Metastasiertes Melanom: Nach der Studie ist vor der Studie

2021 ◽  
pp. 1-2
Author(s):  
Jan Maschke
Keyword(s):  
Progression Free Survival ◽  
Mek Inhibitor ◽  
Phase Iii ◽  
Braf Inhibitors ◽  
Free Survival ◽  
Stadium Iv ◽  
Metastasiertes Melanom

Die IMspire150 Studie wurde als Phase III Zulassungsstudie konzipiert und sollte prüfen, ob es bei behandlungsnaiven erwachsenen Patienten mit BRAF-V600-mutierten metastasierten Melanomen (nicht resezierbares klinisches Stadium IIIC-IV, AJCC 2009) einen Unterschied macht, wenn die Erstlinientherapie allein mit der Kombination des BRAF-Inhibitors Vemurafenib (Vem) und dem MEK-Inhibitor Cobimetinib (Cobi) erfolgt oder um den PDL-1 Antikörper Atezolizumab ergänzt wird. Patienten mit unbehandelten oder fortschreitenden Melanom-Hirnmetastasen, anderen aktiven Tumorerkrankungen und schwerwiegenden Autoimmunerkrankungen in der Vorgeschichte wurden ausgeschlossen. Die Randomi­sierung erfolgte 1:1. Der LDH Wert wurde zur Stratifizierung verwendet, Nebenwirkungen wurden gemäß CTCAE 4.0 Kriterien erfasst und als primärer statistischer Endpunkt der Studie wurde das vom Studienarzt bewertete progressionsfreie Überleben (progression-free survival, PFS) gewählt. Die Zwischenanalyse des Gesamtüberlebens der Patienten erfolgte gemäß Protokoll zum Zeitpunkt der Primäranalyse des PFS. Sekundäre Endpunkte waren das PFS, bewertet durch ein unabhängiges Komitee, das objektive Ansprechen, die Dauer des Tumoransprechens, das Gesamtüberleben und die Zeit bis zur Verschlechterung des Gesamtbefindens bzw. der Organfunktionen der Patienten. In den 112 Studienzentren wurden 514 Patienten eingeschlossen (n = 256 Vem/Cobi+Atezolizumab; n = 258 Vem/Cobi); 79% aller Patienten wurden in Europa rekrutiert. In beiden Studienarmen waren ca. 77% der Patienten jünger als 65, hatten einen unauffälligen Allgemeinstatus (ECOG = 0), ca. 94% waren jeweils im Stadium IV (hiervon ca. 60% Stadium M1c) und je 33% hatten einen erhöhten LDH Wert. Zunächst erhielten alle Patienten in beiden Gruppen 2 x tgl. 960mg Vem (2 x tgl. jeweils 4 Tabletten mit 240mg Vem) plus 1 x tgl. 60mg Cobi (1 x tgl. 3 Tabletten mit 20mg Cobi) per os für 21 Tage. Dann wurde Vem bei den Patienten, die in den Atezolizumab-Arm randomisiert worden waren, auf 2 x tgl. 720mg reduziert (3 × 240mg Vem plus je eine Placebotablette), im anderen Arm bei 2 x tgl. 960mg belassen. Cobi wurde zulassungsgemäß in der letzten Woche der 28 Tage dauernden Behandlungszyklen pausiert. In der Atezolizumab-Gruppe erhielten die Patienten an Tag 1 und 15 jeweils 840mg Atezolizumab i.v., in der anderen Gruppe eine Placeboinfusion. Dosismodifikationen und –unterbrechungen waren für Vem und Cobi erlaubt, für Atezolizumab waren allein Behandlungsunterbrechungen erlaubt.

METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS) compared with chemotherapy (C) in patients (pts) with BRAFV600/k mutant advanced or metastatic melanoma (MM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. LBA8509-LBA8509
Author(s):  
Caroline Robert ◽  
Keith T. Flaherty ◽  
Peter Hersey ◽  
Paul D. Nathan ◽  
Claus Garbe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Metastatic Melanoma ◽  
Progression Free Survival ◽  
Mek Inhibitor ◽  
Phase Iii ◽  
Daily News ◽  
Free Survival ◽  
Online Supplement ◽  
Phase Iii Study ◽  
Final Text

LBA8509 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

Clinical Outcomes and Safety of Patients Treated with NAb-Paclitaxel Plus Gemcitabine in Metastatic Pancreatic Cancer: The NAPA Study

2020 ◽  
Vol 20 (11) ◽  
pp. 887-895 ◽  
Author(s):  
Martina Catalano ◽  
Giandomenico Roviello ◽  
Raffaele Conca ◽  
Alberto D’Angelo ◽  
Valeria Emma Palmieri ◽  
...  
Keyword(s):  
Performance Status ◽  
Real Life ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Hematological Toxicity ◽  
Free Survival ◽  
Grade 3 ◽  
Ecog Ps ◽  
Prognostic And Predictive Markers

Background: The phase III MPACT trial demonstrated the superiority of gemcitabine (Gem) combined with Nab-paclitaxel (Nab-P) versus gemcitabine alone in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to evaluate the effect of Gem/Nab-P in routine clinical practice. Methods: From January 2015 to December 2018, patients with metastatic PDAC receiving firstline treatment with a combination of gemcitabine and Nab-paclitaxel were included in a multicentre retrospective observational study. Exploratory analyses of efficacy, and prognostic and predictive markers, were performed. Results: The cohort comprised 115 patients (median age 65 [range 50-84] years) with good performance status (ECOG PS 0-1). The median overall survival (OS) was 11 months (95% CI; 9-13) and the median progression-free survival (PFS) was 6 months (95% CI 5-7). Partial response and stable disease were achieved in 44 and 30 patients, respectively, yielding an overall disease control rate (DCR) of 64.3%. Grade 3-4 hematological toxicity frequency was 22.61% for neutropenia, 5.22% for anemia, and 3.48% for thrombocytopenia. Grade 3 asthenia was recorded in 2.61% of patients. No grade 4 non-hematological events were reported. Dose reduction was necessary in 51.3% of the patients. Conclusions: Our results confirm the efficacy and safety of a first-line regimen comprising gemcitabine and Nab-paclitaxel in metastatic PDAC in a real-life population.

Phase III Study of Intravenous Vinorelbine in Combination With Epirubicin Versus Epirubicin Alone in Patients With Advanced Breast Cancer: A Scandinavian Breast Group Trial (SBG9403)

2004 ◽  
Vol 22 (12) ◽  
pp. 2313-2320 ◽  
Author(s):  
Bent Ejlertsen ◽  
Henning T. Mouridsen ◽  
Sven T. Langkjer ◽  
Jorn Andersen ◽  
Johanna Sjöström ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Response Rate ◽  
Complete Response Rate ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Complete Response ◽  
Phase Iii ◽  
Severe Toxicity ◽  
Free Survival

Purpose To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer. Patients and Methods A total of 387 patients were randomly assigned to receive IV epirubicin 90 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8, or epirubicin 90 mg/m2 IV on day 1. Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity. In addition, epirubicin was discontinued at a cumulative dose of 1,000 mg/m2 (950 mg/m2 from June 1999). Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed. Reported results were all based on intent-to-treat analyses. Results Overall response rates to vinorelbine and epirubicin, and epirubicin alone, were 50% and 42%, respectively (P = .15). The complete response rate was significantly superior in the combination arm (17% v 10%; P = .048) as was median duration of progression-free survival (10.1 months v 8.2 months; P = .019). Median survival was similar in the two arms (19.1 months v 18.0 months; P = .50). Leukopenia related complications, stomatitis, and peripheral neuropathy were more common in the combination arm. The incidences of cardiotoxicity and constipation were similar in both arms. Conclusion Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.

AMEERA-5: A randomized, double-blind phase III study of amcenestrant (SAR439859) + palbociclib versus letrozole + palbociclib for previously untreated ER+/HER2- advanced breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1104-TPS1104
Author(s):  
Aditya Bardia ◽  
Javier Cortes ◽  
Sara A. Hurvitz ◽  
Suzette Delaloge ◽  
Hiroji Iwata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Phase I ◽  
Advanced Breast Cancer ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Phase Iii ◽  
Double Blind ◽  
Free Survival ◽  
Phase Iii Study

TPS1104 Background: Selective estrogen receptor degraders (SERDs) block estrogen receptor (ER) associated signaling and have created interest for treating patients (pts) with advanced ER+ breast cancer (BC). Fulvestrant is currently the only SERD available for advanced BC but requires intramuscular administration, limiting the applied dose, exposure and receptor engagement. Amcenestrant (SAR439859) is an oral SERD that binds with high affinity to both wild-type and mutant ER, blocking estradiol binding and promoting up to 98% ER degradation in preclinical studies. In the phase I AMEERA-1 study of pretreated pts with ER+/HER2- advanced BC, amcenestrant 150–600 mg once daily (QD) showed a mean ER occupancy of 94% with plasma concentrations > 100 ng/mL and a favorable safety profile (Bardia, 2019; data on file). Combination therapy with amcenestrant + palbociclib (palbo) was also evaluated as part of this ongoing phase I study. CDK 4/6 inhibitors (CDK4/6i) combined with an aromatase inhibitor (AI), the gold standard for first line treatment for advanced breast cancer, prolong progression free survival (PFS) in pts with no prior treatment for ER+/HER2- advanced BC, but OS benefit has not been shown yet in postmenopausal pts. There remains a clinical need for more effective treatments in this setting. Methods: AMEERA-5 (NCT04478266) is an ongoing, prospective, randomized, double-blind phase III study comparing the efficacy and safety of amcenestrant + palbo with that of letrozole + palbo in pts with advanced, locoregional recurrent or metastatic ER+/HER2- BC who have not received prior systemic therapy for advanced disease. The study includes men, pre/peri-menopausal (with goserelin) and post-menopausal women. Pts with progression during or within 12 months of (neo)adjuvant endocrine therapy using any of the following agents are excluded: AI, selective estrogen receptor modulators, CDK4/6i. Pts are randomized 1:1 to either continuous amcenestrant 200 mg or letrozole 2.5 mg QD orally with matching placebos; both combined with palbo 125 mg QD orally (d1–21 every 28-d cycle). Randomization is stratified according to disease type (de novo metastatic vs recurrent disease), the presence of visceral metastasis, and menopausal status. The primary endpoint is investigator assessed progression free survival (PFS) (RECIST v1.1). Secondary endpoints are overall survival, PFS2, objective response rate, duration of response, clinical benefit rate, pharmacokinetics of amcenestrant and palbo, health-related quality of life, time to chemotherapy, and safety. Biomarkers will be measured in paired tumor biopsies and cell free deoxyribonucleic acid (cfDNA) over time. Target enrolment = 1066 pts; enrolment as of 1/2021 = 33 pts. Bardia A, et al., J Clin Oncol. 2019; 37 (15 suppl):1054 Clinical trial information: NCT04478266 .

scholarly journals Advanced melanoma, a pharmacological evaluation

2021 ◽  
Vol 31 (Supplement_2) ◽  
Author(s):  
Anabela Andrade ◽  
Jorge Balteiro
Keyword(s):  
Overall Survival ◽  
Targeted Therapy ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Mek Inhibitor ◽  
Advanced Melanoma ◽  
New Drugs ◽  
High Rate ◽  
Free Survival ◽  
Dismal Prognosis

Abstract Background Cutaneous melanoma is an aggressive cancer that occurs in melanocytes, located in the epidermis. Historically it has a high rate of morbidity and mortality, due to the resistance and toxicity of traditional therapies. Its incidence has increased annually by 4% to 8%. Until 2011 it was still considered a devastating and almost always fatal disease in a few months. Advances in therapies have significantly improved the results of most patients with advanced melanoma, especially those with a BRAFV600 mutation, which account for almost 50% of tumors. Before the recent evolution in treatment, the prognosis and overall survival were considered very bad. The introduction of new drugs has improved progression-free survival and overall survival, as well as producing faster clinical responses. Methods Comparison of endpoints such as progression-free survival and overall melanoma survival from the Summary of Product Characteristics (SPC) studies of each drug in the therapeutic groups under assessment used in the disease. The variables used were the Endpoints Global Survival at various times (12 months, 24 months, 36 months and the median) and Progression-Free Survival. Results Combined immunotherapy (Nivolumab and Ipilimumab) improves overall survival and progression-free survival, achieving better results than targeted therapy. In this, the combination of a BRAF inhibitor and a MEK inhibitor, presents better results with the combination of Encorafenib and Binimetinib. Conclusions Both targeted therapy and immunotherapy transform melanoma with a dismal prognosis into a life-threatening illness.

scholarly journals Combined BRAF and MEK Inhibition with Vemurafenib and Cobimetinib for Patients with Advanced Melanoma

2017 ◽  
Vol 13 (01) ◽  
pp. 1
Author(s):  
Antonio M Grimaldi ◽  
Ester Simeone ◽  
Lucia Festino ◽  
Vito Vanella ◽  
Paolo A Ascierto ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Combined Therapy ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Free Survival ◽  
Mek Inhibition ◽  
Braf Mutant

Acquired resistance is the most common cause of BRAF inhibitor monotherapy treatment failure, with the majority of patients experiencing disease progression with a median progression-free survival of 6-8 months. As such, there has been considerable focus on combined therapy with dual BRAF and MEK inhibition as a means to improve outcomes compared with monotherapy. In the COMBI-d and COMBI-v trials, combined dabrafenib and trametinib was associated with significant improvements in outcomes compared with dabrafenib or vemurafenib monotherapy, in patients with BRAF-mutant metastatic melanoma. The combination of vemurafenib and cobimetinib has also been investigated. In the phase III CoBRIM study in patients with unresectable stage III-IV BRAF-mutant melanoma, treatment with vemurafenib and cobimetinib resulted in significantly longer progression-free survival and overall survival (OS) compared with vemurafenib alone. One-year OS was 74.5% in the vemurafenib and cobimetinib group and 63.8% in the vemurafenib group, while 2-year OS rates were 48.3% and 38.0%, respectively. The combination was also well tolerated, with a lower incidence of cutaneous squamous-cell carcinoma and keratoacanthoma compared with monotherapy. Dual inhibition of both MEK and BRAF appears to provide a more potent and durable anti-tumour effect than BRAF monotherapy, helping to prevent acquired resistance as well as decreasing adverse events related to BRAF inhibitor-induced activation of the MAPK-pathway. Combined BRAF and MEK inhibition is the standard of care in patients with advanced BRAF-mutant melanoma.

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