Advancements of ALK inhibition of non-small cell lung cancer: a literature review

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.

Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions

“…This prolonged PFS is anticipated to transform the disease into a manageable, chronic condition. Effective treatment sequencing will be vital for patient survival, and the potential replacement of tissue biopsies with liquid biopsies is on the horizon [156]. In addition, clinical trials have shown that ALK inhibitors exhibit excellent efficacy against brain metastases.…”

Alectinib continuation beyond progression in ALK-positive non-small cell lung cancer with alectinib-refractory

“…Furthermore, the Asian population-based ALESIA study showed even better efficacy, with an mPFS of 41.6 months and an ORR of 91%. However, despite the significant clinical benefits achieved with alectinib, resistance to alectinib occurred in 53.3% of patients treated with alectinib as the first-line therapy, leading to disease progression, and more progressive disease occurred in second-line alectinib treatment ( 4 , 15 - 17 ). ALK-TKIs resistance mainly arises from ALK mutations and ALK amplification, such as the G1202R mutation ( 18 ).…”

Tailoring Therapeutic Strategies in Non-Small-Cell Lung Cancer: The Role of Genetic Mutations and Programmed Death Ligand-1 Expression in Survival Outcomes

“…For instance, tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR) mutations have dramatically improved the typical prognosis of advanced NSCLC from 12-14 months to 36-48 months [5][6][7][8]. Consequently, the identification of such mutations like anaplastic lymphoma kinase (ALK) [9], ROS proto-oncogene 1 (ROS1), V-raf murine sarcoma viral oncogene homolog B1 (BRAF) [10], MET proto-oncogene, receptor tyrosine kinase (MET) [11], and RET proto-oncogene receptor tyrosine kinase (RET) [12] has become increasingly critical in routine clinical practice.…”