osimertinib and rociletinib

In 2015, the FDA approved an unprecedented number of new therapies for non-small cell lung cancer (NSCLC), among them therapies addressing specific genomic tumor subsets in the setting of development of resistance to first-line targeted therapy. Osimertinib (Tagrisso, formerly AZD9291; AstraZeneca) is indicated for patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy. It received breakthrough therapy designation, priority review status, and accelerated approval from the FDA. Clin Cancer Res; 23(3); 618-22. ©2016 AACR.

Topics: Acrylamides; Adenosine Triphosphate; Aniline Compounds; Antineoplastic Agents; Binding Sites; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Diarrhea; Disease Progression; Drug Eruptions; Drug Resistance, Neoplasm; ErbB Receptors; Genes, erbB-1; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Molecular Targeted Therapy; Mutation, Missense; Neoplasm Proteins; Piperazines; Point Mutation; Protein Kinase Inhibitors; Pyrimidines; Salvage Therapy; Single-Blind Method

The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are widely used in patients with non-small cell lung cancer (NSCLC). However, EGFR T790M mutation leads to resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development. These agents include osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. Osimertinib and rociletinib have shown clinical efficacy in phase I/II trials in patients who had acquired resistance to first- or second-generation TKIs. Osimertinib (AZD9291, TAGRISSO) was recently approved by FDA for metastatic EGFR T790M mutation-positive NSCLC. HM61713, ASP8237, EGF816, and PF-06747775 are still in early clinical development. This article reviews the emerging data regarding third-generation agents against EGFR T790M mutation in the treatment of patients with advanced NSCLC.

Topics: Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation, Missense; Piperazines; Protein Kinase Inhibitors; Pyrimidines

Patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) develop resistance during therapy with EGFR tyrosine kinase inhibitors (TKIs). In about half of the patients, this resistance is because of the emergence of the T790M mutation. Third-generation TKIs are active against EGFR-activating mutations and the T790M resistance mutation and have only limited efficacy against wild-type EGFR. Here we review the current status of the clinical development of these novel TKIs.. Third-generation TKIs in clinical development include osimertinib, rociletinib, and HM61713. Osimertinib and rociletinib have shown clinical efficacy in phase I/II trials in patients who had acquired resistance to first- or second-generation TKIs. Both TKIs are currently further evaluated in phase III trials as first-line or second-line therapy in patients with advanced EGFR mutation-positive NSCLC. HM61713 is in early clinical development.. Third-generation EGFR TKIs have shown activity in patients with acquired resistance to first- and second-generation EGFR TKIs and may further improve clinical outcome in patients with advanced EGFR mutation-positive NSCLC.

Topics: Acrylamides; Aniline Compounds; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Piperazines; Protein Kinase Inhibitors; Pyrimidines

Activating EGFR mutations discovery and efficacy of 1st generation tyrosine kinase inhibitors (TKI), such as erlotinib or gefitinib, inaugurated the beginning of personalized medicine in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, all patients showed a tumor progression of 10 to 16 months after the onset of TKI therapy related to molecular resistance mechanisms as T790M mutation. Till now, patients suffering from EGFR-mutated NSCLC with acquired resistance have conventional treatment options. Two new 3rd generations' TKI, AZD9291 and rociletinib, are currently being studied in phases 1-3 studies. Preliminary results show relevant therapeutic properties in patients with T790M mutated-EGFR NSCLC. This review aims to highlight these new molecules, their effectiveness and their clinical toxicities in the treatment of advanced stages of NSCLC expressing the T790M mutation.

Topics: Acrylamides; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease Progression; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyrimidines

Discovery of activating mutations in EGFR and their use as predictive biomarkers to tailor patient therapy with EGFR tyrosine kinase inhibitors (TKIs) has revolutionised treatment of patients with advanced EGFR-mutant non-small-cell lung cancer (NSCLC). At present, first-line treatment with EGFR TKIs (gefitinib, erlotinib, and afatinib) has been approved for patients harbouring exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. These agents improve response rates, time to progression, and overall survival. Unfortunately, patients develop resistance, limiting patient benefit and posing a challenge to oncologists. Optimum treatment after progression is not clearly defined. A more detailed understanding of the biology of EGFR-mutant NSCLC and the mechanisms of resistance to targeted therapy mean that an era of treatment approaches based on rationally developed drugs or therapeutic strategies has begun. Combination approaches-eg, dual EGFR blockade-to overcome resistance have been trialled and seem to be promising but are potentially limited by toxicity. Third-generation EGFR-mutant-selective TKIs, such as AZD9291 or rociletininb, which target Thr790Met-mutant tumours, the most common mechanism of EGFR TKI resistance, have entered clinical trials, and exciting, albeit preliminary, efficacy data have been reported. In this Review, we summarise the scientific literature and evidence on therapy options after EGFR TKI treatment for patients with NSCLC, aiming to provide a guide to oncologists, and consider how to maximise therapeutic advances in outcomes in this rapidly advancing area.

Topics: Acrylamides; Afatinib; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Protein Kinase Inhibitors; Pyrimidines; Quinazolines

Topics: Acrylamides; Aniline Compounds; Antineoplastic Agents; Disease Progression; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Piperazines; Pyrimidines

Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells or bronchioalveolar stem cells, but not basal cells or club cells of the trachea. It is also demonstrated that these clones are able to retain their epigenetic differences through passaging orthotopically in mice and crucially that they have distinct drug vulnerabilities. This work serves as a blueprint for exploring how epigenetics can be used to stratify patients for precision medicine decisions.

Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Precision Medicine; Protein Kinase Inhibitors; Pyrimidines; Treatment Outcome

Lung cancer is the leading cause of cancer death, and epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small-cell lung cancer (NSCLC), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the EGFR inhibitors Gefitinib and Erlotinib initially, but soon develop resistance to them due to the emergence of the gatekeeper mutation T790M. The new-generation inhibitors such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to Cys 797, but ultimately lose their efficacy upon the emergence of the C797S mutation that abolishes the covalent bonding. Allosteric inhibitors EAI001 and EAI045 are a new type of EGFR inhibitors that bind to EGFR away from the ATP-binding site and not relying on Cys 797. In this study, molecular dynamics simulations and free energy calculations were carried out on EAI001 and EAI045 in complex with EGFR, revealing the detailed inhibitory mechanism of EAI001 and EAI045 as EGFR allosteric inhibitor, which was expected to provide a basis for rational drug design of the EGFR allosteric inhibitors. Communicated by Ramaswamy H. Sarma.

Topics: Acrylamides; Allosteric Regulation; Aniline Compounds; Benzeneacetamides; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Molecular Dynamics Simulation; Mutation; Protein Binding; Protein Kinase Inhibitors; Pyrimidines; Thiazoles

Topics: Acrylamides; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Disease Progression; ErbB Receptors; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Piperazines; Pyrimidines

Topics: Acrylamides; Aniline Compounds; ErbB Receptors; Pyrimidines

Topics: Acrylamides; Aniline Compounds; ErbB Receptors; Pyrimidines

To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).. We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Pyrimidines

Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.. We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632).. Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [. Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing. Clin Cancer Res; 22(20); 5130-40. ©2016 AACR.

Topics: Acrylamides; Afatinib; Aniline Compounds; Animals; Antineoplastic Agents; Biological Transport; Blood-Brain Barrier; Brain Neoplasms; Caco-2 Cells; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Disease Progression; Dogs; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gefitinib; Humans; Lung Neoplasms; Madin Darby Canine Kidney Cells; Male; Mice; Mice, SCID; Middle Aged; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Rats; Xenograft Model Antitumor Assays

The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs; e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants, represent very promising therapeutic options for patients with non-small cell lung cancer (NSCLC) that has become resistant to 1st generation EGFR-TKIs due to T790M mutation. However, eventual resistance to the 3rd generation EGFR-TKIs has already been described in the clinic, resulting in disease progression. Therefore, there is a great challenge and urgent need to understand how this resistance occurs and to develop effective strategies to delay or overcome the resistance. The current study has demonstrated that Met amplification and hyperactivation is a resistance mechanism to both 1st and 3rd generation EGFR-TKIs since both erlotinib- and AZD9291-resistant HCC827 cell lines possessed amplified Met gene and hyperactivated Met, and were cross-resistant to AZD9291 or erlotinib. Met inhibition overcame the resistance of these cell lines to AZD9291 both in vitro and in vivo, including enhancement of apoptosis or G1 cell cycle arrest. Hence, we suggest that Met inhibition is also an effective strategy to overcome resistance of certain EGFR-mutated NSCLCs with Met amplification to AZD9291, warranting the further clinical validation of our findings.

Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Crizotinib; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Female; G1 Phase Cell Cycle Checkpoints; Gene Amplification; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice, Nude; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; RNA Interference; Signal Transduction; Time Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays