Treatment Sequencing for Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer

Abstract

Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases and is the leading cause of cancer-related deaths. Most NSCLC patients are diagnosed with advanced disease and require systemic treatment. Despite emerging advances in chemotherapy and immunotherapy, the prognosis of stage IV patients remains poor. However, the discovery of oncogenic driver mutations including mutations in the epidermal growth factor receptor (EGFR), the anaplastic lymphoma kinase (ALK) and others, characterize a subset of patients with the opportunity of targeted therapies. Fusions between the ALK and echinoderm microtubule-associated protein-like 4 (EML4) are present in ∼ 3–5% of patients with NSCLC. Several first-, second-, and third-generation ALK tyrosine kinase inhibitors (TKIs) have been developed in the last decade and have tremendously changed treatment options and outcomes of ALK-positive NSCLC patients. With increasing treatment options, treatment sequence decisions have become more and more complex. ALK-mutations, fusion variants, or activation of by-pass pathways result in treatment resistance during the course of treatment in nearly all patients. Mutation-guided treatment sequencing can lead to better outcomes, and re-biopsy or liquid-biopsy should be performed whenever possible in case of disease progression in ALK-rearranged patients. In the future, combinational treatment of ALK TKIs with other pathway-inhibitors might further improve patients’ treatment options and outcomes. Here, we review the data for currently available ALK TKIs, discuss approaches of treatment sequencing, and give an outlook on emerging developments.

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

“…To expand PFS and OS, it is crucial to think about evidencebased treatment sequencing. Every ALK TKI has its own advantages and disadvantages (122). Therefore, a second biopsy is recommended for gene sequencing when the patient is resistant (123).…”

Response to ALK‐TKIs in a lung adenocarcinoma patient harboring dual DCTN1‐ALK and ALK‐CLIP4 rearrangements

“…However, because of the rareness of DCTN1‐ALK fusion in NSCLC patients, the efficacy and duration of ALK‐TKI treatment in this subset of patients remained poorly understood. Here, we identified a female patient in our center with concurrent DCTN1‐ALK (D27:A20) and ALK‐CLIP4 (A19:C12) fusions and reported that this patient achieved PR to first‐line crizotinib therapy with a progress‐free survival (PFS) of 12 months, which was very similar to that of patients carrying EML4‐ALK fusion 5 . This may be because of the fact, that like EML4 , the DCTN1 fragment also contains a functional region that can initiate ALK transcription and translation 4 …”

“…Here, we identified a female patient in our center with concurrent DCTN1-ALK (D27:A20) and ALK-CLIP4 (A19:C12) fusions and reported that this patient achieved PR to first-line crizotinib therapy with a progress-free survival (PFS) of 12 months, which was very similar to that of patients carrying EML4-ALK fusion. 5 This may be because of the fact, that like EML4, the DCTN1 fragment also contains a functional region that can initiate ALK transcription and translation. 4 It is worth noting that ALK-CLIP4 (A19:C12) rearrangement (Figure 3) was detected in both plasma and tumor tissue before crizotinib treatment.…”

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

“…ALK rearrangements (typical genomic architecture is provided in Figure 1, upper panel) are present in 2%–6% of NS‐NSCLC 10 . These genomic alterations are sensitive to different molecules, notably to next‐generation TKIs (such as alectinib, brigatinib, and lorlatinib), which if given upfront result in significantly longer survival compared to initial treatment with the first‐generation inhibitor crizotinib or chemotherapy 9,11–13 . Excluding presence of an ALK fusion is also crucial before starting immunotherapy, due to the lack of efficacy and increased toxicity of the immune checkpoints inhibitors (ICIs) in ALK‐ positive NSCLC patients 14–16 .…”

“…Fusions were visualized using Arriba 9 chemotherapy. 9,[11][12][13] Excluding presence of an ALK fusion is also crucial before starting immunotherapy, due to the lack of efficacy and increased toxicity of the immune checkpoints inhibitors (ICIs) in ALKpositive NSCLC patients. [14][15][16] Besides a very low tumor mutational burden of ALK-positive tumors, uniquely below 3 mut/MB on average, 17 an immunosuppressive tumor microenvironment also appears to contribute to the inherent ICI resistance of these tumors.…”