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Lorlatinib for ALK-fused, infant-type hemispheric glioma with lung metastasis: a case report.

ABSTRACT: Infant-type hemispheric glioma, a new subtype of pediatric high-grade glioma, arises in the cerebral hemispheres. Despite better survival outcomes, the treatment of infant-type hemispheric glioma is still facing challenges. Here, we reported a case of QKI-ALK fusion, infant-type hemispheric glioma with lung metastasis who achieved a complete clinical response after lorlatinib treatment. This typical case demonstrated the importance of appropriate molecularly targeted treatments in ALK-fused tumors, and lorlatinib may serve as an effective complement to conventional chemotherapy and radiotherapy in primary glioma harboring ALK fusions and its metastasis.

SUBMITTER: Lai M

PROVIDER: S-EPMC10187722 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Lorlatinib for ALK-fused, infant-type hemispheric glioma with lung metastasis: a case report.

Lai Mingyao M Li Shaoqun S Li Hainan H Hu Qingjun Q Li Juan J Zhou Jiangfen J Ai Ruyu R Zhen Junjie J Zhou Zhaoming Z Wang Lichao L Zhang Yangqiong Y Hu Wanming W Yuan Li L Ma Xuejiao X Zhang Xing X Song Chao C Li Zhi Z Cai Linbo L

Annals of clinical and translational neurology 20230331 5

Infant-type hemispheric glioma, a new subtype of pediatric high-grade glioma, arises in the cerebral hemispheres. Despite better survival outcomes, the treatment of infant-type hemispheric glioma is still facing challenges. Here, we reported a case of QKI-ALK fusion, infant-type hemispheric glioma with lung metastasis who achieved a complete clinical response after lorlatinib treatment. This typical case demonstrated the importance of appropriate molecularly targeted treatments in ALK-fused tumo ...[more]

PMID: 37000961

Similar Datasets

Case report: ATIC-ALK fusion in infant-type hemispheric glioma and response to lorlatinib.

Project description:IntroductionInfant type hemispheric gliomas are a rare tumor with unique molecular characteristics. In many cases these harbor mutations in receptor tyrosine kinase pathways and respond to targeted therapy. Here we describe the case of an infant with this type of tumor with a novel ATIC-ALK fusion that has responded dramatically to the ALK inhibitor lorlatinib, despite being refractory to standard chemotherapy.Case descriptionThe infant was initially treated with standard chemotherapy and found to have an ATIC-ALK fusion. When surveillance imaging revealed progressive disease, the patient was switched to the ALK-inhibitor lorlatinib at 47 mg/m2/day. The patient demonstrated a significant clinical and radiographic response to the ALK inhibitor lorlatinib after just 3 months of treatment and a near complete response by 6 months of therapy.ConclusionThe ALK inhibitor lorlatinib is an effective targeted therapy in infant type hemispheric glioma patients harboring ATIC-ALK fusion.

| S-EPMC10004274 | biostudies-literature

Lorlatinib and compound mutations in ALK+ large-cell neuroendocrine lung carcinoma: a case report.

Project description:Large-cell neuroendocrine lung carcinoma (LCNEC) is a high-grade neoplasm with median survival of 1 year and limited therapeutic options. Here, we report the unusual case of a 47-yr-old female smoker with stage IV LCNEC featuring EML4-ALK variant 2 (E20:A20), wild-type TP53/RB1, and low tumor mutational burden of 3.91 mut/Mb. Despite early progression within 3 mo under crizotinib, a durable response was achieved with alectinib. Oligoprogression in the left breast 10 mo later was treated by surgery, followed by a switch to ceritinib upon multifocal progression and detection of ALK:p.V1180L in the mastectomy specimen, but without success. Another rebiopsy revealed ALK:p.L1196M, but the tumor did not respond to brigatinib or carboplatin/pemetrexed, before stabilization under lorlatinib. Diffuse progression 8 mo later with detection of ALK :p.L1196M/p.G1202R and p.L1196M/ p.D1203N evolving from the previous p.L1196M did not respond to chemoimmunotherapy, and the patient succumbed with an overall survival (OS) of 37 mo. This case illustrates the importance of molecular profiling for LCNEC regardless of smoking status, and the superiority of next-generation ALK inhibitors compared to crizotinib for ALK+ cases. Lorlatinib retained efficacy in the heavily pretreated setting, whereas its upfront use could possibly have prevented the stepwise emergence of compound ALK mutations. Furthermore, the disease course was more aggressive and OS shorter compared to the V2/TP53wt ALK+ lung adenocarcinoma, whereas crizotinib, ceritinib, and brigatinib did not confer the benefit expected according to next-generation sequencing results, which also underline the need for more potent drugs against ALK in the high-risk setting of neuroendocrine histology.

| S-EPMC9632356 | biostudies-literature

Multiple Genetic Alterations as Resistance Mechanism during Second-Line Lorlatinib for Advanced ALK-Rearranged Lung Adenocarcinoma: A Case Report.

Project description:Second and third-generation ALK-TKI inhibitors have showed better activity and have replaced crizotinib in most of cases of advanced ALK-rearranged lung adenocarcinoma. The emergence of resistance adversely affects also the activity of these newer drugs; in particular, lorlatinib often shows multiple and complex resistance mechanisms. The case reported here highlights the importance of reassessing the biomolecular profile during the disease course, both by tissutal and liquid biopsy, with the aim of improving the knowledge of these resistance mechanisms, and so identifying new drugs or sequences able to optimize the management of these patients.

| S-EPMC8947659 | biostudies-literature

Lorlatinib and Bevacizumab Activity in ALK-Rearranged Lung Cancers After Lorlatinib Progression.

Project description: Not available

| S-EPMC7713518 | biostudies-literature

Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report.

Project description:EML4-ALK rearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored. In this case report, we describe a patient with EML4-ALK-rearranged stage IIIB MPM who was administered with alectinib and lorlatinib as first-line and fourth-line therapy, respectively. He had remarkable response evaluated as partial response on both regimens lasting approximately 3.5 months on each regimen. His plasma samples were collected during the treatment course and submitted for targeted sequencing to understand the molecular mechanisms of his therapeutic resistance. Sequencing analysis revealed the emergence of ALK I1171N and L1196M at alectinib progression. Meanwhile, ALK I1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be in cis to G1202R. We speculate that these multiple mutations synergistically mediated his resistance to both alectinib and lorlatinib. Our report describes the detection of EML4-ALK rearrangement in a patient with MPM who had remarkable therapeutic response with ALK inhibitors. Moreover, our case also revealed acquired mechanisms of lorlatinib resistance mediated by multiple mutations ALK I1171N, L1196M, and G1202R, contributing an incremental step to our understanding of the complexity of acquired resistance mechanisms in sequential ALK inhibitor therapy. The reviews of this paper are available via the supplemental material section.

| S-EPMC7328355 | biostudies-literature

STRN-ALK Fusion in Lung Adenocarcinoma with Brain Metastasis Responded Well to Ensartinib: A Case Report.

Project description:STRN-ALK fusion is a rare ALK rearrangement identified in non-small cell lung cancer (NSCLC) patients. Here, we reported a case of lung adenocarcinomas with brain metastasis, harboring STRN-ALK fusion, responded well to ensartinib. This case report could provide more information for the therapeutic strategy selecting of NSCLC patients harboring STRN-ALK fusion.

| S-EPMC9601241 | biostudies-literature

Lorlatinib in a Child with <i>ALK</i>-Fusion-Positive High-Grade Glioma.

Project description: Not available

| S-EPMC8672682 | biostudies-literature

Pathological complete response to neoadjuvant lorlatinib in a patient with stage IIIA <i>ALK</i>-positive non-small cell lung cancer: a case report.

Project description:BackgroundGiven the promising efficacy of targeted therapies in patients with advanced non-small cell lung cancer (NSCLC) harboring oncogenic drivers, its use in adjuvant and even neoadjuvant therapy is increasing. Lorlatinib is a potent brain-penetrating third-generation anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) tyrosine kinase inhibitors (TKIs) with broad ALK mutation coverage. Currently, there is a limited evidence regarding the efficacy of lorlatinib as neoadjuvant therapy in locally advanced NSCLC in the presence of ALK rearrangements. The aim of this case report is to describe a rare case of pathological complete response (pCR) to neoadjuvant lorlatinib in a patient with stage IIIA ALK-positive NSCLC, providing evidence for neoadjuvant targeted therapy.Case descriptionA 35-year-old male was pathologically diagnosed with locally advanced stage IIIA (cT2bN2M0) ALK-positive NSCLC. Clinically, the patient had pulmonary nodules in the left inferior lobe, which were enlarged progressively with follow-up, with the largest measuring approximately 4.6 cm × 2.8 cm by computed tomography (CT) scan and we found that the lymph nodes (stations 4L, 7, and 8) were invaded by metastasis. Following a 3-month neoadjuvant treatment with lorlatinib at 100 mg daily, his CT scan demonstrated a partial response (PR). This patient then underwent a left inferior lobectomy with mediastinal lymph node dissection (MLD) and mediastinal cyst resection via video-assisted thoracoscopic surgery (VATS). Postoperative pathology revealed a pCR. This patient continued to receive lorlatinib and remained disease free at his 10-month follow-up.ConclusionsHerein we reported the case of a pCR in stage IIIA ALK-positive NSCLC patient treated with neoadjuvant lorlatinib. Our findings underscore the potential of lorlatinib as a neoadjuvant treatment for resectable ALK-positive NSCLC.

| S-EPMC11304158 | biostudies-literature

Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer.

Project description:PurposeLorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting.Experimental designResistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance.ResultsDiverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial-mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three ALK kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors.ConclusionsThis study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.

| S-EPMC6942925 | biostudies-literature

Partial response to lorlatinib in thoracic inflammatory myofibroblastic tumor harboring complex and rare ALK fusions: a case report.

Project description:BackgroundTargeted therapy has dramatically altered the treatment paradigm for some patients with inflammatory myofibroblastic tumor (IMT) that possesses specific molecular aberrations. IMT is an exceedingly rare type of sarcoma, with about 50% of cases featuring anaplastic lymphoma kinase (ALK) gene rearrangements. The treatment of IMT with ALK fusions using ALK tyrosine kinase inhibitors (TKIs) has become increasingly common. However, until now, there is a lack of evidence supporting the efficacy of third-generation ALK-TKIs in this disease category.Case descriptionHere, we report the first case of a patient with advanced IMT harboring the EML4-ALK fusion gene along with two rare ALK fusion genes: PLB1-ALK, which has only been reported in two cases of lung adenocarcinoma and large cell neuroendocrine carcinoma, and unreported ALMS1-ALK. The patient achieved partial response (PR) following first-line treatment with lorlatinib and subsequently underwent successful surgical intervention.ConclusionsThis is the inaugural case of a third-generation ALK-TKI achieving therapeutic success in advanced IMT with complex ALK rearrangements, including rare and previously uncharacterized fusion subtypes. Although the biological functions of these two rare ALK fusions still need to be confirmed, this case underscores the dependency of ALK-rearranged IMT on ALK-mediated signaling, suggesting that third-generation ALK-TKIs may offer an optimal targeted therapeutic strategy for ALK-dependent mesenchymal tumor subtypes.

| S-EPMC11921266 | biostudies-literature

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