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

Abstract

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.

Anaplastic lymphoma kinase inhibitors—a review of anticancer properties, clinical efficacy, and resistance mechanisms

“…Subsequent biopsy confirmed small cell lung cancer (Fujita et al, 2016). Transformation of metastatic lesion was recently reported by Xia and others (Xia et al, 2023). Importantly, both tumors remained ALK-positive after transformation.…”

Case report: Clinical complete response in advanced ALK-positive lung squamous cell carcinoma: a case study of successful anti-PD-1 immunotherapy post ALK-TKIs failure

“…To date, there have only been six reported cases documenting such a transformation to SCLC in the context of ALK-positive lung cancer. Post-histological transformation, patients with ALK-positive NSCLC generally exhibit rapid disease progression, with both targeted therapy and chemotherapy proving ineffective in most cases ( 20 , 24 – 28 ). Remarkably, there has been only one documented instance where a patient, transformed to SCLC following ALK-TKI treatment, responded positively to chemotherapy and immunotherapy ( 28 ).…”

“…Post-histological transformation, patients with ALK-positive NSCLC generally exhibit rapid disease progression, with both targeted therapy and chemotherapy proving ineffective in most cases (20, 24-28). Remarkably, there has been only one documented instance where a patient, transformed to SCLC following ALK-TKI treatment, responded positively to chemotherapy and immunotherapy (28). Yan et al presented a case of ALKrearrangement-positive adenocarcinoma with high expression of PD-L1 that was transformed into LSCC after administration of alectinib (29).…”

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

“…Petros Christopoulos: Multiregion sampling has revealed considerable spatial heterogeneity with adverse prognostic implications for many lung cancers ( 40 ). Therefore, performing multiple biopsies at initial diagnosis could improve the yield of potential therapeutic targets and also reveal the presence of an additional histologic component in some mixed pulmonary neoplasms, which can be missed if a small biopsy of one site only is performed ( 41 ). However, multiregion biopsies are not practicable in the routine setting, because they would multiply the health care costs and also increase the procedural risk of complications for the patients.…”