pf-00299804 and Neoplasm-Metastasis

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Progression-Free Survival; Quinazolinones; Survival Rate

Recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) has a dismal prognosis. With the emergence of monoclonal antibodies and tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR), several drugs were developed and tested in HNSCC. To date, the monoclonal antibody cetuximab is the only approved therapy for curative and recurrent/metastatic patients. Other EGFR-targeting drugs either failed in the clinical trials or are still in the early phases of drug development and research.. In this article, previously published data and ongoing studies regarding dacomitinib, a second-generation irreversible TKI, for the treatment of HNSCC are presented and discussed.. The current body of evidence is not mature enough to indicate the use of dacomitinib for the treatment of HNSCC in curative or in recurrent/metastatic settings. Phase II data suggest the potential of improved outcome in selected recurrent/metastatic HNSCC based on several biomarkers, which need to be evaluated in randomized phase III trials. Meanwhile, an ongoing phase I study is investigating dacomitinib's optimal dosing combined with and without cisplatin in the curative concomitant chemoradiotherapy setting.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; ErbB Receptors; Head and Neck Neoplasms; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Protein Kinase Inhibitors; Quinazolinones; Squamous Cell Carcinoma of Head and Neck

Patients with. In this phase II study, patients who had progressed on first-line osimertinib were treated with dacomitinib 45 mg orally daily until disease progression or intolerability. The primary end point was objective response rate.. We enrolled 12 patients. Two partial responses were documented (17% objective response rate; 95% CI, 5 to 45). The median progression-free survival was 1.8 months (95% CI, 1.6 to not reached). One patient with an original sensitizing EGFR G719A mutation and one patient without molecular testing available had partial responses, whereas 0 of the 3 patients with second-site acquired. In the first trial evaluating a second-generation EGFR TKI after first-line third-generation osimertinib, we found that dacomitinib after disease progression on osimertinib has limited benefit.

Topics: Acrylamides; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Disease Progression; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Metastasis; Pilot Projects; Prospective Studies; Quinazolinones; Retreatment

The goals of this study were to investigate the clinical activity, safety, and biomarkers of dacomitinib, an irreversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, in recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN).. Patients were eligible if the diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, and were treated with dacomitinib 45 mg/day. The primary endpoint was objective response rate by RECISTv1.1. Exploratory analysis included the characterization of somatic mutation, gene copy number, gene expression, p16(INK4A) expression by IHC, and investigation of their relationship with clinical outcomes.. Forty-eight patients were evaluable for efficacy and toxicity. Ten patients (20.8%) had partial responses and 31 patients (65%) had stable diseases. The median progression-free survival (PFS) and overall survival (OS) were 3.9 months [95% confidence interval (CI), 2.9-5.0] and 6.6 months (95% CI, 5.4-10.3). Adverse events were mostly grade 1-2. Mutations in the PI3K pathway (PIK3CA, PTEN) and high expression of inflammatory cytokines (IL6, IL8, IL1A, IL1B, IL4, and TNF) were significantly associated with shorter PFS (2.9 vs. 4.9 months without mutations, P = 0.013; 2.8 vs. 9.9 months with low expression, P = 0.004). Those harboring PI3K pathway mutations or high inflammatory cytokine expression had shorter median OS (6.1 vs. 12.5 months lacking PI3K pathway mutations and with low inflammatory cytokine expression, P = 0.005).. Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-SCCHN patients. Screening of PI3K pathway mutation and inflammatory cytokine expression may help identify which R/M-SCCHN patients are likely to gain benefit from dacomitinib.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Carcinoma, Squamous Cell; Cluster Analysis; Female; Gene Dosage; Gene Expression Profiling; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Protein Kinase Inhibitors; Quinazolinones; Retreatment; Risk Factors; Squamous Cell Carcinoma of Head and Neck; Treatment Outcome

Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease.. In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025.. Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]).. Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor.. Canadian Cancer Society Research Institute and Pfizer.

Topics: Adult; Aged; Aged, 80 and over; Canada; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Double-Blind Method; ErbB Receptors; Female; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Placebo Effect; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Quinazolinones; ras Proteins

Approximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with brain metastasis, which is related to poor survival outcomes. The ability of tyrosine kinase inhibitor drugs to penetrate the blood-brain barrier makes them a potential option for intracranial metastases. Dacomitinib, an irreversible second-generation pan-HER tyrosine kinase inhibitor, has become a standard therapy for patients with epidermal growth factor receptor mutations. However, its efficacy in patients with brain metastases (BMs) is not yet established. Here, we present 2 patients with epidermal growth factor receptor-mutant NSCLC with brain metastasis. After initiation of dacomitinib as first-line treatment, a significant clinical response was achieved, and a long-lasting complete remission was achieved in 1 patient up to this date.. Case 1 was a 47-year-old man who was admittedtothe hospital because of recurrent cough and expectoration for >1 year. Chest computed tomography scans revealed a high-density shadow in the left upper lobe. Cranial magnetic resonance imaging indicated an abnormal nodular enhancement in the right cerebellar hemisphere. Case 2 was a 55-year-old man with a chief complaint of intermittent cough and expectoration for >1 month. Chest computed tomography revealed a high-density mass in the left superior lobe. Magnetic resonance imaging of the central nervous system revealed 2 abnormal nodular enhancements in the left frontal lobe.. Both patients were diagnosed with lung adenocarcinoma by bronchoscopy and lymph node biopsy.. Both patients received dacomitinib 30 mg once daily as first-line therapy for 8 and 11 months, respectively until disease progression.. After treatment with dacomitinib, both patients achieved complete response in BMs. Progression-free survival was 11 and 8 months, respectively.. Dacomitinib strongly controlled BMs in patients with advanced NSCLC, and the adverse reactions were tolerable. Dacomitinib may be considered a new treatment option for these patients. Further prospective studies are recommended to confirm this conclusion.

Topics: Brain Neoplasms; Bronchoscopy; Carcinoma, Non-Small-Cell Lung; Genes, erbB-1; Humans; Male; Middle Aged; Neoplasm Metastasis; Quinazolinones; Tomography, X-Ray Computed

Dacomitinib (PF-00299804) is a second-generation irreversible HER tyrosine kinase inhibitor (TKI). In preclinical studies, dacomitinib has demonstrated anti-tumor activity in lung cancer cell lines with sensitive and resistant EGFR mutations (including the T790 mutation). Safety and well tolerability of dacomitinib were demonstrated in Phase I studies with stomatitis, diarrhea and skin toxicities being the dose-limiting toxicities. The maximum tolerated dose was established to be 45 mg/day. In Phase II and III studies, dacomitinib has shown clinical activity in both HER tyrosine kinase-naive and HER tyrosine kinase failure settings. Further clinical trials are underway to evaluate the efficacy of dacomitinib in non-small-cell lung cancer.

Topics: Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Evaluation; Drug-Related Side Effects and Adverse Reactions; ErbB Receptors; Humans; Maximum Tolerated Dose; Mutation; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinazolinones

Topics: Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Adenoid Cystic; Clinical Trials, Phase I as Topic; Female; Humans; Immunoglobulins, Intravenous; Neoplasm Metastasis; Neoplasm Staging; Precision Medicine; Quinazolinones; Treatment Outcome; Xenograft Model Antitumor Assays