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

Wiedemann, Christiane; Kazdal, Daniel; Cvetković, Jelena; Kunz, J; Fisch, David; Kirchner, Martina; Kriegsmann, Mark; Sueltmann, Holger; Heußel, Claus-Peter; Bischoff, Helge; Thomas, Michael; Christopoulos, Petros

doi:10.1101/mcs.a006234

Cited by 5 publications

(3 citation statements)

References 46 publications

(63 reference statements)

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“…Petros Christopoulos: A squamous transformation of ALK+ ADC is rare with very few published cases in the literature to guide therapeutic decisions. If more potent ALK -TKI are available, which have not been used before for this particular patient, they should definitely be considered first, as several studies show that ALK+ NSCLC with deviant histology, for example squamous or neuroendocrine lung carcinomas, retain sensitivity to ALK inhibitors if the ALK fusion remains detectable ( 34 , 35 ). If next-generation sequencing reveals any other druggable alterations, the treatment should target these, as well, otherwise standard (immuno-) chemotherapy should be considered.…”

Section: International Multidisciplinary Team (Imdt) Discussionmentioning

confidence: 99%

An advanced NSCLC patient with ALK-RNF144A and HIP1-ALK fusions treated with ALK-TKI combination therapy: a case report

Li,

Liu,

Lan

et al. 2023

Transl Lung Cancer Res

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Background Anaplastic lymphoma kinase ( ALK ) rearrangement is one of the most important drivers in non-small cell lung cancer (NSCLC). Despite the effectiveness to canonical 3'- ALK fusions, the clinical efficacy of ALK inhibitors in patients with complex ALK fusions, such as nonreciprocal/reciprocal translocation remains uncertain. Exploring the optimal therapeutic regimens for this subset of patients is of crucial clinical significance. Case Description We reported a female patient diagnosed with stage IVB lung adenocarcinoma (LUAD) harboring a novel ALK-RNF144A fusion, concurrent with a Huntingtin-interacting protein 1 ( HIP1 )-ALK fusion and a RB1 loss-of-function variant. The patient sequentially received multiple lines of treatment with ALK -tyrosine kinase inhibitor (TKI), chemotherapy, radiotherapy and ALK -TKI combined with anti-angiogenesis. Disease progression accompanied by a squamous cell carcinoma transformation was indicated after ALK -TKI combined with anti-angiogenesis and both ALK-RNF144A and HIP1-ALK fusions were retained in the tumor. The patient was subsequently treated with a third generation ALK -TKI, lorlatinib, in combination with albumin-bound paclitaxel and anlotinib, and then achieved stable disease. The patient remained on the treatment as of the last follow-up resulting in an overall survival (OS) of more than 18 months. Conclusions We have reported an advanced NSCLC patient with a complex nonreciprocal/reciprocal ALK translocation containing a novel ALK-RNF144A fusion, concurrent with a RB1 loss-of-function mutation, who subsequently experienced pathological squamous cell carcinoma transformation. The combined treatment with ALK -TKI, chemotherapy, and anti-angiogenesis demonstrates clinical efficacy and may provide optional therapeutic strategies for this phenotype.

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Section: International Multidisciplinary Team (Imdt) Discussionmentioning

confidence: 99%

An advanced NSCLC patient with ALK-RNF144A and HIP1-ALK fusions treated with ALK-TKI combination therapy: a case report

Li,

Liu,

Lan

et al. 2023

Transl Lung Cancer Res

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“…For example, although the SCLC component of c-SCLC and “SCLC after transformation” share many common characteristics, like a high frequency of concomitant TP53/RB1 mutations, the “SCLC after transformation” generally loses important NSCLC-related therapeutic susceptibilities, like the sensitivity to EGFR or ALK inhibitors, even in cases where the original EGFR or ALK mutation is preserved; this is partly attributable to a downregulation of the respective oncoproteins in transformed tumors ( 23 ). Besides, the sensitivity of the same driver mutation to therapy can vary according to the histological subtype, for example ALK-mutated lung neuroendocrine tumors are less sensitive to ALK inhibitors than their adenocarcinoma counterparts ( 24 ).…”

Section: Questions To Be Further Discussed and Consideredmentioning

confidence: 99%

Transformation of ALK-positive NSCLC to SCLC after alectinib resistance and response to combined atezolizumab: a case report

Gao¹,

Huang²,

Ni³

et al. 2023

Transl Lung Cancer Res

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Background: The genotypic and histological evolution of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) has been described as a mechanism of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). However, it was extremely rare in anaplastic lymphoma kinase (ALK) positive NSCLC, and the follow-up care and outcomes of patients with this rare condition were unclear. This case was the first described the effectiveness of combined chemo-immunotherapy in a patient, with a transformed ALK positive NSCLC into SCLC after the administration of an ALK-TKIs.Case Description: We described a unique case in which a patient with ALK-positive NSCLC underwent SCLC transformation at a metastatic site and remained ALK positive after TKI treatment. In July 2019, a 77-year-old man was diagnosed with ALK-positive stage IVB NSCLC, received alectinib and responded to alectinib. It was not until more than 7 months later that a cranial MRI showed brain metastases. And whole-brain radiotherapy was administered, and secondary epilepsy and metastatic progression occurred.One year later, computed tomography showed a left submandibular mass with multiple lymph node metastases, a left lower lung mass, and right pleura thickening. A left submandibular biopsy revealed SCLC.Echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion and low tumor mutation burden (2.23 muts/Mb) were identified by next generation sequencing. The patient was administered atezolizumab (1,200 mg, d1) in combination with etoposide (0.13 g, d1-d3) and carboplatin (350 mg, d1). The left neck mass was reduced significantly, showing a partial response. Serum NSE (from 106 to 15 ng/mL), CA19-9 (from 49.4 to 34.6 U/mL) and CEA (from 4.18 to 3.09 ng/mL) returned to normal. Only mild myelosuppression (Grade 1), fatigue (Grade 1), and anorexia (Grade 1) were present. The patient had an overall survival time of 21 months.Conclusions: This case highlighted the importance of re-biopsies to reveal pathological SCLC transformation after ALK-TKI resistance, and suggested the treatment of atezolizumab in combination with etoposide and carboplatin were potentially helpful for this phenotype.

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“…Five of the 13 patients with brain metastases were initially treated with crizotinib, while the other eight received alectinib as their first-line therapy. Both treatment regimens were effective, except for three patients experiencing PD within three months (12,25,27). In total, 11 patients benefited from second-line ALK TKIs, such as ceritinib, brigatinib, and lorlatinib.…”

Section: Clinical Characteristics Of Patients With Lcnecs and Alk Rea...mentioning

confidence: 99%

Two case reports: EML4-ALK rearrangement large cell neuroendocrine carcinoma and literature review

Chen,

Zhang,

Wang

et al. 2023

Front. Oncol.

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Anaplastic lymphoma kinase gene (ALK) rearrangement is present in only approximately 5% of non-small cell lung cancers (NSCLCs) and is scarce in LCNEC patients. The conventional first-line treatment options are chemotherapy combined with immunotherapy or chemotherapy followed by palliative radiotherapy. In this report, we present two cases of metastatic LCNEC with EML4-ALK fusion that were treated with ALK-TKI inhibitors and demonstrated a rapid therapeutic response. Both patients were nonsmoking women who declined cytotoxic chemotherapy, underwent Next-Generation Sequencing (NGS), and confirmed EML4-ALK fusion. They were treated with alectinib as first-line therapy, and the tumors showed significant shrinkage after two months, achieving a PR (defined as a more than 30% decrease in the sum of maximal dimensions). The PFS was 22 months and 32 months, respectively, until the last follow-up. A systematic review of all previously reported cases of LCNEC with ALK mutations identified only 21 cases. These cases were characterized by being female (71.4%), nonsmoking (85.7%), diagnosed at a relatively young age (median age 51.1), and stage IV (89.5%), with an overall response rate (ORR) of 90.5%. PFS and OS were significantly longer than those treated with conventional chemotherapy/immunotherapy. Based on the clinical characteristics and the effective therapeutic outcomes with ALK inhibitors in LCNEC patients with ALK fusion, we recommend routine ALK IHC (economical, affordable, and convenient, but with higher false positives) as a screening method in advanced LCNEC patients, particularly nonsmoking females or those who are not candidates for or unwilling to undergo cytotoxic chemotherapy. Further molecular profiling is necessary to confirm these potential beneficiaries. We suggest TKI inhibitors as the first-line treatment for metastatic LCNEC with ALK fusion. Additional studies on larger cohorts are required to assess the prevalence of ALK gene fusions and their sensitivity to various ALK inhibitors.

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

Cited by 5 publications

References 46 publications

An advanced NSCLC patient with ALK-RNF144A and HIP1-ALK fusions treated with ALK-TKI combination therapy: a case report

An advanced NSCLC patient with ALK-RNF144A and HIP1-ALK fusions treated with ALK-TKI combination therapy: a case report

Transformation of ALK-positive NSCLC to SCLC after alectinib resistance and response to combined atezolizumab: a case report

Two case reports: EML4-ALK rearrangement large cell neuroendocrine carcinoma and literature review

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