Emerging EGFR-Mutated Subclones in a Patient With Metastatic ALK-Rearranged Lung Adenocarcinoma Treated With ALK-Targeted Therapy: A Case Report

Abstract

We report a case of pathologically confirmed ALK-rearranged metastatic lung adenocarcinoma with emergence of EGFR L858R mutation on disease progression after two lines of treatment with ALK inhibitors. At initial diagnosis, tumoral ALK expression was detected without EGFR mutation by standard allele-specific polymerase chain reaction. There was sustained partial response to both first-line crizotinib and subsequent brigatinib. On disease progression to brigatinib, result of a liquid biopsy with circulating tumor DNA revealed only EGFR L858R, which was confirmed by tumor rebiopsy on the supraclavicular lymph node. The patient was then treated initially with pemetrexed and carboplatin, and erlotinib was subsequently added after two cycles of chemotherapy. The combination treatment has resulted in very good partial response and mild adverse effects. The overall clinical course would suggest the initial presence of two separate tumor clones, with ALK dominance at diagnosis. The subsequent breakthrough disease progression after initial response to brigatinib was related to uncontrolled growth of the EGFR-mutated tumor subpopulation. The implication on defining molecular mechanism of acquired resistance and treatment strategy would be discussed.

Keywords: Anaplastic lymphoma kinase; Case report; Epidermal growth factor receptor; Lung adenocarcinoma; Targeted therapy.

Figure 1

Immunostaining of FNA samples of the right supraclavicular lymph node (H&E stain 200× magnification). (A, C) Positive TTF-1 staining on FNA specimen. (B) FNA specimen with ALK stain positive. (D) FNA specimen with ALK stain negative. (A) and (B) were taken on January 2, 2019, and (C) and (D) were taken on December 8, 2020. FNA, fine-needle aspiration; H&E, hematoxylin and eosin.

Figure 2

Serial chest radiographs. (A) At disease progression after brigatinib. (B) After six cycles of doublet chemotherapy with erlotinib.

Figure 3

Temporal sequence of representative CT scans. (A) At diagnosis on November 30, 2018. (B) Before brigatinib on February 14, 2020. (C) Before chemotherapy on November 23, 2020. (D) After chemotherapy plus erlotinib on April 1, 2021. CT, computed tomography.