Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial

Hauschild, Axel; Grob, Jean-Jacques; Демидов, Лев В.; Jouary, Thomas; Gutzmer, Ralf; Millward, Michael; Rutkowski, Piotr; Blank, Christian U.; Miller, Wilson H.; Kaempgen, Eckhart; Martín‐Algarra, Salvador; Karaszewska, Bogusława; Mauch, Cornelia; Chiarion-Sileni, Vanna; Martin, Anne Marie; Swann, S.; Haney, Patricia; Mirakhur, Beloo; Guckert, Mary; Goodman, Vicki; Chapman, Paul B.

doi:10.1016/s0140-6736(12)60868-x

Cited by 2,703 publications

(2,123 citation statements)

References 11 publications

Supporting

Mentioning

1,998

Contrasting

Unclassified

Order By: Relevance

“…In phase 2, the primary end‐point was confirmed ORR (based on the investigator's assessment). In phase 2, with a threshold ORR of 10% and an expected ORR of 70% (based on phase 3 studies with dacarbazine, vemurafenib and dabrafenib therapies),13, 22 the sample size of six was estimated to provide 90% or more of power, given a one‐sided alpha error of less than 0.05. Patients who were not evaluable were treated as non‐responders, that is, they were included in the denominator when calculating the percentage.…”

Section: Methodsmentioning

confidence: 99%

“…Dabrafenib, a potent and selective inhibitor of BRAF kinase activity, was approved based on the results of a phase 3 trial which demonstrated significant improvement in progression‐free survival (PFS) in patients with BRAF V600E mutation‐positive unresectable or metastatic melanoma 12, 13. Trametinib, a reversible, highly selective allosteric inhibitor of MEK1/MEK2 activation and kinase activity was approved for use in the treatment of adult patients with unresectable or metastatic melanoma containing BRAF V600E/K mutations based on the results demonstrated in a phase 3 trial 14, 15.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Yamazaki¹,

Tsutsumida²,

Takahashi³

et al. 2018

The Journal of Dermatology

View full text Add to dashboard Cite

The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end‐point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end‐points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end‐points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator‐assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9–99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Yamazaki¹,

Tsutsumida²,

Takahashi³

et al. 2018

The Journal of Dermatology

View full text Add to dashboard Cite

show abstract

“…This agent provided a clinical benefit not previously observed in metastatic melanoma: in the randomized phase III BRIM3 trial comparison against dacarbazine chemotherapy 49 , the objective response rate (ORR) by RECIST criteria 50 was 48% versus 5%, and the median progression-free survival (PFS) was 5.3 months versus 1.6 months; a median overall survival of 13.3 months versus 10.0 months (hazard ratio (HR) 0.75; P = 0.0085) was reported in an extended follow-up study 51 . The selective BRAF inhibitor dabrafenib was developed soon thereafter, showing very similar clinical benefit to vemurafenib when compared with dacarbazine -ORR 50% versus 6% and a median PFS of 5.1 months versus 2.7 months (HR 0.30; P <0.0001) 52 .…”

Section: Braf-targeted Therapiesmentioning

confidence: 99%

“…The toxicities commonly associated with BRAF inhibitors include rash, photosensitivity (vemurafenib only), arthralgia, fatigue, and fever (specifically for dabrafenib) 49,51,52 .…”

Section: Braf-targeted Therapiesmentioning

confidence: 99%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

View full text Add to dashboard Cite

“…For metastatic melanoma, small-molecule inhibitors of BRAF V600E protein have demonstrated clinical activity and have rapidly changed standard treatment of BRAFmutated melanoma patients. [7][8][9] Similarly, these targeted therapies might also have antitumor activity in various other BRAF-mutated neoplasias. [10][11][12][13][14] Accurate and rapid detection of BRAF mutations in metastatic melanoma is therefore essential for optimal patient care and may possibly be also required in other tumor entities in the near future.…”

mentioning

confidence: 99%

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

et al. 2014

View full text Add to dashboard Cite

BRAF mutations have emerged as an important predictive biomarker for metastasized melanoma. Other types of cancer may also benefit from BRAF mutation-targeted therapies. In biliary tract cancer, reported BRAF mutation rates are highly controversial, ranging from 0 to 33% in adenocarcinoma of the gallbladder and 0 to 22% in cholangiocarcinoma. We here analyzed tissue microarrays of a large cohort of biliary tract cancer (n ¼ 377) including 159 intrahepatic cholangiocarcinomas, 149 extrahepatic cholangiocarcinomas, and 69 adenocarcinomas of the gallbladder for BRAF V600E mutation using a highly sensitive immunohistochemical screening approach implementing the BRAF V600E protein-specific antibody VE1. All VE1-positive cases as well as 42 VE1-negative cases were additionally analyzed by Sanger sequencing. In total, only 5 VE1-positive cases were detected (5/377; 1%). BRAF V600E mutation was confirmed by direct sequencing in all cases. All 5 mutated cases were intrahepatic cholangiocarcinomas (5/159; 3%). None of the extrahepatic cholangiocarcinomas and adenocarcinomas of the gallbladder were VE1 positive. Apart from the subtype restriction of BRAF V600E mutation to intrahepatic cholangiocarcinoma and a female predominance (4 female, 1 male), no significant correlation with clinicopathological data and patient outcome was detected. In conclusion, we demonstrate that BRAF V600E mutation is a rare event in biliary tract cancer, accounting for only 1% of all subtypes, and is restricted to intrahepatic cholangiocarcinoma. In addition, we demonstrate that VE1 immunohistochemistry is a feasible approach to routinely screen for BRAF V600E mutation in biliary tract cancer patients, thereby facilitating the detection of rare patients who may benefit from BRAF mutation-targeted therapies.

show abstract

Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial

Cited by 2,703 publications

References 11 publications

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Targeted agents and immunotherapies: optimizing outcomes in melanoma

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

Contact Info

Product

Resources

About