Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial

Long, Georgina V.; Trefzer, Uwe; Davies, Michael A.; Kefford, Richard; Ascierto, Paolo A.; Chapman, Paul B.; Puzanov, Igor; Hauschild, Axel; Robert, Caroline; Algazi, Alain P.; Mortier, Laurent; Tawbi, Hussein A.; Wilhelm, Tabea; Zimmer, Lisa; Switzky, Julie; Swann, S.; Martin, Anne Marie; Guckert, Mary; Goodman, Vicki; Streit, Marcus R.; Kirkwood, John M.; Schadendorf, Dirk

doi:10.1016/s1470-2045(12)70431-x

Cited by 827 publications

(649 citation statements)

References 30 publications

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“…In two previously analyzed cholangiocarcinoma cohorts, tumors with BRAF mutations other than V600E have been reported that may potentially also respond to targeted therapy. For BRAF V600K (detected in one intrahepatic cholangiocarcinoma by Sia et al 27 ) response of melanoma metastases has been observed in a phase II trial, 37 and for BRAF V600D (detected in two cholangiocarcinomas not otherwise specified by Tannapfel et al 29 ) in vitro inhibitor Figure 2 Overall survival probability in intrahepatic cholangiocarcinoma patients in correlation with BRAF V600E status. Kaplan-Meier curves show no difference in overall survival of patients in correlation with BRAF V600E status in intrahepatic cholangiocarcinoma (P ¼ 0.38).…”

Section: Discussionmentioning

confidence: 98%

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

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 98%

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

et al. 2014

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“…Incidentally, pyrexia has been reported as a common AE with BRAF‐inhibitor monotherapy in the range of 16–26% when given as monotherapy 18, 19, 26, 27. In the current study, the first fever was observed within 8 weeks of initiation of therapy in all nine patients in whom pyrexia was observed, while the median time to onset of the first fever in a global clinical study conducted was reported to be 4.3 weeks after treatment initiation 27. Thus, there seemed to be little difference between Japanese and other ethnicities in terms of pyrexia during dabrafenib and trametinib combination.…”

Section: Discussionmentioning

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

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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.

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“…Emerging evidence indicates, however, that patients with brain metastases are nearly as likely to initi ally respond to BRAF-inhibitor therapy as those without brain metastases. In uncontrolled phase I-II trials of monotherapy with dabrafenib or vemurafenib in patients with melanoma brain metastasis [161][162][163] (TABLE 3), ORRs and PFS were only marginally inferior to those observed in trials that included only patients without active brain metastases. These benefits are presumed, although not yet proven, to translate into prolonged overall survival, and have led to BRAF-inhibitor therapy becoming a mainstay treatment for patients with untreated metastatic melanoma involving the brain.…”

Section: Response Criteriamentioning

confidence: 92%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial

Cited by 827 publications

References 30 publications

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

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

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

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