Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC

Abstract

Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. Methods: We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with continued next-generation regimens upon progression. Results: The tumor showed progression on crizotinib, but long tumor control was achieved following the incremental administration of next-generation ALK inhibitors, despite lack of evident resistance mechanisms. Conclusion: TP53 status should be taken into consideration when selecting ALK-inhibitor treatment for personalized therapies. In TP53-mutant tumors, switching TKI generations may overcome treatment exhaustion even in the absence of ALK-dependent resistance mechanisms.

The importance of precision medicine in modern molecular oncology

“…TP53 mutations are frequently associated with failure of crizotinib treatment. When ALK inhibitor is going to be considered for treatment, the status of TP53 should be carefully checked 83 . For further NGS detection, the focus may be shifting to answering the question of how to overcome resistance to corresponding inhibitors.…”

Serum and Glucocorticoid-Inducible Kinase 1 (SGK1) in NSCLC Therapy

“…There are a variety of genetic and epigenetic alterations that can negatively impact the efficacy of a treatment regimen. They can affect the primary target of the drug or other proteins, which can activate pathways parallel or downstream in respect to the original target, thus overcoming its direct inhibition [ 20 , 21 , 22 , 23 , 24 , 25 ].…”

Molecular Pathology of Cancer: The Past, the Present, and the Future

“…However, a theme common to most of the contributions is the elucidation of biomarkers for targeted therapies, such as BRCA 1/2 mutations in ovarian cancer [ 3 ] and homologous recombination DNA repair deficiency [ 4 ], which are at present amenable to PARP inhibitor therapy. Furthermore, fusions of the ALK , ROS1 , and NTRK genes, although overall rare in cancers, are frequently effectively inhibited by targeted drugs and addressed in this compendium for glioma [ 5 ] and non-small cell lung cancer [ 6 ]. In very rare tumor entities, such as primary diffuse leptomeningeal melanomatosis, with no effective and established standard therapy available, molecular profiling of tumor cells may reveal potential targets for therapy [ 7 ].…”