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From crizotinib to lorlatinib: continuous improvement in precision treatment of ALK-positive non-small cell lung cancer
  1. Robert Pirker,
  2. Martin Filipits
  1. Internal Medicine I, Medical University of Vienna, Vienna, Austria
  1. Correspondence to Dr Robert Pirker; Robert.Pirker{at}

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Patients with advanced non-small cell lung cancer (NSCLC) have received first-line chemotherapy with a platin-based doublet in case of good performance status and with a single agent or well tolerated doublet in case of older age for many years.1–3 Chemotherapy has been combined with bevacizumab or necitumumab in selected patients. Two major advances have changed this therapeutic landscape. The first change refers to the identification of driver mutations and the establishment of corresponding tyrosine kinase inhibitors (TKIs) as preferred first-line therapy for patients harbouring these mutations in their tumours. The second change refers to the establishment of immune checkpoint inhibitors in routine clinical practice. Patients with driver-negative NSCLC and good performance status nowadays receive first-line therapies with either chemotherapy plus pembrolizumab or atezolizumab, pembrolizumab as single agent in case of PD-L1 expression in ≥50% of tumour cells, or nivolumab plus ipilimumab in case of high tumour mutational load. Second-line therapies are docetaxel (plus/minus nintedanib or ramucirumab), pemetrexed, erlotinib, afatinib or immune checkpoint inhibitors.

The identification of driver mutations has affected both diagnosis and therapy of NSCLC.4 5 Advanced NSCLC is currently classified based on histology, immunohistochemistry and driver mutation status. Adenocarcinomas are routinely assessed for the presence of EGFR mutations, anaplastic lymphoma kinase (ALK) or ROS1 re-arrangements, and BRAF mutations. Additional tests are performed based on both their availability and access to corresponding targeted drugs. Patients with driver mutation-positive NSCLC receive corresponding TKIs as preferred first-line therapy. ALK-positive NSCLC is a representative example on how continuous improvements in precision treatment have been achieved. Here, we summarise the clinical establishment of ALK inhibitors for the treatment of patients with advanced NSCLC with focus on phase III trials.

ALK inhibitors

In 2007, a transforming ALK fusion gene was described in NSCLC.6 ALK fusion genes can be detected in approximately 4% of …

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