pf-00299804 and Adenocarcinoma-of-Lung

Dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non-small-cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib).. The phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of dacomitinib. In the phase II portion, patients received dacomitinib at the RP2D. The primary end point was progression-free survival at 4 months (PFS4m).. Twelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS4m was 47.2% (95% confidence interval [CI], 31.6-61.3; one-sided p-value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7-17.6); median overall survival was 46.3 weeks (95% CI, 32.7-not reached); and the objective response rate was 17.1% (95% CI, 7.2-32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms "cough" and "pain" showed improvement within 3 weeks of initiating treatment.. Dacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Female; Gefitinib; Genes, ras; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Quinazolines; Quinazolinones; ras Proteins; Republic of Korea; Treatment Outcome

Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance.. We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation.. Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%-88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%-58%).. We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Prospective Studies; Protein Kinase Inhibitors

Topics: Adenocarcinoma of Lung; Drug Eruptions; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Up-Regulation

Dual inhibition of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor pathways for the treatment for EGFR-mutated, metastatic non-small cell lung cancer is supported by previous randomized controlled trials. However, the use of second-generation irreversible EGFR tyrosine kinase inhibitor (TKI) dacomitinib in combination with antiangiogenic therapy has not been reported in the literature. Here, we report the case of a 73-year-old man who presented with hemoptysis and dyspnea on exertion and was diagnosed with right upper lung adenocarcinoma with pleural metastasis and L858R mutation. The second case is of a 60-year-old woman who presented with low back pain and was diagnosed with right lower lung adenocarcinoma with bone metastasis and L858R mutation. Both patients underwent first-line therapy with the TKI dacomitinib in combination with bevacizumab. The first patient showed a nearly complete response, and the second patient showed a partial response after the combination therapy and no severe side effects.

Topics: Adenocarcinoma of Lung; Aged; Bevacizumab; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Quinazolinones; Vascular Endothelial Growth Factor A

Uncommon epidermal growth factor receptor (EGFR) mutations are increasingly being identified in non-small cell lung cancer. Insertion and deletion mutations have been detected in exons 18, 19, and 20, but not in exon 21. In patients with uncommon mutations, the second-generation EGFR tyrosine kinase inhibitor afatinib has shown good efficacy, whereas that of dacomitinib, another second-generation EGFR-tyrosine kinase inhibitor, remains unknown. Here, we reported a patient with a novel EGFR21 exon insertion-deletion (indel) mutation and demonstrated the efficacy of dacomitinib.. A 59-year-old nonsmoking Chinese male was admitted to the hospital with lung cancer after a chest computed tomography for coughing and sputum. The patient's condition progressed after multiple treatments including surgery, chemotherapy, and radiotherapy.. The patient had clinical manifestations of cough and sputum and was pathologically confirmed to have T2bN1M0 (stage IIB) lung adenocarcinoma according to the seventh edition of tumor-node-metastasis staging. The patient underwent a second operation after detection of recurrence, and postoperative pathology confirmed adenocarcinoma of the lung. The patient progressed again after surgery, and the tumor-node-metastasis stage was changed to T4N0M1a (stage IVA) before treatment with dacomitinib.. After detection of the EGFR exon 21 indel mutation, the patient began treatment with dacomitinib (45 mg once a day) on March 12, 2021.. After 1 month of targeted therapy, the patient showed a partial response to dacomitinib. As of March 19, 2022, his condition remained stable and he continued to receive dacomitinib. Progression-free survival reached 12.4 months. The patient experienced mild adverse reactions of pruritus during the use of dacomitinib, but recovered after drug treatment.. We reported a novel EGFR exon 21 indel mutation in a lung adenocarcinoma patient. Dacomitinib showed efficacy in the treatment of a patient with this mutation, suggesting that its efficacy in patients with uncommon mutations should be explored further. The next-generation sequencing is recommended as a guiding tool for the treatment of advanced non-small cell lung cancer.

Topics: Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Exons; Humans; INDEL Mutation; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Quinazolinones

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Humans; Lung Neoplasms; Mutation; Quinazolinones

The epidermal growth factor receptor (EGFR) kinase domain T790M (amino acid substitution at position 790 in EGFR from threonine [T] to methionine [M]) mutation in non-small-cell lung cancer (NSCLC) results in resistance to EGFR tyrosine kinase inhibitors (TKIs). We used a patient-derived tumor xenograft (PDX) model containing an EGFR exon 19 deletion/T790M mutation to assess response to the EGFR-directed antibody cetuximab. Changes in the EGFR signaling pathway and ligand expression after treatment were investigated.. PDX were randomized into control and treatment arms. Pharmacodynamic studies were performed at 2 and 24 hours and at 4 days after a single administration of cetuximab, erlotinib, or dacomitinib. Changes in the EGFR signaling pathway were assessed using Western blot analysis, and baseline mRNA expression of EGFR ligands using microarray analysis. Relative changes after treatment were assessed using quantitative polymerase chain reaction.. The xenograft showed a dramatic response to cetuximab. A complete reduction of total EGFR and phosphorylated EGFR occurred after cetuximab treatment. The PDX had increased baseline levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) compared with other PDX models with or without EGFR mutations. Amphiregulin was significantly reduced 2 hours after treatment with cetuximab. Compared with control mice, cetuximab- and EGFR-TKI-treated mice had significantly reduced HB-EGF gene expression at 2 hours, however, by day 4 the level of HB-EGF expression was higher. The effect of cetuximab compared with EGFR TKI on HB-EGF gene expression levels differed significantly at 2 and 24 hours but not at 4 days.. We showed a dramatic tumor response with cetuximab in an exon 19 deletion/T790M EGFR mutant lung adenocarcinoma PDX model, which suggests a role for the autocrine feedback loop in the mutant EGFR signaling pathway. Further investigation using cetuximab in NSCLC with T790M mutation is warranted.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cetuximab; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms; Mice; Middle Aged; Mutation; Protein Kinase Inhibitors; Quinazolinones; Random Allocation; Signal Transduction; Time Factors; Xenograft Model Antitumor Assays

Although epidermal growth factor receptor (EGFR) -mutated adenocarcinomas initially have high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients eventually develop resistance. Patient-derived xenografts (PDXs) are considered preferred preclinical models to study the biology of patient tumors. EGFR-mutant PDX models may be valuable tools to study the biology of these tumors and to elucidate mechanisms of resistance to EGFR-targeted therapies.. Surgically resected early-stage non-small-cell lung carcinoma (NSCLC) tumors were implanted into nonobese diabetic severe combined immune deficient (NOD-SCID) mice. EGFR TKI treatment was initiated at tumor volumes of 150 μL. Gene expression analysis was performed using a microarray platform.. Of 33 lung adenocarcinomas with EGFR activating mutations, only 6 (18%) engrafted and could be propagated beyond passage one. Engraftment was associated with upregulation of genes involved in mitotic checkpoint and cell proliferation. A differentially expressed gene set between engrafting and nonengrafting patients could identify patients harboring EGFR-mutant tumor with significantly different prognoses in The Cancer Genome Atlas Lung Adenocarcinoma datasets. The PDXs included models with variable sensitivity to first- and second-generation EGFR TKIs and the monoclonal antibody cetuximab. All EGFR-mutant NSCLC PDXs studied closely recapitulated their corresponding patient tumor phenotype and clinical course, including response pattern to EGFR TKIs.. PDX models closely recapitulate primary tumor biology and clinical outcome. They may serve as important laboratory models to investigate mechanisms of resistance to targeted therapies, and for preclinical testing of novel treatment strategies.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Afatinib; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cetuximab; Crizotinib; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Mutation; Predictive Value of Tests; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Quinazolines; Quinazolinones; Signal Transduction; Up-Regulation