Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).
Although the combination of gemcitabine and radiation produces a high frequency of complete responses in the treatment of locally advanced head and neck cancer, substantial toxicity suggests that an improvement in the therapeutic index is required. The purpose of this study was to determine if gefitinib could improve the efficacy of gemcitabine and if drug schedule is important. We hypothesized that gemcitabine followed by gefitinib would be superior to the opposite order because of both cell cycle and growth factor signaling interactions. Using UMSCC-1 cells in vitro, we confirmed that gefitinib arrested cells in G 1 and suppressed phospho-epidermal growth factor receptor (p Y845 EGFR) and that gemcitabine arrested cells in S phase and stimulated p Y845 EGFR. The schedule of gemcitabine followed by gefitinib caused arrest of cells in S phase. Gefitinib suppressed gemcitabine-mediated p Y845 EGFR stimulation. This schedule caused decreased p S473 AKT, increased poly(ADP-ribose) polymerase cleavage, and increased apoptosis compared with gemcitabine alone. The schedule of gefitinib followed by gemcitabine also caused suppression of p Y845 EGFR but arrested cells in G 1 . This schedule in which gefitinib was used first was associated with stable levels of p S473 AKT and minimal poly(ADP-ribose) polymerase cleavage and apoptosis. These results were reflected in experiments in nude mice bearing UMSCC-1 xenografts, in which there was greater tumor regression and apoptosis when animals received gemcitabine followed by gefitinib during the first week of therapy. These findings suggest that the schedule of gemcitabine followed by gefitinib may increase the therapeutic index over gemcitabine alone and, combined with clinical data, encourage exploration of combination of gemcitabine, EGFR inhibitors, and radiation. (Cancer Res 2006; 66(2): 981-8)
We have recently reported that treatment with gemcitabine, a potent chemotherapeutic agent and radiation sensitizer, stimulates phosphorylation of the epidermal growth factor receptor (EGFR). Because phosphorylation of EGFR is known to precede receptor degradation, we hypothesized that gemcitabine treatment may also result in EGFR degradation. In two human head and neck cancer cell lines, UMSCC-1 and UMSCC-6, we demonstrated an approximately 80% decrease in total EGFR levels at 72 h after a 2-h treatment with 1 lM gemcitabine. Neither cisplatin nor 5-fluorouracil, which are used to treat head and neck cancer, caused EGFR degradation. EGFR downregulation did not occur at the level of transcription, as assessed by reverse transcription-polymerase chain reaction (RT-PCR), but instead occurred via phosphorylation and ubiquitination of the receptor along a proteosome/lysosome-mediated pathway. Inhibition of EGFR degradation, by either pretreatment with the EGFR tyrosine kinase inhibitor gefitinib or by exposure to the proteosome/lysosome inhibitor MG132, significantly reduced gemcitabine-induced cell death. These results suggest that EGFR degradation may be a novel mechanism for gemcitabine-mediated cell death. These findings also indicate that caution should be exercised when combining gemcitabine with agents that may prevent EGFR degradation, such as EGFR tyrosine kinase inhibitors administered in a suboptimal sequence or proteosome inhibitors.
Purpose: To optimally integrate epidermal growth factor receptor (EGFR) inhibitors into the clinical treatment of head and neck cancer, two important questions must be answered: (a) does EGFR inhibition add to the effects of radiochemotherapy, and (b) if so, which method of inhibiting EGFR is superior (an EGFR antibody versus a small molecule tyrosine kinase inhibitor)? We designed an in vivo study to address these questions. Experimental Design: Nude mice with UMSCC-1 head and neck cancer xenografts received either single, double, or triple agent therapy with an EGFR inhibitor (either cetuximab or gefitinib), gemcitabine, and/or radiation for 3 weeks. Tumor volumes and animal weights were measured for up to 15 weeks. Immunoblotting and immunofluorescent staining were done on tumors treated with either cetuximab or gefitinib alone. Results: The addition of an EGFR inhibitor significantly delayed the tumor volume doubling time, from a median of 40 days with radiochemotherapy (gemcitabine and radiation) alone, to 106 days with cetuximab and 66 days with gefitinib (both P < 0.005). Cetuximab resulted in significantly less weight loss than gefitinib. Immunoblot analysis and immunofluorescent staining of tumors show that although levels of phosphorylated AKTand extracellular signal^regulated kinase were decreased similarly in response to cetuximab or gefitinib, cetuximab caused prolonged suppression of pEGFR, pSTAT3, and Bcl XL compared with gefitinib. Conclusions: EGFR inhibition, particularly with cetuximab, improves the effectiveness of radiochemotherapy in this model of head and neck cancer. The correlation of response with prolonged suppression of EGFR, STAT3, and Bcl XL offers the possibility that these may be candidate biomarkers for response.The epidermal growth factor receptor (EGFR) is overexpressed in a wide variety of solid tumors, including 80% to 90% of squamous cell carcinomas of the head and neck. High tumor EGFR levels have been associated with aggressive clinical features in a number of malignancies; in head and neck cancers, these characteristics include decreased survival, advanced stage, increased tumor size, decreased radiosensitivity, and increased risk of recurrence (1, 2). On a molecular level, EGFR activation results in the initiation of key intracellular signaling pathways that promote malignant behavior, including survival, proliferation, and cell cycle progression. Given its correlation with poor clinical outcome and its role in oncogenic transformation, activated EGFR has emerged as a leading target in anticancer therapy, encouraging the development of monoclonal antibodies and low -molecular weight tyrosine kinase inhibitors (TKI) specifically directed against the receptor.Although there is a strong rationale for therapy based on EGFR inhibition, monotherapy with EGFR inhibitors has met with only limited success, with response rates between 5% and 15% in recurrent or metastatic head and neck cancer (3, 4). Therefore, EGFR inhibitors are now being combined on an empirical basis ...
Background: AMV564 is a novel bivalent, bispecific (2:2) CD33/CD3 T-cell engager that binds CD33 on target cells and CD3 on T-cells leading to T-cell-directed lysis of CD33+ leukemic blasts and myeloid derived suppressor cells (MDSCs), as well as T-cell expansion, differentiation and proliferation. By design, AMV564 has reduced clearance and therefore has a longer half-life (t1/2) than monovalent, bispecific T-cell engagers. In preclinical investigations using both leukemic cell lines and primary cells from AML patients, AMV564 eliminated myeloid blasts with picomolar potency and broad activity independent of cytogenetic or molecular abnormalities, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res. 2016;22:5829-38). Methods: This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), cytokine changes, and immunophenotyping are secondary objectives. Key inclusion/exclusion criteria are: adults with relapsed/refractory AML after 1-2 prior induction regimens (with a standard anthracycline-based regimen or hypomethylating agent) and no more than 2 prior salvage regimens. AMV564 is administered by continuous intravenous infusion (CIV) for 14 consecutive days over a 28 day cycle, with prophylactic antiemetics, antipyretics, and antihistamines. AMV564 and cytokine (IL2, IL4, IL6, IL8, IL10, TNF-α, and IFN-γ) concentrations were measured by validated immunoassays. T-cell activation was measured using flow cytometry to quantify T cells expressing CD25, CD38, CD69, or HLA-DR. Results: To date, 36 patients (20 male/16 female) with a median age of 71 years (range 24-85 years) have been enrolled in 10 dose cohorts from 0.5 to 300 mcg/day. Twenty-four patients (67%) had secondary AML and/or adverse cytogenetics, including 9 patients (25%) with a TP53 mutation. Fourteen patients (39%) had received at least 1 prior salvage regimen and 23 (64%) had received prior intensive chemotherapy, including 13 patients (36%) who had received a high-dose (≥ 1 g/m2) cytarabine-based regimen and 1 patient (3%) with prior allogeneic stem cell transplant. At the time of this analysis, 36 patients were evaluable for safety and 35 patients were evaluable for activity. No dose-limiting toxicities were reported. Median duration of treatment was 20 days (range 3-204 days). Using a lead-in dose escalation schedule, no Grade 3 or higher cytokine release syndrome has been observed. The most common Grade ≥3 treatment-emergent AE has been anemia, reported in 4 (11%) patients. No patient has died within 30 days of treatment initiation. Bone marrow blast reductions have been observed in 17 (49%) of 35 efficacy evaluable patients. Objective responses have been observed including 1 complete response (CR) during cycle 1 at the 200 mcg/day assigned dose, 1 CRi (CR with incomplete hematologic recovery) during cycle 2 at the 150 mcg/day assigned dose, and 1 partial response (PR) during cycle 1 at the 100 mcg/day assigned dose. In addition, 3 patients had hematologic improvement in neutrophil counts. AMV564 PK was dose proportional through the 100 mcg/day dose level with a terminal half-life of 2-3 days. Serum concentrations increased gradually, with times to steady-state concentration of 3-7 days. T-cell redistribution from the periphery upon initiation of dosing (consistent with T-cell activation) was observed, as was evidence of increased bone marrow T-cells with repeated cycles of treatment. Conclusions: AMV564 is well-tolerated and demonstrates anti-leukemic activity through T-cell engagement. Disclosures Cortes: Sun Pharma: Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Altman:Novartis: Consultancy; Cancer Expert Now: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PeerView: Speakers Bureau; prIME Oncology: Speakers Bureau; France Foundation: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy; NCCN: Consultancy. Gojo:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Merck: Research Funding; Juno: Research Funding; Amgen Inc: Consultancy, Honoraria, Research Funding; Amphivena: Research Funding. Guenot:Amphivena Therapeutics, Inc.: Employment. Chun:Amphivena Therapeutics, Inc: Employment. Roboz:Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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