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Precision Therapy for Lung Cancer: Tyrosine Kinase Inhibitors and Beyond.

ABSTRACT: For patients with advanced cancers there has been a concerted effort to transition from a generic treatment paradigm to one based on tumor-specific biologic, and patient-specific clinical characteristics. This approach, known as precision therapy has been made possible owing to widespread availability and a reduction in the cost of cutting-edge technologies that are used to study the genomic, proteomic, and metabolic attributes of individual tumors. This review traces the evolution of precision therapy for lung cancer from the identification of molecular subsets of the disease to the development and approval of tyrosine kinase, as well as immune checkpoint inhibitors for lung cancer therapy. Challenges of the precision therapy era including the emergence of acquired resistance, identification of untargetable mutations, and the effect on clinical trial design are discussed. We conclude by highlighting newer applications for the concept of precision therapy.

SUBMITTER: Rajan A

PROVIDER: S-EPMC6360071 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Precision Therapy for Lung Cancer: Tyrosine Kinase Inhibitors and Beyond.

Rajan Arun A Schrump David S DS

Seminars in thoracic and cardiovascular surgery 20150408 1

For patients with advanced cancers there has been a concerted effort to transition from a generic treatment paradigm to one based on tumor-specific biologic, and patient-specific clinical characteristics. This approach, known as precision therapy has been made possible owing to widespread availability and a reduction in the cost of cutting-edge technologies that are used to study the genomic, proteomic, and metabolic attributes of individual tumors. This review traces the evolution of precision ...[more]

PMID: 26074108

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Project description:Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12?months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the known mechanisms of resistance.

Project description:Lung cancer still represents the leading cause of cancer-related mortality. However, the recent advent of tyrosine kinase inhibitors (TKI), pioneering drugs against targetable mutations, have dramatically improved prognosis of advanced non-small cell lung cancer (NSCLC) patients. Anaplastic lymphoma kinase (ALK) gene rearrangements, identified in 3–7% of NSCLC cases, reflects in the constitutive activation of downstream signalling pathways, stimulating tumour cell proliferation, differentiation and survival. To accurately detect the wide spectrum of ALK rearrangements, the introduction of innovative techniques, like reverse transcriptase polymerase chain reaction (RT-PCR) or next generation sequencing (NGS) now allows for a more precise detection of variants and a more objective reading assessment, compared to the traditional diagnostic approaches. In some occasions, these new tools may dynamically monitor tumor evolution and even guide the choice of the most appropriate ALK inhibitor. In fact, among ALK TKIs available, crizotinib was the first to receive FDA accelerate approval for ALK rearranged NSCLC patients. Notwithstanding its response rate, ranging from 57% to 74%, the majority of patients progress within the first year of drug administration, due to acquired resistance. Both ALK-dependent and independent mechanisms of acquired resistance to TKIs have been identified. If the activation of multiple bypass signaling pathways constitutes the most common ALK-independent mechanism of resistance and one of the most difficult to overcome, ALK-dependent escape strategy mainly consists of mutations in the kinase domain, where the type of mutation largely depends on the TKI administered. Second and third generation TKIs are now available and are demonstrating high systemic and central nervous system (CNS) efficacy in clinical trials. Even though appropriate timing and sequencing of these compounds are still unclear, the large number of ALK inhibitors is now a precious resource aiming to prolong progression-free survival (PFS) and finally overall survival (OS). Here Authors provide an overview of the current approaches in the clinical management of advanced NSCLC patients harboring ALK rearrangement and discuss future perspectives to address current issues, highlighting the perception that ALK-rearranged advanced NSCLC patients benefit from maintained ALK inhibition for as long as possible.

Dataset Information

Precision Therapy for Lung Cancer: Tyrosine Kinase Inhibitors and Beyond.

Publications

Precision Therapy for Lung Cancer: Tyrosine Kinase Inhibitors and Beyond.

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