Rekombinante Proteine als Therapeutika in derklinischen Onkologie

2011 ◽  
Vol 68 (11) ◽  
pp. 618-630 ◽  
Author(s):  
Martin F. Fey
Keyword(s):  
Monoklonale Antikörper ◽  
Phase Iii ◽  
Rekombinante Proteine ◽  
Her 2

Proteine, die als rekombinante Moleküle der Onkologie zur klinisch-therapeutischen Verfügung stehen, umfassen im Wesentlichen monoklonale Antikörper, Interferone und hämatopoietische Wachstumsfaktoren. Etablierte Antikörper sind Rituximab (Lymphome), Trastuzumab (HER-2 positives Mamma- und Magenkarzinom), Bevacizumab (Antiangiogenese-Faktor bei diversen Tumoren) und ein paar andere - die Liste mehrt sich laufend. Interferone, zunächst mit großen therapeutischen Hoffnungen verknüpft, haben einiges an Bedeutung verloren, beispielsweise in der Behandlung der chronischen myeloischen Leukämie oder der Haarzellenleukämie. Unter den Wachstumsfaktoren gehören G-CSF (Stimulation der Myelopoiese und Gewinnung hämatopoietischer Stammzellen) und teilweise Erythropoietin (Verbesserung der zytostatika-bedingten Anämie) zum onkologischen Alltag. Wie bei allen Medikamenten sind gute kontrollierte klinische Phase-III-Studien erforderlich, um diesen interessanten Substanzen den angemessenen Stellenwert in der klinischen Praxis zuzuteilen. Die hohen Kosten rekombinanter Proteine erfordern zunehmend Kosten-Nutzen-Analysen als Zusatz zu den „klassischen“ Phase-III-Registrierstudien.

scholarly journals Relationship of Serum HER-2/neu and Serum CA 15-3 in Patients with Metastatic Breast Cancer

2002 ◽  
Vol 48 (8) ◽  
pp. 1314-1320 ◽  
Author(s):  
Suhail M Ali ◽  
Kim Leitzel ◽  
Vernon M Chinchilli ◽  
Linda Engle ◽  
Laurence Demers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Surrogate Marker ◽  
Metastatic Breast ◽  
Tumor Burden ◽  
Normal Serum ◽  
Phase Iii ◽  
Breast Cancer Patients ◽  
Serum Samples ◽  
Her 2

Abstract Background: Serum HER-2/neu antigen concentrations have been reported to correlate with increased tumor volume in patients with breast cancer. We measured serum CA 15-3, a surrogate marker of disease burden, and correlated serum CA 15-3 with serum HER-2/neu and analyzed the association of both markers with clinical outcomes. Methods: Pretreatment serum samples from 566 patients were retrospectively analyzed from 2 phase III clinical trials of estrogen receptor-positive (ER+), ER−/progesterone receptor-positive, or ER status unknown metastatic breast cancer patients randomized in two similar studies to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole). The extracellular domain of the HER-2/neu (c-erbB-2) oncogene and serum CA 15-3 were measured by ELISA on the Bayer Immuno 1. Results: Serum HER-2/neu protein was increased in 168 patients (30%), and CA 15-3 was increased in 337 (60%) patients. Serum CA 15-3 and HER-2/neu were weakly correlated (r = 0.39; P <0.0001). The clinical benefit (complete responses plus partial responses plus stable disease) of endocrine therapy was significantly lower in patients with increased serum HER-2/neu. When adjusted for serum HER-2/neu, serum CA 15-3 was not predictive of response rates. The median time to progression was shorter in patients with increased serum HER-2/neu (89 days) compared with patients with normal serum HER-2/neu (176 days). Survival was significantly shorter in patients with increased serum HER-2/neu (513 vs 869 days; P <0.0001) or increased serum CA 15-3 (689 vs 939 days; P <0.0001). This observation was confirmed by multivariate analysis. Conclusions: Serum HER-2/neu is a significant independent predictive and prognostic factor in hormone receptor-positive metastatic breast cancer, even when adjusted for tumor burden as measured by CA 15-3. The combination of increased serum HER-2/neu and increased serum CA 15-3 predicts a worse prognosis than does increased CA 15-3 alone.

Prognostic value of immunohistochemical phenotypes (IP) of 141 operable breast cancer patients (pts) included in phase III trials of adjuvant therapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21040-21040
Author(s):  
R. Trujillo ◽  
E. Gallego ◽  
A. Márquez ◽  
N. Ribelles ◽  
J. Trigo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cox Regression ◽  
Phase Iii ◽  
Rank Test ◽  
Prognostic Effect ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Phase Iii Trials ◽  
Her 2

21040 Background: Gene expression arrays and IP studies classified breast cancer in three distinct subtypes: basal, HER2/neu and luminal that are associated with different clinical outcomes. Methods: In 141 pts with operable breast cancer, included in phase III trials of adjuvant therapy in our center, immunohistochemical staining was performed on 3μm sections of paraffin blocks, containing tissue-arrays of tumour tissue.A basal phenotype (BP) was defined by negative estrogen receptor (ER) and progesterone receptor (PR) and positive cytokeratin (CK) 5/6 or EGFR immunoreactivity. HER2/neu phenotype as positive c-erb B2 by HercepTest™ and luminal phenotype (LP) by positive ER, PR and CK 7/8 and negative HER-2. Survival curves were calculated by the Kaplan-Meier method. The differences between survivals were estimated using the log rank test. Multivariate Cox regression analysis was used to evaluate any independent prognostic effect of the variables on disease-free survival (DFS). Results: Complete clinical follow-up information was available for 141 pts. The median follow-up period was 52 months (range 1–103 months). During this period, 13.8% pts died from breast cancer and 27.7% pts relapsed. At the time of the primary diagnosis 10.4% of the pts had lymph node negative disease and 89.6% had positive lymph nodes. 50.8% pts received taxane chemotherapy, 7.7% Trastuzumab, 62.3% radiotherapy and 61% pts received hormonotherapy. Positivity for LP was 65.2%, BP 9.9% and Her-2 phenotype 8.5%. 16.3% didn't fit for any of the three subtypes. Median DFS for BP: 24 moths, for LP and Her-2 phenotypes median DFS was not reached. 5 years DFS were; BP: 19%, LP: 63% and Her-2: 56%. Kaplan-Meier survival analyses demonstrated that the presence of a detectable BP was highly significantly associated with a worse DFS compared with the presence of a LP, log rank test (p= 0.0001). Multivariate Cox regression analyses estimated that the prognostic effect of BP in relation to DFS was independent of lymph node, stage and tumor size, HR: 0.12 95% CI (0.05–0.2). Conclusions: We found that expression of BP was associated with poor prognostic in the context of randomized phase III trials. No significant financial relationships to disclose.

Gemcitabine plus docetaxel versus docetaxel in patients (pts) with HER2-negative locally advanced or metastatic breast cancer (MBC): A randomized phase III study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1015-1015
Author(s):  
D. L. Nielsen ◽  
S. T. Langkjer ◽  
K. Bjerre ◽  
S. Cold ◽  
L. Stenbygaard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Agent ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Rank Test ◽  
Hematologic Toxicity ◽  
Phase Iii Study ◽  
Her 2 ◽  
Grade 3

1015 Background: Gemcitabine (G), either as a single agent or in combination with taxanes, has demonstrated efficacy in MBC in phase II and III studies. We conducted a phase III study to compare time to progression (TTP) of G plus docetaxel (T) versus (vs.) T alone. The secondary endpoints included overall survival (OS), overall response rate (ORR), and toxicity. Methods: Females with HER-2-negative locally advanced or MBC and a WHO performance status ≤ 2 were randomized to GT (G 1,000mg/m2 day 1 + 8; T 75mg/m2 day 1) or T (100mg/m2 day 1) every 21 days. Pts were previously untreated, had prior anthracycline-based (neo)adjuvant chemotherapy or had received a single prior anthracycline-bsed chemotherapy regimen for MBC. Time-to-event endpoints were estimated using the Kaplan-Meier method, and the log-rank test was applied for comparisons between regimens. The planned sample size was 254 evaluable pts with α I and β of 0.05 and 0.90, respectively. Results: A total of 336 pts were randomized (170 GT; 166 T), data from one centre are yet missing and the present evaluation is based on data from 306 pts (155 GT; 151 T). The pts had a median age of 58 years in both regimens; range 36–73 years and 30–74 years, respectively. The median TTP was 7.5 months for the GT regimen vs. 6.5 months for the T regimen. The GT arm demonstrated an ORR of 44% vs. 38% in the T arm with 4 and 3 % complete responses, respectively. The OS was 13.4 vs. 13.2 months in the GT and T arm, respectively. Hematologic toxicity was common, especially grade 3–4 neutropenia (GT = 69%; T = 61%); infection was reported in 22 and 20% of the pts, respectively (none of the pts received G-CSF). The most commonly reported non-hematologic toxicities of grade 3–4 included mucositis (GT = 2%; T = 5%), diarrhea (GT = 4%; T = 7 %), fatigue (GT = 6%; T = 11%), oedema (GT = 10%; T = 3%), and peripheral neuropathy (GT = 9%; T = 28%). Conclusions: Preliminary data of GT as first- or second-line chemotherapy demonstrates a TTP advantage among HER-2-negative pts with advanced breast cancer. Updated results and proper statistical analyses will be presented. No significant financial relationships to disclose.

Assessment of ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients (pts) with advanced HER2-negative gastric or gastroesophageal junction cancers: The ARMANI phase III trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4151-TPS4151 ◽  
Author(s):  
Federica Morano ◽  
Monica Niger ◽  
Salvatore Corallo ◽  
Sara Lonardi ◽  
Stefano Tamberi ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Phase Iii Trial ◽  
First Line Therapy ◽  
Line Therapy ◽  
Her 2

TPS4151 Background: Platinum/fluoropyrimidine regimens are the backbone of first-line therapy for advanced gastric cancer (AGC). The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only 40% of AGC pts are eligible for second-line treatment. This study aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after a first-line with a platinum/fluoropyrimidine regimen. The hypothesis is that the early administration of an active, non-cross resistant regimen may delay disease progression and, consequently, improve pts’ quality of life. This strategy may also rescue all those subjects that become ineligible for a second-line therapy due to the rapid clinical deterioration. Methods: This is a randomized, open-label, multicenter, phase III trial. Eligibility criteria are: unresectable/metastatic HER-2 negative AGC or gastroesophageal junction (GEJ) cancer; ECOG PS 0-1; measurable and/or evaluable disease by RECIST v1.1; no progression after 3 months of therapy with either FOLFOX4, mFOLFOX6 or XELOX . The primary endpoint is to compare PFS of pts in ARM A (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine) versus ARM B (switch maintenance to ramucirumab and placlitaxel). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of pts receiving a second-line therapy per treatment arm, safety and quality of life. Exploratory analyses to identify primary resistance and prognosis biomarkers are planned, including Next-Generation Sequencing (NGS) on archival tumor tissues. The ARMANI study is sponsored by the Fondazione IRCCS Istituto Nazionale dei Tumori and it is ongoing at 29 Italian centers with a planned population of 280 pts. Clinical trial information: NCT02934464.

scholarly journals Phase III, Double-Blind, Randomized Study Comparing Lapatinib Plus Paclitaxel With Placebo Plus Paclitaxel As First-Line Treatment for Metastatic Breast Cancer

2008 ◽  
Vol 26 (34) ◽  
pp. 5544-5552 ◽  
Author(s):  
Angelo Di Leo ◽  
Henry L. Gomez ◽  
Zeba Aziz ◽  
Zanete Zvirbule ◽  
Jose Bines ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Phase Iii ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Her 2 ◽  
Epidermal Growth

PurposeLapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2–positive locally advanced or metastatic breast cancer (MBC). This phase III trial evaluated the efficacy of lapatinib in HER-2–negative and HER-2–uncharacterized MBC.Patients and MethodsWomen with MBC were randomly assigned to first-line therapy with paclitaxel 175 mg/m2every 3 weeks plus lapatinib 1,500 mg/d or placebo. A preplanned retrospective evaluation of HER-2 status was performed using fluorescence in situ hybridization and immunohistochemistry. The primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS), and overall survival (OS).ResultsIn the intent-to-treat population (n = 579), there were no significant differences in TTP, EFS, or OS between treatment arms, although differences in ORR and CBR were noted. In 86 HER-2–positive patients (15%), treatment with paclitaxel-lapatinib resulted in statistically significant improvements in TTP, EFS, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any end point in HER-2–negative patients. The most common adverse events were alopecia, rash, and diarrhea. The incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm. The rate of cardiac events was low, and no difference was observed between treatment arms.ConclusionPatients with HER-2–negative or HER-2–untested MBC did not benefit from the addition of lapatinib to paclitaxel. However, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2–positive patients. Prospective evaluation of the efficacy and safety of this combination is ongoing in early and metastatic HER-2–positive breast cancer patients.

Impact of single/dual HER2 inhibition and chemotherapy (CT) backbone upon pathologic complete response (pCR) in patients receiving neoadjuvant CT for operable/locally advanced breast cancer (O/LABC): A treatment-interaction analysis of randomized trials.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 630-630
Author(s):  
Jenny Furlanetto ◽  
Vanja Vaccaro ◽  
Chiara Caliolo ◽  
Michele De Laurentiis ◽  
Maria Bonomi ◽  
...  
Keyword(s):  
Significant Interaction ◽  
Interaction Analysis ◽  
Locally Advanced Breast Cancer ◽  
Random Effect ◽  
Locally Advanced ◽  
Random Effect Model ◽  
Pathologic Complete Response ◽  
Phase Iii ◽  
Her 2 ◽  
Dual Inhibition

630 Background: Although the addition of trastuzumab to neoadjuvant CT for O/LABC have dramatically increased pCR, clinical research is moving forward to further improve the overall outcome. In this regard, the DUAL inhibition of the HER-2 pathway and the choice of the best CT backbone may represent an issue to be addressed. Methods: Phase II randomized/Phase III trials were considered. pCR events/rates were extracted from papers/presentation and cumulated (R[pCR]) according to a random-effect model; 95% confidence intervals (CI) were derived. A sensitivity analysis according to SINGLE/DUAL HER-2 inhibition and to administered CT (anthracyclines-taxanes: anthra-TAX; TAX alone) was accomplished, in order to test for interaction. Results: 7 trials (2155 pts) were gathered; 1855 pts were enrolled in arms where anti-HER-2 targeted therapy was administered. HER-2 inhibition was obtained with trastuzumab, lapatinib and pertuzumab (alone or combined). Results according to HER-2 inhibition follow in the table below. With regard to CT, a significant interaction (p=0.0001) in favour of the addition of Anthra to TAX was found in the context of SINGLE HER-2 inhibition subgroup (R[pCR] 46.5%, 95% CI 37-51, vs 26.9%, 95% CI 23-31), while no significant interaction was determined in the context of the DUAL subgroup (R[pCR] 49.0%, 95% CI 26-72, vs 49.0%, 95% CI 43-55). A significant interaction (p=0.0001) in favour of the addition of Anthra to TAX was found for pts receiving trastuzumab (R[pCR] 45.5%, 95% CI 37-53, vs 26.5%, 95% CI 21-32) as well. Conclusions: Although biases in the pCR definition, the DUAL inhibition of HER-2 pathway may significantly increase pCR, regardless of the CT backbone; if confirmed, this strategy allows to reduce toxicities by sparing Anthra. For pts receiving SINGLE HER-2 inhibition, Anthra-TAX-based CT should be still considered the best treatment option. [Table: see text]

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