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

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-year-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 months under crizotinib, a durable response was achieved with alectinib. Oligoprogression in the left breast 10 months later was treated by surgery, followed by 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 months 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 months. 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, while 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, while crizotinib, ceritinib and brigatinib did not confer the benefit expected according to NGS results, which also underline the need for more potent drugs against ALK in the high-risk setting of neuroendocrine histology.