Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial

Dummer, Reinhard; Ascierto, Paolo A.; Gogas, Helen; Arance, Ana; Mandalà, Mario; Liszkay, Gabriella; Garbe, Claus; Schadendorf, Dirk; Krajsová, Ivana; Gutzmer, Ralf; Chiarion-Sileni, Vanna; Dutriaux, Caroline; Groot, Jan Willem B. de; Yamazaki, Naoya; Loquai, Carmen; Parseval, Laure A Moutouh-de; Pickard, Michael D.; Sandor, Victor; Robert, Caroline; Flaherty, Keith T.

doi:10.1016/s1470-2045(18)30497-2

Cited by 495 publications

(442 citation statements)

References 27 publications

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“…In both parts, the arms were well balanced (Table ). In part 1, COMBO450 significantly improved PFS and OS over vemurafenib (but not encorafenib monotherapy) ; in part 2, COMBO300 demonstrated significantly improved PFS and ORR versus encorafenib monotherapy (therefore showing that binimetinib directly contributes to the efficacy of the combination; Table ) .…”

Section: Resultsmentioning

confidence: 98%

“…Subgroup data are available from part 1 of COLUMBUS, showing reductions in the risk of progression or death for encorafenib plus binimetinib versus vemurafenib of 53% and 27% for those with LDH levels lower than the ULN and at the ULN or higher, respectively (supplemental online Table 2) . Updated subgroup data showed reductions in the risk of death for COMBO450 versus vemurafenib of 49% and 5% for those with LDH levels at the ULN or lower and higher than the ULN, respectively (supplemental online Table 3) .…”

Section: Resultsmentioning

confidence: 99%

“…These agents include several checkpoint inhibitors—namely, the anti‐cytotoxic T‐lymphocyte associated protein‐4 (anti‐CTLA‐4) antibody ipilimumab and the anti‐programmed death‐1 (anti‐PD‐1) antibodies nivolumab and pembrolizumab—as well as the BRAF inhibitors vemurafenib and dabrafenib and the mitogen‐activated extracellular signal‐regulated kinase (MEK) inhibitors trametinib and cobimetinib . Additional agents that have completed phase III clinical trials for advanced melanoma include the BRAF inhibitor encorafenib, the MEK inhibitor binimetinib, and the oncolytic virus talimogene laherparepvec (T‐VEC) .…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive Clinical Trial Data Summation for BRAF-MEK Inhibition and Checkpoint Immunotherapy in Metastatic Melanoma

Luke

2019

The Oncologist

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Background Immune checkpoint inhibitors, along with BRAF and MEK inhibitors, have dramatically changed the management of and outlook for patients with metastatic melanoma. Analyses of long‐term follow‐up data and subanalyses based on disease characteristics may inform clinical decision making. Methods Reports of clinical trials in metastatic melanoma published between January 1, 2012, and August 30, 2018, were identified using PubMed (terms: melanoma AND [dabrafenib OR trametinib OR vemurafenib OR cobimetinib OR encorafenib OR ipilimumab OR nivolumab OR pembrolizumab]) and were systematically reviewed. Relevant congress proceedings were also assessed. Efficacy data from key phase III trials were analyzed and trends identified. Results Substantial improvements in objective response rates, progression‐free survival, and overall survival were documented across 14 identified publications. Subgroup findings supported that patients with lower disease burden derive greater benefit than patients with more advanced disease, limiting the value of disease burden in the clinical decision‐making process. However, these agents consistently conferred benefits despite the presence of poor prognostic features. Several clinically relevant questions remain, including how best to sequence immune checkpoint inhibitors and combination targeted therapy. Conclusion This research, coupled with ongoing investigations, including those on predictive biomarkers, suggests that the treatment decision‐making process is likely to become more nuanced. Implications for Practice The management of melanoma has been rapidly advancing with new classes of agents, including immune checkpoint and BRAF inhibitors. With long‐term follow‐up, their impact on response rates and survival outcomes is well documented. Additional findings from subgroup analyses suggest that patients with lower disease burden derive greater benefit, yet both consistently confer benefit in patients with higher disease burden. Currently, there is a paucity of data to guide first‐line treatment selection between immunotherapy and BRAF‐targeted therapy in clinical practice or to estimate their impact when sequenced. Gaining these insights will facilitate a more nuanced management approach.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comprehensive Clinical Trial Data Summation for BRAF-MEK Inhibition and Checkpoint Immunotherapy in Metastatic Melanoma

Luke

2019

The Oncologist

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“…However, the duration of clinical response is limited in the majority of patients. Due to drug resistance, disease progression will occur within 6–8 months with BRAFi monotherapy, and within 11–18 months with BRAFi/MEKi combination therapy . Disease progression is the reason most commonly cited for discontinuation of treatment, even though TT is continued in a number of patients once progression has set in.…”

Section: Summary Of Published Data On the Rechallenge Of Targeted Thementioning

confidence: 99%

Rechallenge of targeted therapy in metastatic melanoma

Reschke¹,

Simon²,

Ziemer³

2019

J Deutsche Derma Gesell

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Summary Rechallenge of targeted therapy in patients with BRAFV600‐mutated melanoma plays an important role, because of the prolonged overall survival of melanoma patients. Patients may be rechallenged after a drug‐free interval following adverse drug reactions, after radiation therapy or surgery, following disease progression on subsequent immunotherapy or chemotherapy, or after disease progression without interim therapeutic intervention. To date, only few data has been published on treatment outcomes associated with rechallenge. The articles published on this topic included a total of 238 patients. In general, it was shown that patients did respond to rechallenge, even if they had previously experienced disease progression on targeted therapy. Patient response varied from stable disease to partial response and even complete remission in some cases. Our analysis showed overall response rates to rechallenge of 47 %, with disease control rates of 67 %. While mean progression‐free survival was 6.4 months, this was shorter than after the first round of targeted therapy (mean progression‐free survival of 9.2 months). Rechallenge of targeted therapy offers another option in the management of melanoma patients who have received extensive prior treatment. In particular, it will be important to clarify whether the type of interim treatment has an impact on the response to rechallenge.

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“…Die Dauer des klinischen Ansprechens ist jedoch für die Mehrzahl der Patienten begrenzt. Unter Monotherapie mit BRAFi kommt es nach 6–8 Monaten und unter Kombinationstherapie aus BRAFi und MEKi nach 11–18 Monaten aufgrund einer Resistenzentwicklung zum Progress der Erkrankung . Ein Krankheitsprogress ist der häufigste Grund für den Abbruch der Therapie, auch wenn bei einem Teil der Patienten die TT über den Progress hinaus fortgeführt wird.…”

Section: Publikation (R – Retrospektiv; P – Prospektiv) Patienten (N)unclassified

Reinduktion zielgerichteter Therapie beim metastasierten Melanom

Reschke

Simon

Ziemer

2019

J Deutsche Derma Gesell

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Zusammenfassung Die Reinduktion bzw. Rechallenge zielgerichteter Therapie bei Patienten mit BRAFV600‐mutierten Melanomen gewinnt zunehmend an Bedeutung. Die erneute Gabe von zielgerichteter Therapie erfolgt nach einer Medikamentenpause bei Nebenwirkungen, nach Bestrahlung oder Operation, nach Tumorprogress unter zwischengeschalteter Immun‐ oder Chemotherapie oder nach erneutem Progress ohne zwischengeschaltete Therapie. Bisher sind nur wenige Daten zu den Ergebnissen einer Rechallenge publiziert. Diese sind in der folgenden Arbeit präsentiert. Alle Arbeiten mit einer Gesamtpatientenzahl von 238 Patienten konnten zeigen, dass auch bei Patienten, die zuvor unter zielgerichteter Therapie einen Progress erlitten hatten, ein erneutes Ansprechen nach Wiedereinleitung möglich ist. Dieses variiert von stabiler Erkrankung, über partielles Ansprechen bis hin zu einzelnen Fällen mit kompletter Remission. Die Daten zeigen Ansprechraten auf eine Rechallenge von 47 %, wobei eine Krankheitskontrolle bei 67 % der Patienten erreicht werden konnte. Das mittlere progressionsfreie Überleben lag bei 6,4 Monaten. Das Ansprechen fiel allerdings kürzer aus als bei der erstmaligen zielgerichteten Therapie (mittleres progressionsfreies Überleben 9,2 Monate). Die Reinduktion zielgerichteter Therapie bietet somit eine weitere Option in der Behandlung bereits ausgiebig behandelter Krankheitszustände. Es bleibt zu klären, ob die Art der zwischengeschalteten Therapie einen Einfluss auf das erneute Ansprechen hat.

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Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial

Cited by 495 publications

References 27 publications

Comprehensive Clinical Trial Data Summation for BRAF-MEK Inhibition and Checkpoint Immunotherapy in Metastatic Melanoma

Comprehensive Clinical Trial Data Summation for BRAF-MEK Inhibition and Checkpoint Immunotherapy in Metastatic Melanoma

Rechallenge of targeted therapy in metastatic melanoma

Reinduktion zielgerichteter Therapie beim metastasierten Melanom

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