Abstract and Introduction
Abstract
Background and Objective: The therapeutic landscape for non-small cell lung cancer (NSCLC) has evolved considerably in the last few years. The targeted drugs and molecular diagnostics have been developed together at a fast pace. This narrative review explores the evolution of anaplastic lymphoma kinase (ALK) targeting therapies from discovering the ALK protein, molecular tests, present clinical trial data and future perspectives. Since the body of evidence on lung cancer is growing daily, most oncologists need time to implement data in their daily practice.
Methods: We developed a narrative review to provide up-to-date help in the clinical decision-making of ALK-altered NSCLC patients. In 2022, the authors reviewed PubMed's published pivotal randomized Phase 3 trial results.
Key Content and Findings: The development of ALK inhibitors was a revolution that is still ongoing; second and third-generation ALK inhibitors provided more than 30 months of progression-free survival (PFS) and impressive "brain-control". Brigatinib provided a survival benefit for patients with baseline brain metastases (HR 0.43, 95% CI: 0.21–0.89), and Lorlatinib demonstrated intracranial response rates of 82%, with 71% of complete intracranial responses. Personalized medicine is the new paradigm, from performing broad genetic panels for diagnosis to individual targeted therapy or combinations of different targeted agents.
Conclusions: In the future, performing broad molecular panels should be the standard of care in the front line and after each progression to detect arising resistance mechanisms. Longer PFS will substantially convert a deadly condition into an almost chronic disease in the following decades. Treatment sequencing will be the cornerstone for patient survival, and liquid biopsies may replace tissue biopsies.
Introduction
Lung cancer is the leading cause of death worldwide. Recent data from Globocan demonstrated that lung cancer stood first in mortality in 2020, accounting for 1,796,144 deaths, followed by colorectum, liver and stomach.[1] Non-small cell lung cancer (NSCLC) accounts for 85% of lung cases and usually is diagnosed in an advanced stage.[2]
The therapeutic arsenal for the treatment of advanced lung cancer has evolved significantly in recent years; in addition to previous cytotoxic chemotherapy, strategies have been shown to inhibit epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), changing the natural course of the disease.[2]
The different combinations of platinum-based therapies (platinum-doublet) were considered standard when treating advanced NSCLC; all of them proved to be equivalent when compared with each other in a clinical trial published in 2002 by Eastern Cooperative Oncology Group (ECOG).[3] At that time, the standard of care was established with no need to refine the patient selection based on clinical characteristics other than performance status.[3] Chemotherapy was almost the only treatment that could be used.
Despite the high heterogeneity of NSCLC, the characterization of driver mutations allows for treating each patient with a personalized approach.[3] The use of next-generation sequencing (Foundation One, Oncomine, Therascreen, Guardant360 and others) is also expanding, and these advancements have led to the rapid evolvement of novel target-selected therapies.[4]
Objectives
The evidence in lung cancer ALK translocated lung cancer is growing daily, and oncologists must identify the best approach for each patient. A data review is important to compare the ALK inhibitors in light of new studies. This review aims to help clinicians to choose the best therapy for their clinical practice. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-619/rc).
Transl Lung Cancer Res. 2023;12(7):1563-1574. © 2023 AME Publishing Company
