Update on HER1–3 in Advanced Non–Small-Cell Lung Cancer

Abstract

The human ErbB, or epidermal growth factor receptor (EGFR), is a family of four structurally related receptor tyrosine kinases—ErbB-1 or EGFR, ErbB-2 or HER2/neu, ErbB-3 or HER3, and ErbB-4 or HER4. Ligand binding to the receptor induces receptor homo or heterodimerization with other ErbB family members or with other extracellular receptors. Receptor activation signals key downstream pathways that regulate cell proliferation, differentiation, and survival. The EGFR pathway has been extensively investigated in non–small-cell lug cancer (NSCLC) patients. Overexpression of EGFR has been reported in 50% to 80% of NSCLC patients, and activating mutations within the EGFR kinase domain have been detected in up to 17% of North American patients diagnosed with metastatic lung adenocarcinoma.1Kris MG Johnson BE Kwiatkowski DJ et al.Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI's Lung Cancer Mutation Consortium (LCMC).J Clin Oncol. 2011; (ASCO Annual Meeting Proceedings. 2011;29 CRA7506)Google Scholar EGFR tyrosine kinase inhibitors (TKIs) are approved as second- or third-line therapy in unselected patients with advanced NSCLC. However, recent studies have demonstrated improved response rate (RR) and progression-free survival (PFS) in patients with EGFR mutation-positive NSCLC treated with an EGFR TKI before chemotherapy.2Mok TS Wu YL Thongprasert S et al.Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma.N Engl J Med. 2009; 361: 947-957Crossref PubMed Scopus (7031) Google Scholar, 3Maemondo M Inoue A Kobayashi K et al.Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.New Engl J Med. 2010; 362: 2380-2388Crossref PubMed Scopus (4628) Google Scholar, 4Mitsudomi T Morita S Yatabe Y et al.Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.Lancet Oncol. 2010; 11: 121-128Abstract Full Text Full Text PDF PubMed Scopus (3563) Google Scholar, 5Zhou C Wu YL Chen G et al.Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study.Lancet Oncol. 2011; 12: 735-742Abstract Full Text Full Text PDF PubMed Scopus (3402) Google Scholar, 6Rosell R Gervais R Vergnenegre A et al.Erlotinib versus chemotherapy (CT) in advanced non-small-cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial.ASCO Meeting Abstr. 2011; 29: 7503Google Scholar HER2 kinase domain mutations are less common in NSCLC and are found in approximately 2% to 4% of patients with metastatic lung adenocarcinoma.1Kris MG Johnson BE Kwiatkowski DJ et al.Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI's Lung Cancer Mutation Consortium (LCMC).J Clin Oncol. 2011; (ASCO Annual Meeting Proceedings. 2011;29 CRA7506)Google Scholar The efficacy of HER2 inhibitors in this setting is yet to be determined, however, there is a single case report of a patient with HER2 mutant NSCLC, who responded to weekly trastuzumab (the anti-HER2 antibody) with paclitaxel.7Cappuzzo F Bemis L Varella-Garcia M HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer.New Eng J Med. 2006; 354: 2619-2621Crossref PubMed Scopus (192) Google Scholar All patients with EGFR mutant tumors treated with EGFR TKIs eventually develop acquired resistance. Approximately 50% of patients have tumors that harbor a second-site mutation within the EGFR kinase domain, the most common of which involves a threonine to methionine change at position 790 (T790M).8Pao W Miller VA Politi KA et al.Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.PLoS Med. 2005; 2: e73Crossref PubMed Scopus (3088) Google Scholar,9Kobayashi S Boggon TJ Dayaram T et al.EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.New Engl J Med. 2005; 352: 786-792Crossref PubMed Scopus (3476) Google Scholar Other mechanisms of acquired resistance have been described.10Sequist LV Waltman BA Dias-Santagata D et al.Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.Sci Transl Med. 2011; 3: 75ra26Crossref PubMed Scopus (2691) Google Scholar At the time of progression, there are as of now no approved targeted therapies. Afatinib (BIBW2992) is an irreversible Pan-ErbB inhibitor. Dr. Mok presented the LUX-Lung Program. LUX-Lung I was a randomized phase IIb/III trial in NSCLC patients who progressed after at least 12 weeks of erlotinib or gefitinib. Patients treated with afatinib had a higher RR and PFS as compared with those treated with placebo. However, median overall survival was lower for afatinib-treated patients (10.8 versus 12.0 months). LUX-Lung II was a phase II trial of first-line afatinib in EGFR mutation-positive NSCLC patients and reported a PFS of 10.1 months. LUX-Lung III and IV both compare first-line afatinib with chemotherapy (cisplatin/pemetrexed or cisplatin/gemcitabine) in EGFR mutation-positive NSCLC. Data from LUX-Lung IV are expected within the year. LUX-Lung V is randomized phase III trial comparing chemotherapy with or without afatinib in patients who have progressed on erlotinib or gefitinib. LUX-Lung VII is a phase IIb trial of first-line afatinib compared with gefitinib in EGFR mutation-positive patients, and LUX-Lung VIII is a randomized phase III trial of afatinib versus erlotinib in squamous cell lung cancer patients. A phase I b trial, based on preclinical data suggesting that combination afatinib and cetuximab is efficacious in EGFR mutant lung cancer patients who have developed acquired resistance to erlotinib or gefitinib, was presented by Dr. Horn. This trial demonstrated a 40% RR and 93% disease control in the first 91 patients enrolled. PFS is not mature. Dacomitinib is an irreversible Pan-ErbB inhibitor. Dr. Miller presented a trial of dacomitinib in never or former light smokers who were Asian, or whose tumors were either KRAS wild-type (wt), or EGFR mutated. Forty-six percent of enrolled patients had an EGFR mutation, RR was 42%, and disease control was 86% (55% and 94%, respectively in EGFR mutation-positive patients). PFS is not mature. A phase II trial comparing dacomitinib with erlotinib in 188 patients with advanced NSCLC favored dacomitinib with a median PFS of 3.0 versus 2.0 months. The PFS was 3.8 versus 2.0 months in the KRAS wt cohort and OS was 9.9 versus 7.7 months. The phase III Archer trial comparing dacomitinib with erlotinib as second- or third-line therapy for patients with advanced NSCLC is ongoing. CO1686 is an oral small-molecule mutant-selective irreversible inhibitor of EGFR. Dr. Camidge reported on two phase I/II trials with CO1686, which are currently open or in development; a phase I trial for patients with known EGFR mutations is open in the dose-escalation phase, and a trial for patients who are T790M positive will open in the expansion phase. AZD8931 is an oral small-molecule pan-ErbB inhibitor. Dr. Nash presented phase I studies with AZD8931 alone in all patients with advanced malignancies and in combination with paclitaxel in breast cancer patients. MM151 is an oligoclonal therapeutic consisting of a mixture of three fully human monoclonal antibodies designed to bind to nonoverlapping epitopes of EGFR. Dr. Nielsen presented preclinical data on this agent that is currently in early phase I clinical trials. TABLE 1Ongoing Clinical Trials of HER1–3 targeting agents in NSCLCDrugTargetMode of AdministrationStudies Open to EnrollmentSmall-Molecule InhibitorsAfatinibHER1–3Oral NCT00809133aDenotes phase I trial.NCT01480141aDenotes phase I trial.NCT01466660NCT01156545NCT01523587NCT00993499NCT01542437NCT01090011NCT01074177DacomitinibHER 1–3OralNCT01360554CO1686EGFR and T790MOral NCT01465802NCT00818441NCT01526928aDenotes phase I trial.AZD8931HER2 and HER3NoneMM151HER1/EGFRIVNCT01520389aDenotes phase I trial.ARRY380HER2OralNoneNeratinibHER2OralNoneAntibodiesCetuximabHER1/EGFRIV NCT01109524NCT00408499NCT00946712NCT01263782NCT01059188NCT01212627NCT00985855NCT01102231NCT00842712NCT01090011NCT01451632aDenotes phase I trial.NecitumumabEGFRIV NCT01184482aDenotes phase I trial.NoneMM302HER2IVNoneMM111HER2IVNCT01304784aDenotes phase I trial.AVO203HER3IVNoneMM121HER3IV NCT00994123NCT01447225aDenotes phase I trial.NCT01451632aDenotes phase I trial.NCT00734305aDenotes phase I trial.NCT01436565aDenotes phase I trial.U3–1287HER3IVNCT01211483a Denotes phase I trial. Open table in a new tab Afatinib in HER2 positive NSCLC was presented by Dr. Chand. A phase II trial of single-agent afatinib in HER2 positive NSCLC patients is ongoing. Dr. Kris presented an ongoing phase II trial of dacomitinib in NSCLC patients who are either EGFR mutation positive, HER2 mutation positive, or HER2 amplified. ARRY380 is a small-molecule inhibitor of HER2. Dr. Winkler presented a phase I dose-escalation study of ARRY380 that established an maximum tolerated dose of 600 mg twice daily. This dose has been administered to an expansion cohort of patients with metastatic breast cancer. Dr. Winkler queried the audience as to whether there is need to evaluate ARRY380 in NSCLC patients with activating HER2 mutations. Neratinib (HKI272) is an irreversible Pan-ErbB inhibitor. Dr. Gandhi presented a phase I trial of neratinib and temsirolimus (a mammalian target of rapamycon inhibitor) in HER2 mutant NSCLC patients with encouraging clinical activity—disease control in five of six evaluable HER2 NSCLC patients and median time to progression of 5.62 months. Cetuximab is a monoclonal antibody that was shown to improve overall survival when added to chemotherapy (cisplatin/vinorelbine) in patients with stage IV NSCLC.11Pirker R Pereira JR Szczesna A et al.Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.Lancet Oncol. 2009; 373: 1525-1531Abstract Full Text Full Text PDF Scopus (1255) Google Scholar Dr. Herbst provided an update on open NSCLC trials evaluating cetuximab. Dr. Hirsch discussed the reproducibility of immunohistochemistry scores and staining for EGFR. He also presented on necitumumab, a fully human IgG1 monoclonal antibody directed against EGFR currently in phase III clinical trials; the INSPIRE trial has closed because of safety concerns whereas the SQUIRE trial, a randomized phase III study of cisplatin/gemcitabine with or without necitumumab in patients with squamous carcinoma of the lung, remains open. Two antibodies that target HER2 were presented by Dr. Nielsen. MM302, a nanotherapeutic encapsulation of doxorubicin with attached HER2 antibodies that are designed to target MM302 specifically to cells with HER2 overexpression. Phase I trials of this agent, in patients with breast cancer, are ongoing. MM111, a biospecific antibody that targets cells that overexpress HER2 is also in phase I trials in combination with other HER2 inhibitors and chemotherapy in patients with solid tumors. A randomized phase II trial with trastuzumab and paclitaxel with or without MM111 in breast cancer patients is ongoing. AVO-203 is a humanized ErbB-3 inhibitor antibody. Dr. Vincent presented preclinical data demonstrating potent in vitro and in vivo antitumor activity. The company will be filing for an investigational new drug in 2012. MM121 is a fully humanized IgG2 antibody with high affinity for ErbB-3. Dr. Sequist presented a phase I study of MM121 in combination with erlotinib, which has been completed and will be presented later this year. A phase II trial of erlotinib, with or without MM121, is ongoing with three patient cohorts: (1) EGFR mutation positive; and (2) EGFR wt cohorts will be randomized to erlotinib with or without MM121, (3) patients with acquired resistance to erlotinib will be treated with erlotinib + MM121. U3-1287 is a fully humanized anti-HER monoclonal antibody. Dr. von Pawel presented on a phase Ib/II trial of combination erlotinib and U3-1297. The phase Ib portion of the trial reported a best response of stable disease in four patients, lasting from 83 to 117 days. The phase II trial of erlotinib with or without U3-1287 is ongoing with a planned enrollment of 195 patients. The HER family of receptors remains an important target in lung cancer. Agents that effectively overcome or delay acquired resistance in EGFR mutation-positive NSCLC patients with acceptable toxicities are still needed. HER2 represents a relatively new target in NSCLC patients, and the role of antibodies versus TKIs remains to be determined. Acquired resistance will also emerge as an issue in this patient population. The role of HER3 antibodies in the treatment of lung cancer patients remains under active investigation.