Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene rearrangement is a distinct subtype of lung cancer, and it is highly sensitive to the ALK kinase inhibitors such as crizotinib or alectinib [1, 2]. The ALK fusion mutation is called the “diamond mutation”, and the patient who has a tumor harbouring ALK mutation usually has a more prolonged progression-free survival (PFS). For ALK-positive patients taking crizotinib, the median PFS was 11.8 months [3], and 62% of patients can achieve a 3-years PFS after treatment with alectinib [4]. Drug resistance frequently occurs due to alterations in the oncogene-driven genes and phenotypic transformation [3]. Various resistance mechanisms, similar to other oncogene-driven cancers treated with tyrosine kinase inhibitors (TKIs), may be classified into three different groups: 1) alterations in the oncogene-driven genes (such as ALK L1196M or C1156Y mutations [5]); 2) activation of bypass pathways (for example insulin-like growth factor 1 receptor (IGF-1R) [6], SRC proto-oncogene, non-receptor tyrosine kinase (SRC) [7] and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK/ERK) [8] activation); 3) phenotypic transformation (to small cell lung cancer) [9]. The histological shift has been reported as a resistance mechanism in 3–14% of the patients treated with epidermal growth factor receptor (EGFR) TKIs [10, 11]. However, phenotypic transformation is rarely reported in ALK-positive patients. Herein, we presented a case of ALK rearrangement-positive adenocarcinoma with high expression of programmed death-ligand 1 (PD-L1) that was transformed into squamous cell carcinoma after administration of alectinib.

To the best of our knowledge, this is the first clinical case demonstrating the relationship between histological morphological changes after administration of alectinib and the expression of PD-L1. Although histological transformation has been reported in the patients treated with EGFR-TKIs, there are very few reports of this transformation in ALK-positive patients, especially the transformation of adenocarcinoma into squamous cell carcinoma. Given that our patient is a never-smoker, EML4 Exon 13 and ALK Exon 20 fusion mutations were detected in the two biopsies at first diagnosis and recurrence, and 80% of the tumor cells in the two specimens showed diffuse and strong positive expression of PD-L1, the tissues after resistance were not likely to originate from an independent new tumor. In addition, primary ALK-positive squamous cell carcinoma often showed a remarkably positive response to alectinib [12, 13], but in this case the squamous cell carcinoma was not sensitive to alectinib. Since the patient was taking alectinib for treatment without chemotherapy or radiotherapy, we believe that changes in the initial tumor morphology could be caused by treatment with alectinib. The mechanism can be partly explained by the fact that the histological changes caused by alectinib, which is a highly selective ALK-TKI, inhibit multiple crizotinib-resistant ALK mutations. Importantly, the IC50 of inhibited cell growth was 12 nmol/L, which was about one-sixth of crizotinib [9]. These characteristics of alectinib put more severe selective pressure on the adenocarcinoma cells during treatment with alectinib. After overcoming the evolutionary process of selective pressure, alectinib-resistant tumor cells undergo biological changes more frequently. This may explain the appearance of recurring tumors within ten months of continuing alectinb therapy after the primary tumor almost completely disappeared in this case.

Patients with ALK fusions usually have a longer PFS. Nevertheless, in this case, the patient was taking alectinib for treatment, and the PFS was only 18 months. The most likely explanation is that the patient has a high level (PD-L1 TPS of ≥50%) of PD-L1 expression. We reviewed the first liver puncture specimens and found that the tumors had a PD-L1 TPS of 80%. Yang et al. [3] revealed that patients with ALK-positive lung adenocarcinoma followed by strong PD-L1 expression have a shorter PFS than those with negative PD-L1 expression after crizotinib treatment. Hsu et al. [14] found similar results among patients with EGFR-mutant lung adenocarcinoma treated with EGFR-TKIs. Therefore, the shorter PFS in our patient can be explained by alectinib therapy.

Our study provides evidence that 1) although crizotinib is the first-line medication for the treatment of ALK-positive patients, the serious abnormality occuring on liver and heart needs more attention after giving crizotinib. 2) alectinib has been proved a better curative effect for the ALK-rearrangement lung adenocarcinoma, and repeated biopsies are needed to determine histological changes when resistance emerges. 3) Patients having a high level of PD-L1 expression are more likely to have drug resistance. For clinicians, a patient who shows a PD-L1 TPS of ≥50% will need more careful monitoring of drug resistance during treatment, thus the appropriate and timely therapy can be performed to improve the survival of patients.