Reference Detail

Ref Type

Journal Article

PMID

(36207130)

Authors

Wiedemann C, Kazdal D, Cvetkovic J, Kunz J, Fisch D, Kirchner M, Kriegsmann M, Sültmann H, Heussel CP, Bischoff H, Thomas M, Stenzinger A, Christopoulos P

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cold Spring Harbor molecular case studies	8	6	2022 Oct		Cold Spring Harb Mol Case Stud

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK	large cell neuroendocrine carcinoma	predicted - sensitive	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, Xalkori (crizotinib) treatment resulted in stable disease with early progression after 3 months in a patient with metastatic large cell neuroendocrine lung carcinoma harboring EML4-ALK (e20:e20) (PMID: 36207130).	36207130
EML4 - ALK ALK V1180L	large cell neuroendocrine carcinoma	predicted - resistant	Alectinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK V1180L was identified on post-progression biopsy in a patient with large cell neuroendocrine lung carcinoma harboring EML4-ALK (e20:e20), who previously responded to Alecensa (alectinib) treatment (PMID: 36207130).	36207130
EML4 - ALK ALK L1196M ALK G1202R ALK D1203N	large cell neuroendocrine carcinoma	predicted - resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK L1196M, ALK D1203N, and ALK G1202R were identified on post-progression biopsy in a patient with metastatic large cell neuroendocrine lung carcinoma harboring EML4-ALK (e20:e20), who previously achieved disease stabilization for 8 months with Lorbrena (lorlatinib) treatment (PMID: 36207130).	36207130
EML4 - ALK ALK L1196M	large cell neuroendocrine carcinoma	no benefit	Brigatinib	Case Reports/Case Series	Actionable	In a clinical case study, a heavily pretreated patient with metastatic large cell neuroendocrine lung carcinoma harboring EML4-ALK (e20:e20) and ALK L1196M did respond to Alunbrig (brigatinib) treatment (PMID: 36207130).	36207130
EML4 - ALK	large cell neuroendocrine carcinoma	predicted - sensitive	Alectinib	Case Reports/Case Series	Actionable	In a clinical case study, second-line Alecensa (alectinib) treatment resulted in a partial response lasting 10 months in a patient with metastatic large cell neuroendocrine lung carcinoma harboring EML4-ALK (e20:e20) (PMID: 36207130).	36207130