Driver mutations

Classical treatments for lung cancer include surgery, radiotherapy, chemotherapy, and combinations of these approaches. The discovery of genes that drive tumor growth and progression has opened up novel treatment strategies.

For stage 4 (metastasized) lung cancer, chemotherapy was once the standard, and only, treatment option. The median overall survival time was 9 months, regardless of the type of chemotherapy used. Since then, treatment options have evolved significantly, with immunotherapy and targeted therapies emerging as more effective alternatives for patient survival.

Currently, the majority of lung cancer patients (80%) still have smoking-related lung cancer, which is characterized by a high mutation burden. These cases are treated with immunotherapy alone or, in some instances, in combination with chemotherapy, depending on the PD-L1 status of the tumor. The five-year survival rate for these treatments ranges from 12% to 30%.

Driver mutations

However, the remaining 20% of lung cancer cases are not related to smoking. These patients tend to be younger and more frequently female. Often, their tumors have a driver mutation — a genetic mutation that gives cancer cells a selective advantage by enhancing their survival or reproduction. Driver mutations typically lead to clonal expansions. Targeting these mutations can provide significant therapeutic benefits. The first notable driver mutation discovered in lung cancer was the EGFR mutation, which stands for epidermal growth factor receptor. The IPASS landmark study demonstrated that lung cancer patients with EGFR mutations responded better to gefitinib (a first-generation EGFR inhibitor) than to chemotherapy. Conversely, gefitinib had no effect on tumors without EGFR mutations.

The first notable driver mutation discovered in lung cancer was the EGFR mutation, which stands for epidermal growth factor receptor. The IPASS landmark study demonstrated that lung cancer patients with EGFR mutations responded better to gefitinib (a first-generation EGFR inhibitor) than to chemotherapy. Conversely, gefitinib had no effect on tumors without EGFR mutations. In these patients gefitinib was even detrimental as compared to chemotherapy.

Today, many more driver mutations have been identified in lung cancer. In Western Europe, the most relevant mutations include EGFR (10%), ALK (3%), BRAFV600E (2%), MET (2%), and ROS1 (1%), with new treatable mutations continually being discovered. Most of these mutations can be targeted by drugs that inhibit the tyrosine kinase enzymes that signal downstream of the receptor. These drugs are known as tyrosine kinase inhibitors (TKIs). One of the key advantages of TKIs is their specificity; they target a particular mutation, resulting in fewer systemic side effects compared to traditional cytotoxic treatments like chemotherapy. Furthermore, by addressing the specific driver mutation on which the tumor depends, the tumor can be controlled for years, depending on the type of mutation.

A recent update from the American Society of Clinical Oncology (ASCO) highlighted significant progress in treating ALK translocations. In the phase III CROWN trial, patients with ALK translocations treated with lorlatinib (a third-generation ALK TKI) had a median progression-free survival of more than 5 years, compared to 9.1 months for those treated with crizotinib (a first-generation ALK TKI).