scholarly journals Therapeutic Sequencing in ALK+ NSCLC

2021 ◽  
Vol 14 (2) ◽  
pp. 80
Author(s):  
Mei Elsayed ◽  
Petros Christopoulos
Keyword(s):  
Disease Progression ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Fourth Generation ◽  
Cell Therapies ◽  
Anaplastic Lymphoma ◽  
Phase Ii Studies ◽  
Tumor Mutational Burden ◽  
Potential Clinical Utility

Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. Of particular interest are cases with off-target resistance, for example MET, HER2 or KRAS alterations, which require special therapeutic maneuvers, e.g., inclusion in early clinical trials or off-label administration of respectively targeted drugs. On the other hand, up to approximately half of the patients failing TKI, develop anatomically restricted progression, which can be initially tackled with local ablative measures without switch of systemic therapy. Among the overall biologically favorable ALK+ tumors, with a mean tumor mutational burden uniquely below 3 mutations per Mb and the longest survival among NSCLC currently, presence of the EML4-ALK fusion variant 3 and/or TP53 mutations identify high-risk cases with earlier treatment failure and a need for more aggressive surveillance and treatment strategies. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK+ tumors.

scholarly journals Prospects in the management of patients with follicular lymphoma beyond first-line therapy

Haematologica ◽  
2022 ◽  
Vol 107 (1) ◽  
pp. 19-34 ◽  
Author(s):  
David Qualls ◽  
Gilles Salles
Keyword(s):  
Follicular Lymphoma ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Cytotoxic Agents ◽  
Treatment Regimens ◽  
First Line Therapy ◽  
Phase Ii Studies ◽  
Clinical Scenarios ◽  
Histological Transformation ◽  
Anti Cd20

The management of patients with relapsed or refractory follicular lymphoma has evolved markedly in the last decade, with the availability of new classes of agents (phosphoinositide 3-kinase inhibitors, immunomodulators, epigenetic therapies, and chimeric antigen receptor T cells) supplementing the multiple approaches already available (cytotoxic agents, anti-CD20 antibodies, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants). The diversity of clinical scenarios, the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies preclude firm recommendations and require personalized decisions. Patients with early progression require specific attention given the risk of histological transformation and their lower response to standard therapies. In sequencing therapies, one must consider prior treatment regimens and the potential need for future lines of therapy. Careful evaluation of risks and expected benefits of available options, which vary depending on location and socioeconomics, should be undertaken, and should incorporate the patient’s goals. Preserving quality of life for these patients is essential, given the likelihood of years to decades of survival and the possibility of multiple lines of therapy. The current landscape is likely to continue evolving rapidly with other effective agents emerging (notably bispecific antibodies and other targeted therapies), and multiple combinations being evaluated. It is hoped that new treatments under development will achieve longer progression-free intervals and minimize toxicity. A better understanding of disease biology and the mechanisms of these different agents should provide further insights to select the optimal therapy at each stage of disease.

scholarly journals Management of Oligoprogression in Patients with Metastatic NSCLC Harboring ALK Rearrangements

2021 ◽  
Author(s):  
Chiara Pisano ◽  
Marco De Filippis ◽  
Francesca Jacobs ◽  
Silvia Novello ◽  
Maria Lucia Reale
Keyword(s):  
Disease Progression ◽  
Kinase Inhibitors ◽  
Local Treatment ◽  
Treatment Strategies ◽  
Local Therapy ◽  
Integrated Treatment ◽  
System Level ◽  
Alk Rearrangement ◽  
Comprehensive Overview ◽  
Sequential Administration

Personalized treatment based on driver molecular alterations, such as ALK rearrangement, has revolutionized the therapeutic management of advanced oncogene addicted NSCLC patients. Multiple effective ALK tyrosine kinase inhibitors (TKIs), with the amelioration of the activity at central nervous system level, are now available, leading to substantial prognosis improvement. The exposure to TKIs triggers resistance mechanisms and the sequential administration of other TKIs and chemotherapy is, for the most part, not targeted. In this context, extending the benefit deriving from precision medicine is paramount, above all when disease progression occurs in a limited number of sites. Retrospective data indicate that, in oligoprogressive disease, targeted therapy beyond progression combined with definitive local treatment of the progressing site(s) is an effective alternative. In these cases, multidisciplinary approach becomes essential for an integrated treatment strategy, depending on the site of disease progression, in order to improve not only survival, but also quality of life. In this review we provide an updated and comprehensive overview of the main treatment strategies in case of ALK rearranged oligoprogression, including systemic treatment as well as local therapy, and report real-world clinical stories, with the final aim of identifying the most promising management for this subset of patients.

scholarly journals Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways

2018 ◽  
Vol 11 (557) ◽  
pp. eaar5680 ◽  
Author(s):  
Jimmy Van den Eynden ◽  
Ganesh Umapathy ◽  
Arghavan Ashouri ◽  
Diana Cervantes-Madrid ◽  
Joanna Szydzik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Expression Profiles ◽  
Neuroblastoma Cell ◽  
Treatment Strategies ◽  
Tyrosine Kinase Receptor ◽  
Anaplastic Lymphoma ◽  
Major Interest

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is a clinical target of major interest in cancer. Mutations and rearrangements inALKtrigger the activation of the encoded receptor and its downstream signaling pathways.ALKmutations have been identified in both familial and sporadic neuroblastoma cases as well as in 30 to 40% of relapses, which makes ALK a bona fide target in neuroblastoma therapy. Tyrosine kinase inhibitors (TKIs) that target ALK are currently in clinical use for the treatment of patients with ALK-positive non–small cell lung cancer. However, monotherapy with the ALK inhibitor crizotinib has been less encouraging in neuroblastoma patients withALKalterations, raising the question of whether combinatorial therapy would be more effective. In this study, we established both phosphoproteomic and gene expression profiles of ALK activity in neuroblastoma cells exposed to first- and third-generation ALK TKIs, to identify the underlying molecular mechanisms and identify relevant biomarkers, signaling networks, and new therapeutic targets. This analysis has unveiled various important leads for novel combinatorial treatment strategies for patients with neuroblastoma and an increased understanding of ALK signaling involved in this disease.

scholarly journals Rapid regression of neurological symptoms in patients with metastasised ALK+ lung cancer who are treated with lorlatinib: a report of two cases

2019 ◽  
Vol 12 (7) ◽  
pp. e227299 ◽  
Author(s):  
Huda Gafer ◽  
Quincy de Waard ◽  
Annette Compter ◽  
Michel van den Heuvel
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Kinase Inhibitors ◽  
Performance Status ◽  
Poor Performance ◽  
Neurological Symptoms ◽  
Poor Performance Status ◽  
Third Generation ◽  
Anaplastic Lymphoma ◽  
Almost All

Oral anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) have shown significant benefit in the management of ALK-rearranged non-small cell lung cancer (NSCLC). However, almost all patients will experience disease progression after front-line ALK-TKIs such as crizotinib. Treatment with third generation ALK-TKI lorlatinib can have a significant clinical impact following disease progression, even in patients with a very poor performance status. Here, we review two clinical cases with metastatic ALK-rearranged NSCLC who had pulmonary disease control with first-generation ALK inhibitor. However, disease progressed rapidly in the central nervous system with severe neurological symptoms. Treatment with lorlatinib, a third-generation ALK-TKI, led to a rapid radiological and clinical cerebral response in both patients. Lorlatinib can overcome ALK resistance to crizotinib, and the presented cases suggest a potential role for lorlatinib in patients with rapidly progressive cerebral and leptomeningeal metastases.

Molecular and clinical features of second-generation anaplastic lymphoma kinase inhibitors: ceritinib

2017 ◽  
Vol 13 (29) ◽  
pp. 2629-2644 ◽  
Author(s):  
Tommaso De Pas ◽  
Laura Pala ◽  
Chiara Catania ◽  
Fabio Conforti
Keyword(s):  
Clinical Features ◽  
Anaplastic Lymphoma Kinase ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Anaplastic Lymphoma
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