neurological function gradually improved and the tumor markedly regressed. Although significant weight gain and hyperlipidemia occurred, imaging eight months later showed transformation of the solid mass into a cystic structure, allowing gross surgical resection.
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| Response to Lorlatinib |
Postoperative imaging demonstrated no radiographic evidence of tumor, and treatment was temporarily discontinued.
However, six months later, the boy developed facial paralysis, with new metastatic lesions involving the seventh cranial nerve, the third ventricle, and the spine.
Lorlatinib was reinitiated once daily, after which the patient again demonstrated a rapid clinical and radiographic response. Facial paralysis showed noticeable improvement within one week, and follow-up MRI at one month indicated near-complete resolution of the lesions.
The uniqueness of this case lies in its suggestion of potential activity of lorlatinib in a rare pediatric brain tumor.
As an ALK inhibitor designed for CNS penetration, it may hold clinical relevance for primary central nervous system tumors harboring ALK alterations, although prospective clinical trial evidence remains lacking.
Resistance and Resensitization:
The L1198F Mutation Restores Sensitivity to Crizotinib
Lorlatinib has broad coverage of acquired resistance mutations and is primarily approved for the treatment of ALK-positive metastatic non-small cell lung cancer.
The protracted battle of targeted therapy is often accompanied by the emergence of drug resistance, and the resistance mechanisms themselves can sometimes lead to unexpected treatment strategies.
Researchers followed a 52-year-old female patient, "Emma," from San Francisco, USA. She initially responded to the first-line ALK inhibitor crizotinib, but subsequently developed an ALK C1156Y resistance mutation.
Eight months after switching to Lorlatinib, her disease progressed again.
At this point, next-generation genetic testing revealed the "evolution" of the tumor: in addition to the original mutation, a new L1198F mutation had appeared.
Interestingly, further biochemical analysis revealed that while the L1198F mutation blocked the binding of Lorlatinib to its target, it unexpectedly restored the tumor's sensitivity to the first-generation drug crizotinib.
This phenomenon is explained by structural biology: the steric hindrance caused by the L1198F mutation makes the "pocket" shape of the target protein more suitable for crizotinib to rebind.
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| Structural Basis for Resistance to Lorlatinib and Sensitivity to Crizotinib Mediated by ALK C1156Y–L1198F |
Emma's treatment regimen was thus "regressed" back to crizotinib, and she regained considerable progression-free survival.
This case reveals a deeper medical logic: in the era of precision oncology, drug resistance is not the absolute end of treatment, but may be the starting point for the next round of precision-based treatment.
Dynamic and continuous genetic monitoring is crucial.
Regional Disparities and Policy Dynamics
While doctors and patients battle disease on the front lines, healthcare policies and payment systems are engaged in another game of value versus accessibility.
The fate of Lorlatinib in different countries is a microcosm of this game.
In South Korea, despite five-year follow-up data from the CROWN study demonstrating the superiority of Lorlatinib as first-line treatment, the access process has long been hampered by cost-effectiveness and budget assessments.
The core disagreement lies in the inability of pharmaceutical companies and health insurance institutions to agree on the exorbitant "annual expected total claims."
This means that for South Korean patients with advanced lung cancer, although Lorlatinib may be the best option, it is unavailable through public health insurance unless they have substantial commercial insurance or the ability to pay out of pocket.
This contrasts sharply with the cautious acceptance in the UK.
The UK's National Institute for Health and Care Excellence (NICE) initially rejected Lorlatinib due to cost-effectiveness concerns.
However, with the accumulation of more real-world evidence and the possibility of a price agreement, NICE ultimately changed its decision, conditionally recommending it for first-line treatment.
Even in regions with well-developed healthcare systems, the exorbitant out-of-pocket costs remain an unbearable burden for patients' families. The situation in Hong Kong vividly illustrates this.
A Hong Kong lung cancer patient bluntly stated, "How can an average worker afford HK$40,000 to HK$50,000 per month for medication?"
Lorlatinib is typically listed as a self-funded drug within the Hong Kong Hospital Authority system.
Patients must bear tens of thousands of Hong Kong dollars in medication costs each month, a huge financial black hole for ordinary income families.
This economic burden directly impacts treatment adherence and choices.
Some patients may be forced to choose older, less effective treatments that are eligible for subsidies, or discontinue treatment after exhausting their savings.
This "economic hardship" itself has become a significant negative factor affecting prognosis and quality of life.
Pathways to Access: Bridging the Treatment Gap
When a therapy such as lorlatinib is reimbursed in some regions but not others, significant disparities in medical need and market access arise.
Across the Asia–Pacific region, cancer therapeutics represent one of the fastest-growing pharmaceutical sectors.
Yet regulatory requirements, import licensing, and reimbursement frameworks vary widely, and hospitals or pharmacies often cannot directly procure medicines from multinational manufacturers.
Within this context, DengYueMed, as a global pharmaceutical distributor, contributes beyond logistics alone by supporting integrated compliance and market-access solutions, including:
● Regulatory Affairs: Handling registration, filing, and compliance documents with drug regulatory agencies in different countries.
● Cold Chain Logistics: Ensuring the stability of biologics or small molecule drugs requiring specific temperature control throughout transportation.
● Inventory Management and Financing: Bearing inventory costs and alleviating financial pressure on downstream medical institutions.
● Channel Management and Market Coverage: Reaching hospitals, clinics, and pharmacies that are difficult for pharmaceutical companies' direct sales networks to fully cover.
With broader adoption of biomarker testing, patient populations suitable for lorlatinib may be identified with increasing precision.
Industry analyses generally anticipate continued demand growth alongside advances in molecular diagnostics.
Conclusion
Individual clinical cases provide meaningful reference points for the global clinical understanding of lorlatinib, while discussions surrounding policy, reimbursement, and supply infrastructure continue to evolve.
From molecular discovery to real-world patient access, the journey of a targeted therapy spans science, regulation, economics, and distribution.
Only when these systems function in coordination can the progress of precision medicine be translated into tangible survival benefits for patients worldwide.
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