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Clinical evaluation of dacomitinib for the treatment of metastatic non-small cell lung cancer (NSCLC): current perspectives.

ABSTRACT: Systemic treatment of advanced non-small cell lung cancer (NSCLC) has undergone remarkable changes in the last decade, with the introduction of targeted therapies and immunotherapy. The identification of activating mutations in the epidermal growth factor receptor (EGFR) gene (deletions in exon 19 [Del19] and point mutation L858R in exon 21) has been the first important step toward molecularly guided precision therapy in lung cancer. Several randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, and afatinib) to standard chemotherapy in first-line treatment of advanced EGFR-mutant NSCLC showed significant improvement in progression-free survival (PFS) and in response rate, with lower rates of adverse events (AEs) and better symptom control. However, none of these trials showed significant improvement in overall survival (OS). Despite impressive responses with EGFR-TKI, disease invariably progresses after 9 to 13 months, due to acquired resistance. Dacomitinib is a potent, irreversible, highly selective, second-generation EGFR-TKI, which inhibits the signaling from both heterodimers and homodimers of all the members of the human epidermal growth factor receptor (HER) family. Here, we review the clinical development of dacomitinib from phase I to phase III, with particular attention to its toxicity and on its activity on T790M mutation. Then, we critically examine the results of ARCHER 1050, a study that was crucial for Food and Drug Administration (FDA) approval. ARCHER 1050 was the first randomized phase III study comparing dacomitinib with gefitinib, in first-line treatment of patients with advanced EGFR-mutated NSCLC. Dacomitinib was superior to gefitinib in terms of primary end-point (14.7 vs 9.2 months) and OS (34.1 vs 26.8 months). The incidence of diarrhea, skin rash, mucositis and, consequently, dose reductions was higher with dacomitinib, while hepatic toxicity was higher with gefitinib. Dacomitinib constitutes one of the standard first-line options in patients with advanced EGFR-mutated NSCLC.

SUBMITTER: Lavacchi D

PROVIDER: S-EPMC6735534 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Clinical evaluation of dacomitinib for the treatment of metastatic non-small cell lung cancer (NSCLC): current perspectives.

Lavacchi Daniele D Mazzoni Francesca F Giaccone Giuseppe G

Drug design, development and therapy 20190906

Systemic treatment of advanced non-small cell lung cancer (NSCLC) has undergone remarkable changes in the last decade, with the introduction of targeted therapies and immunotherapy. The identification of activating mutations in the epidermal growth factor receptor (EGFR) gene (deletions in exon 19 [Del19] and point mutation L858R in exon 21) has been the first important step toward molecularly guided precision therapy in lung cancer. Several randomized trials comparing EGFR tyrosine kinase inhib ...[more]

PMID: 31564835

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Project description:Lung cancer is the leading killer of both men and women in the US, and the 5-year survival remains poor. However, the approval of checkpoint blockade immunotherapy has shifted the treatment paradigm and provides hope for improved survival. The ability of non-small-cell lung cancer (NSCLC) to evade the host immune system can be overcome by agents such as pembrolizumab (MK-3475/lambrolizumab), which is a monoclonal antibody targeting the programmed death 1 (PD-1) receptor. In early studies, treatment with pembrolizumab led to dramatic and durable responses in select patients (PD-L1+ tumors). This remarkable efficacy lead to approval of pembrolizumab in the second-line setting as response rates were almost doubled compared to standard of care (SOC) chemotherapy. Most recently, data in the first-line setting from the KEYNOTE-024 study have redefined the SOC therapy for a selected subset of patients. In patients with ≥50% PD-L1+ tumors, pembrolizumab had a clear progression-free survival and overall survival benefit. Toxicity was mostly immune related and similar to checkpoint blockade toxicities observed in previous studies. The initial approval and subsequent studies of pembrolizumab required and utilized a companion diagnostic test, Dako's IHC 22C3, to assess PD-L1 status of patients. The evaluation and scoring system of this assay has been used by other companies as a reference to develop their own assays, which may complicate selection of patients. Finally, the impact of pembrolizumab in NSCLC is growing as evidenced by the numerous, ongoing trials open for combinations with chemotherapy, chemoradiation, other immunotherapeutics, immunomodulators, tyrosine kinase inhibitors, PI3K inhibitors, MEK inhibitors, hypomethylating agents, and histone deacetylase inhibitors. Further studies are also evaluating pembrolizumab in small-cell lung cancer and malignant pleural mesothelioma. This explosion of studies truly conveys the lack of therapeutic answers for lung cancer patients and the promise of pembrolizumab.

Project description:Purpose: Atezolizumab is a programmed death ligand 1 (PDL-1) blocking antibody that was approved for metastatic non-small cell lung cancer (NSCLC) in patients with disease progression. Various studies have been initiated to explore the effectiveness of atezolizumab among different patient cohorts and disease statuses, including as first-line therapy. The purpose of this paper is to identify and summarize the trials that use atezolizumab as a first-line agent in chemotherapy-naïve patients with NSCLC. Methods: A database search was performed on Pubmed, Embase, and Wiley Cochrane Library-Central Register of Controlled Trials to identify clinical trials using atezolizumab as first-line therapy in NSCLC. Additionally, ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP) were searched to identify relevant clinical trials. Conference abstracts from the American Society of Clinical Oncology, the European Society for Medical Oncology, and the American Association for Cancer Research were hand-searched. Any trial in which atezolizumab was used as first-line therapy in chemotherapy-naive patients with NSCLC was included. Results: Fifteen studies were ultimately included, all of which are current and ongoing. Of the 15 studies, 5 have reported results. When given in the first-line setting, atezolizumab had higher rates of objective response, progression-free survival, and overall survival, compared to the second and third-line settings. Among the 15 studies, atezolizumab is used as monotherapy (n = 5), in combination with chemotherapy (n = 6), in combination with targeted therapy such as bevacizumab (n = 1), as neoadjuvant/adjuvant therapy (n = 3), in combination with stereotactic body radiation therapy (n = 1), and in combination with or following chemoradiation (n = 1). Conclusion: Available evidence shows promising safety and efficacy with the use of atezolizumab as first-line therapy in NSCLC. Atezolizumab is currently being studied in a variety of treatment settings. If clinical benefits are shown, atezolizumab may deem to be a useful first-line agent in NSCLC.

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Clinical evaluation of dacomitinib for the treatment of metastatic non-small cell lung cancer (NSCLC): current perspectives.

Publications

Clinical evaluation of dacomitinib for the treatment of metastatic non-small cell lung cancer (NSCLC): current perspectives.

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