Joo Hyuk Sohn

Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial

BACKGROUND The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy. METHODS In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/kg [DOSAGE ERROR CORRECTED], subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m(2)) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358. FINDINGS 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1-59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5%; 22·4-37·5]; difference 21·1%, 9·1-34·2, p=0·0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24·7%, 18·1-32·3]) and the trastuzumab (difference -4·8%, -17·6 to 8·2, p=0·34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23·4%]) and lapatinib plus trastuzumab (32 [21·1%]) than with trastuzumab (three [2·0%]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17·5%]) and lapatinib plus trastuzumab (15 [9·9%]) than with trastuzumab (11 [7·4%]). INTERPRETATION Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting. FUNDING GlaxoSmithKline.

Phase III Study of Bevacizumab Plus Docetaxel Compared With Placebo Plus Docetaxel for the First-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer

PURPOSE The efficacy and safety of combining bevacizumab (7.5 and 15 mg/kg) with docetaxel as first-line therapy for human epidermal growth factor receptor 2 (HER2) -negative, locally recurrent or metastatic breast cancer (MBC) was investigated in a three-arm, placebo-controlled, phase III trial. PATIENTS AND METHODS Patients (N = 736) were randomly assigned to docetaxel 100 mg/m(2) plus either placebo or bevacizumab 7.5 or 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS); secondary end points included best overall response, duration of response, time to treatment failure, overall survival, and safety. RESULTS Combination of bevacizumab 15 mg/kg, but not 7.5 mg/kg, with docetaxel showed superior median PFS (mPFS) to placebo plus docetaxel in unstratified analysis (placebo mPFS, 8.2 months; 7.5 mg/kg mPFS, 9.0 months [hazard ratio (HR), 0.86; P = .12]; 15 mg/kg mPFS, 10.1 months [HR, 0.77; P = .006]) and stratified analysis (placebo mPFS, 8.1 months; 7.5 mg/kg mPFS, 9.0 months [HR, 0.80; P = .045]; 15 mg/kg mPFS, 10.0 months [HR, 0.67; P < .001]). Response rates in patients with measurable disease at baseline also increased with bevacizumab 15 mg/kg (46% [placebo] v 55% [7.5 mg/kg; P = .07] and 64% [15 mg/kg; P < .001]). Combination with bevacizumab had limited impact on the known toxicity profile of docetaxel. CONCLUSION Combination of bevacizumab with docetaxel did not significantly impact on the safety profile of docetaxel. Bevacizumab 15 mg/kg every 3 weeks significantly increased PFS when combined with docetaxel as first-line therapy for MBC compared with docetaxel plus placebo.

Continuous separation of breast cancer cells from blood samples using multi-orifice flow fractionation (MOFF) and dielectrophoresis (DEP)

Circulating tumor cells (CTCs) are highly correlated with the invasive behavior of cancer, so their isolations and quantifications are important for biomedical applications such as cancer prognosis and measuring the responses to drug treatments. In this paper, we present the development of a microfluidic device for the separation of CTCs from blood cells based on the physical properties of cells. For use as a CTC model, we successfully separated human breast cancer cells (MCF-7) from a spiked blood cell sample by combining multi-orifice flow fractionation (MOFF) and dielectrophoretic (DEP) cell separation technique. Hydrodynamic separation takes advantage of the massive and high-throughput filtration of blood cells as it can accommodate a very high flow rate. DEP separation plays a role in precise post-processing to enhance the efficiency of the separation. The serial combination of these two different sorting techniques enabled high-speed continuous flow-through separation without labeling. We observed up to a 162-fold increase in MCF-7 cells at a 126 µL min(-1) flow rate. Red and white blood cells were efficiently removed with separation efficiencies of 99.24% and 94.23% respectively. Therefore, we suggest that our system could be used for separation and detection of CTCs from blood cells for biomedical applications.

Phase II Study of Erlotinib in Advanced Non–Small-Cell Lung Cancer After Failure of Gefitinib

PURPOSE This study was designed to evaluate the efficacy and toxicity of erlotinib in patients with advanced non-small-cell lung cancer (NSCLC) who experienced disease progression after treatment with gefitinib. PATIENTS AND METHODS The study included stage IIIB/IV recurrent or metastatic NSCLC patients who received two or three prior chemotherapy regimens and showed progressive disease within 4 months of gefitinib therapy discontinuation. Patients received erlotinib 150 mg/d until disease progression or unacceptable toxicity. Epidermal growth factor receptor (EGFR) mutations and other genetic abnormalities were analyzed from available tumor samples. RESULTS Patient and disease characteristics (N = 21) included median age 56 years; number of prior chemotherapy regimens (three; n = 11); female sex (n = 11); adenocarcinoma (n = 15); and never-smoker status (n = 11). Among the 17 patients with tumor samples available, EGFR mutations were detected in five. The disease control rate (DCR) and response rate (RR) for all patients were 28.6% and 9.5%, respectively. The median duration of disease control was 125 days. The median time to progression and overall survival were 60 days and 158 days, respectively. Patients who had stable disease (SD) while receiving gefitinib showed significantly higher DCR (75% v 17.6% in non-SD patients; P = .050) and RR (50.0% v 0% in non-SD patients; P = .029). Among 17 patients with biomarker results available, those lacking EGFR mutations who had SD while receiving gefitinib showed significantly higher DCR and RR. CONCLUSION Erlotinib seems to be a potential therapeutic option for the treatment of advanced NSCLC patients with wild-type EGFR who had SD while receiving gefitinib.

MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy.

Purpose MONARCH 2 ( ClinicalTrials.gov identifier: NCT02107703) compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, plus fulvestrant with fulvestrant alone in patients with advanced breast cancer (ABC). Patients and Methods MONARCH 2 was a global, double-blind, phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), ≤ 12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease. Patients were randomly assigned 2:1 to receive abemaciclib or placebo (150 mg twice daily) on a continuous schedule and fulvestrant (500 mg, per label). The primary end point was investigator-assessed progression-free survival (PFS), and key secondary end points included overall survival, objective response rate (ORR), duration of response, clinical benefit rate, quality of life, and safety. Results Between August 2014 and December 2015, 669 patients were randomly assigned to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). Abemaciclib plus fulvestrant significantly extended PFS versus fulvestrant alone (median, 16.4 v 9.3 months; hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P < .001). In patients with measurable disease, abemaciclib plus fulvestrant achieved an ORR of 48.1% (95% CI, 42.6% to 53.6%) compared with 21.3% (95% CI, 15.1% to 27.6%) in the control arm. The most common adverse events in the abemaciclib versus placebo arms were diarrhea (86.4% v 24.7%), neutropenia (46.0% v 4.0%), nausea (45.1% v 22.9%), and fatigue (39.9% v 26.9%). Conclusions Abemaciclib at 150 mg twice daily plus fulvestrant was effective, significantly improving PFS and ORR and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who progressed while receiving ET.

Ad-mTERT-Δ19, a Conditional Replication-Competent Adenovirus Driven by the Human Telomerase Promoter, Selectively Replicates in and Elicits Cytopathic Effect in a Cancer Cell-Specific Manner

Human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, functions to stabilize telomere length during chromosomal replication. Previous studies have shown that hTERT promoter is highly active in most tumor and immortal cell lines but inactive in normal somatic cell types. The use of wild-type hTERT promoter, however, may be limited by its inability to direct high level and cancer cell-specific expression necessary for effective targeted gene therapy. To improve cancer cell specificity and the strength of the hTERT promoter, a modified hTERT, m-hTERT promoter was generated in which additional copies of c-Myc and Sp1 binding sites were incorporated adjacent to the promoter. As assessed using relative lacZ expression, hTERT and m-hTERT promoter activity was significantly upregulated in cancer cells but not in normal cells, and within these upregulated cancer cells, m-hTERT promoter strength was substantially higher than that of the wild-type hTERT. Next, to restrict viral replication to tumor cells, a conditional replication-competent adenoviruses, Ad-TERT-Delta19 and Ad-mTERT-delta19 were generated in which the E1A gene, which is essential for viral replication, was placed under the control of the hTERT and m-hTERT promoter, respectively. While the wild-type Ad-TERT-delta19 replicated in and induced cytopathic effect in cancer and in some normal cell lines, Ad-mTERT-delta19 enhanced viral replication and cytopathic effect only in cancer cells. Furthermore, the growth of established human cervical carcinoma in nude mice was significantly suppressed by intratumoral injection of Ad-mTERT-delta19. Taken together, present results strongly suggest that the use of the m-hTERT promoter is not only useful in the regulation of therapeutic gene expression but also that replication-competent oncolytic adenovirus under the control of the m-hTERT promoter may be a new promising tool for the treatment of human malignancies.

Concurrent delivery of GM-CSF and B7-1 using an oncolytic adenovirus elicits potent antitumor effect

Oncolytic adenoviral vectors are currently being developed as biologic anticancer agents. Coupling the lytic function of an oncolytic adenovirus (Ad) with its ability as a transgene delivery system represents a powerful extension of this methodology. A clear advantage is the amplification of a therapeutic gene, as replicating vectors would be able to infect and deliver the gene of interest to neighboring cells. Granulocyte–macrophage colony-stimulating factor (GM-CSF) is one of the most potent stimulators of a specific and long-lasting antitumor immunity and its important role in the maturation of antigen-presenting cells to induce T-cell activation has been well documented. Similarly, the B7 family has also been shown to play an integral role in mediating an antitumor response. Most tumor cells, however, lack the expression of these costimulatory molecules on their surface, thus escaping immune system recognition. To increase the antitumor effect of an oncolytic Ad, we have generated an E1B 55 kDa-deleted oncolytic adenoviral vector, YKL-GB, that expresses both GM-CSF and B7-1. The therapeutic efficacy of YKL-GB Ad was evaluated in immunocompetent mice bearing murine melanoma B16-F10 tumors. Significant inhibition of tumor growth was seen in mice treated with YKL-GB compared to those treated with the analogous vector, YKL-1. Moreover, YKL-GB oncolytic Ad demonstrated enhanced antitumor activity and higher incidences of tumor regression compared to a replication-incompetent Ad, dl-GB, which coexpresses GM-CSF and B7-1. Localized GM-CSF and B7-1 gene transfer also conferred long-lasting immunity against a tumor re-challenge. To establish that the observed antitumor effect is associated with the generation of a tumor-specific immune response, we carried out interferon-γ enzyme-linked immune spot assay. We observed that YKL-GB induced significantly higher immune cell activation than YKL-1. Furthermore, immunohistochemical studies demonstrated robust dendritic cells and CD4+/CD8+ T-cell infiltration in these mice compared to the YKL-1-treated groups. In agreement with these results, splenocytes from tumor-bearing mice treated with YKL-GB expressed high levels of the costimulatory and activation molecules. These findings demonstrate the effectiveness of enhancing the immune response against tumors with an oncolytic Ad expressing both GM-CSF and B7-1 and provide a potential therapeutic strategy for the management of neoplasia.

MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer

This report describes the results of an analysis of patient‐reported outcomes from EMILIA (TDM4370g/BO21977), a randomized phase 3 study of the antibody–drug conjugate trastuzumab emtansine (T‐DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2 (HER2)–positive locally advanced or metastatic breast cancer.

Active targeting and safety profile of PEG-modified adenovirus conjugated with herceptin

PEGylation of adenovirus (Ad) increases plasma retention and reduces immunogenicity, but decreases the accessibility of virus particles to target cells. We tested whether PEGylated Ad conjugated to Herceptin (Ad-PEG-HER) can be used to treat Her2/neu-positive cells in vitro and in vivo to demonstrate the therapeutic feasibility of this Ad formulation. Ad-PEG-HER transduced Her2/neu-overexpressing cancer cells through a specific interaction between Herceptin and Her2/neu. Ad-PEG-HER treatment resulted in higher plasma retention and lower neutralizing antibody and IL-6 production than naked Ad. This formulation was extended to generate a Her2/neu-targeted, PEGylated oncolytic Ad (DWP418-PEG-HER). DWP418-PEG-HER specifically killed Her2/neu-positive cells and performed better than non-targeted and naked Ad in vivo. DWP418-PEG-HER showed a 10(10)-fold increase in the liver to tumor biodistribution compared with naked Ad. Immunohistochemical staining confirmed accumulation of Ad E1A in tumors. These data suggest that targeted gene therapy with the PEGylated Ad conjugated with Herceptin might shed a light on its therapeutic application for metastatic cancer in the future.