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

Abstract

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.

Keywords: lung adenocarcinoma.

Figure 1.

Radiologic findings over the course of the disease. (A) Chest computed tomography (CT) scan at initial diagnosis. (B) Head magnetic resonance imaging (MRI) 4 mo after crizotinib start with oligoprogression in the right parotid gland. (C) Chest and cranial CT scans with multifocal progression after radiotherapy. (D) Chest CT scan showing response to alectinib. (E) Chest CT scan showing oligoprogression in the left breast 8 mo later. (F) Chest CT and head MRI showing multifocal progression after partial mastectomy. (G,H) Chest CT and head MRI showing multifocal progression under certinib and brigatinib. (I) Chest CT and head MRI showing multifocal progression under carboplatin-pemetrexed. (J) Chest CT showing response to lorlatinib. (K) Chest CT and head MRI showing multifocal progression under lorlatinib. (L) Chest CT showing multifocal progression under carboplatin-paclitaxel-bevacizumab-atezolizumab; the patient died 3 wk later. (L) Treatment line, (RT) radiotherapy, (PR) partial response, (SD) stable disease, (LN) lymph nodes.

Figure 2.

Histological characteristics of large-cell neuroendocrine lung carcinoma (LCNEC) in the initial biopsy of the lung tumor (A–K) and third tumor rebiopsy from a chest wall lesion in 02/2019 after ceritinib (L–R, see Table 1; Fig. 1). At initial diagnosis, the neoplasia showed a solid and trabecular growth pattern (A,B) with recognizable areal necrosis (A,C). The cells were medium- to large-sized, featured enlarged nuclei, granular karyoplasm with clearly recognizable nucleoli, and broad cytoplasm (D). Immunohistochemical staining was positive for TTF-1, CD56, and synaptophysin and negative for p40 and Napsin-A, and the Ki-67 proliferation rate was 40% (E–K). At the third tumor rebiopsy, tumor cells showed higher-grade features, including larger nuclei and more prominent nucleoli (L–R).

Figure 3.

The primary gene fusion and secondary ALK mutations identified in the patient. (A) EML4 exons 1–20 and ALK exons 20–29 were involved in the primary gene fusion (E20:A20, aka EML4–ALK variant 2). (B) The resulting chimeric protein with its main domains and the position of detected ALK resistance mutations in the last rebiopsy of the patient at the time of lorlatinib failure in 03/2020. (C) Reads of resistance mutations in the last rebiopsy of the patient at the time of lorlatinib failure in 03/2020, which reveals outgrowth of two distinct clones with compound mutations: p.L1196M in combination with p.D1203N, and p.L1196M in combination with ALK p.G1202R. Both have likely arisen on the ground of the preexistent p.L1196M mutation (Table 1; Fig. 1) because of the selective pressure under lorlatinib and are known to be highly lorlatinib resistant, as explained in the main text. (D) Fishplot of relative clonal abundance based on the genetic alterations detected in the patient's samples after correction for the tumor cell content (Table 1).