When an individual's adverse reactions are under effective management, dose re-escalation following the same dosing steps as de-escalation may be considered. The dose should not exceed 150 mg twice daily.
The safety and efficacy of dabrafenib in non-Caucasian patients have not been established. No data are available.
No adjustment of the initial dose is required in patients > 65 years of age.
No dose adjustment is required for patients with mild or moderate renal impairment. There are no clinical data in subjects with severe renal impairment and the potential need for dose adjustment cannot be determined (see section 5.2). Dabrafenib should be used with caution in patients with severe renal impairment.
No dose adjustment is required for patients with mild hepatic impairment. There are no clinical data in subjects with moderate to severe hepatic impairment and the potential need for dose adjustment cannot be determined (see section 5.2). Hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites and patients with moderate to severe hepatic impairment may have increased exposure. Dabrafenib should be used with caution in patients with moderate or severe hepatic impairment.
The safety and efficacy of dabrafenib have not yet been established in children and adolescents (< 18 years). No clinical data are available. Studies in juvenile animals have shown adverse effects of dabrafenib which had not been observed in adult animals (see section 5.3).
Method of administration
The capsules are to be swallowed whole with water. They should not be chewed or crushed and should not be mixed with food or liquids due to chemical instability of dabrafenib.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF melanoma therefore dabrafenib should not be used in patients with wild-type BRAF melanoma (see sections 4.2 and 5.1).
Fever has been reported in clinical trials. In 1 % of patients in clinical trials, serious non-infectious febrile events were identified defined as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency of pre-renal origin in subjects with normal baseline renal function (see section 4.8). The onset of these serious non-infectious febrile events was typically within the first month of therapy. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care.
Therapy with dabrafenib should be interrupted if the patient's temperature is ≥ 38.5°C. Patients should be evaluated for signs and symptoms of infection. Dabrafenib can be restarted once the fever resolves with appropriate prophylaxis using non-steroidal anti-inflammatory medicinal products or paracetamol. If fever is associated with other severe signs or symptoms, dabrafenib should be restarted at a reduced dose once fever resolves and as clinically appropriate (see section 4.2).
Cutaneous Squamous Cell Carcinoma (cuSCC)
Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with dabrafenib (see section 4.8). It is recommended that skin examination be performed prior to initiation of therapy with dabrafenib and monthly throughout treatment and for up to six months after treatment for cuSCC. Monitoring should continue for 6 months following discontinuation of dabrafenib or until initiation of another anti-neoplastic therapy.
Cases of cuSCC should be managed by dermatological excision and dabrafenib treatment should be continued without any dose adjustment. Patients should be instructed to immediately inform their physician if new lesions develop.
New primary melanoma
New primary melanomas have been reported in clinical trials. These cases were identified within the first 5 months of therapy, were managed with excision and did not require treatment modification. Monitoring for skin lesions should occur as described for cuSCC.
Non-cutaneous secondary/recurrent malignancy
In vitro experiments have demonstrated paradoxical activation of mitogen activated protein kinase (MAP kinase) signalling in BRAF wild type cells with RAS mutations when exposed to BRAF inhibitors. This may lead to increased risk of non-cutaneous malignancies with dabrafenib exposure when RAS mutations are present. Cases of RAS-associated malignancies have been reported, both with another BRAF inhibitor (Chronic myelomonocytic leukemia and non-cutaneous SCC of the head and neck) and with dabrafenib when administered in combination with the MEK inhibitor, trametinib (colorectal cancer, pancreatic cancer).
Prior to initiation of treatment patients should undergo a head and neck examination with minimally visual inspection of oral mucosa and lymph node palpation, as well as chest/abdomen Computerised Tomography (CT) scan. During treatment patients should be monitored as clinically appropriate which may include a head and neck examination every 3 months and a chest/abdomen CT scan every 6 months. Anal examinations and pelvic examinations (for women) are recommended before and at the end of treatment or when considered clinically indicated. Complete blood cell counts should be performed as clinically indicated.
Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices.
Renal failure has been identified in < 1 % of patients treated with dabrafenib. Observed cases were generally associated with pyrexia and dehydration and responded well to dose interruption and general supportive measures. Granulomatous nephritis has been reported (see section 4.8). Patients should be routinely monitored for serum creatinine while on therapy. If creatinine increases, dabrafenib may need to be interrupted as clinically appropriate. Dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting (see section 5.2).
Ophthalmologic reactions, including uveitis and iritis have been reported. Patients should be routinely monitored for visual signs and symptoms (such as, change in vision, photophobia and eye pain) while on therapy.
Pancreatitis has been reported in < 1 % of dabrafenib-treated subjects. One of the events occurred on the first day of dosing and recurred following re-challenge at a reduced dose. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when re-starting dabrafenib after an episode of pancreatitis.
Worst-case QTc prolongation of > 60 millisecond (msec) was observed in 3 % of dabrafenib-treated subjects (One > 500 msec in the integrated safety population). Treatment with dabrafenib is not recommended in patients with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or who are taking medicinal products known to prolong the QT interval.
Electrocardiogram (ECG) and electrolytes (including magnesium) must be monitored in all patients before treatment with dabrafenib, after one month of treatment and after dose modification. Further monitoring is recommended in particular in patients with moderate to severe hepatic impairment monthly during the first 3 months of treatment followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with dabrafenib is not recommended in patients with QTc > 500 msec. If during treatment the QTc exceeds 500 msec, dabrafenib treatment should be temporarily interrupted, electrolyte abnormalities (including magnesium) should be corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur once the QTc decreases below 500 msec and at a lower dose as described in Table 2. Permanent discontinuation of dabrafenib treatment is recommended if the QTc increase meets values of both > 500 msec and > 60 msec change from pre-treatment values.
Effects of other substances on dabrafenib
Dabrafenib is a substrate of CYP2C8 and CYP3A4. Potent inducers of these enzymes should be avoided when possible as these agents may decrease the efficacy of dabrafenib (see section 4.5).
Agents that increase gastric pH might decrease the bioavailability of dabrafenib and should be avoided when possible (see section 4.5).
Effects of dabrafenib on other substances
Dabrafenib is an inducer of metabolising enzymes which may lead to loss of efficacy of many commonly used medicinal products (see examples in section 4.5). A drug utilisation review (DUR) is therefore essential when initiating dabrafenib treatment. Concomitant use of dabrafenib with medicinal products that are sensitive substrates of certain metabolising enzymes or transporters (see section 4.5) should generally be avoided if monitoring for efficacy and dose adjustment is not possible.
Concomitant administration of dabrafenib with warfarin may result in decreased warfarin exposure. Caution should be exercised and additional International Normalized Ratio (INR) monitoring is recommended when dabrafenib is used concomitantly with warfarin and at discontinuation of dabrafenib (see section 4.5).
Concomitant administration of dabrafenib with digoxin may result in decreased digoxin exposure. Caution should be exercised and additional monitoring of digoxin is recommended when digoxin (a transporter substrate) is used concomitantly with dabrafenib and at discontinuation of dabrafenib (see section 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on dabrafenib
Dabrafenib is a substrate for the metabolising enzymes CYP2C8 and CYP3A4, while the active metabolites hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are therefore likely to increase or decrease, respectively, dabrafenib concentrations. Alternative agents should be considered during administration with dabrafenib when possible. Use caution if strong inhibitors (e.g. ketoconazole, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir) are coadministered with dabrafenib. Avoid coadministration of dabrafenib with potent inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St John's wort (Hypericum perforatum)) of CYP2C8 or CYP3A4.
Pharmacokinetic data showed an increase in repeat dose dabrafenib Cmax (26 %) and AUC (57 %) with ketoconazole (a CYP3A4 inhibitor), and increases in hydroxy- and desmethyl-dabrafenib AUC (increases of 48 and 61 %, respectively). A decrease of 33 % in AUC was noted for carboxy-dabrafenib.
Dabrafenib solubility is pH-dependent with decreased solubility at higher pH. Medicinal products such as proton pump inhibitors that inhibit gastric acid secretion to elevate gastric pH may decrease the solubility of dabrafenib and reduce its bioavailability. No clinical study has been conducted to evaluate the effect of pH on dabrafenib pharmacokinetics. Due to the theoretical risk that pH-elevating agents may decrease oral bioavailability and exposure to dabrafenib, these medicinal products that increase gastric pH should, if possible, be avoided during treatment with dabrafenib.
Effect of dabrafenib on other medicinal products
Dabrafenib is an enzyme inducer and increases the synthesis of drug-metabolising enzymes including CYP3A4, CYP2Cs and CYP2B6 and may increase the synthesis of transporters. This results in reduced plasma levels of medicinal products metabolised by these enzymes, and may affect some transported medicinal products. The reduction in plasma concentrations can lead to lost or reduced clinical effect of these medicinal products. There is also a risk of increased formation of active metabolites of these medicinal products. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGTs (glucuronide conjugating enzymes). The transport protein Pgp may also be induced as well as other transporters, e g MRP-2, BCRP and OATP1B1/1B3.
In vitro, dabrafenib produced dose-dependent increases in CYP2B6 and CYP3A4. In a clinical drug interaction study, Cmax and AUC of oral midazolam (a CYP3A4 substrate) decreased by 61 % and 74 %, respectively with co-administration of repeat dose dabrafenib using a formulation with lower bioavailability than dabrafenib formulation.
Interactions with many medicinal products eliminated through metabolism or active transport is expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.
The number of affected medicinal products is expected to be large; although the magnitude of the interaction will vary. Groups of medicinal products that can be affected include, but are not limited to:
• Analgesics (e.g. fentanyl, methadone)
• Antibiotics (e.g. clarithromycin, doxycyline)
• Anticancer agents (e.g. cabazitaxel)
• Anticoagulants (e.g. acenocoumarol, warfarin (see section 4.4))
• Antiepileptic (e.g. carbamazepine, phenytoin, primidone, valproic acid)
• Antipsychotics (e.g. haloperidol)
• Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)
• Cardiac glycosides (e.g. digoxin, see section 4.4)
• Corticosteroids (e.g. dexamethasone, methylprednisolone)
• HIV antivirals (e.g. amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir)
• Hormonal contraceptives (see section 4.6)
• Hypnotics (e.g. diazepam, midazolam, zolpidem)
• Immunosuppressants (e.g. cyclosporin, tacrolimus, sirolimus)
• Statins metabolized by CYP3A4 (e.g. atorvastatin, simvastatin)
Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib. Upon discontinuation of dabrafenib offset of induction is gradual, concentrations of sensitive CYP3A4, CYP2B6, CYP2C8, CYP2C9 and CYP2C19, UDP glucuronosyl transferase (UGT) and transporter substrates may increase and patients should be monitored for toxicity and dosage of these agents may need to be adjusted.
In vitro, dabrafenib is a mechanism based inhibitor of CYP3A4. Therefore, transient inhibition of CYP3A4 may be observed during the first few days of treatment.
Effects of dabrafenib on substance transport systems
Dabrafenib is an in vitro inhibitor of of human organic anion transporting polypeptide (OATP) 1B1 (OATP1B1) and OATP1B3 and clinical relevance can not be excluded. Therefore caution is recommended at co-administration of dabrafenib and OATB1B1 or OATP1B3 substrates such as statins.
Although dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib and desmethyl-dabrafenib, were inhibitors of humanorganic anion transporter (OAT) 1 and OAT3 in vitro, the risk of a drug-drug interaction is minimal based on clinical exposure. Dabrafenib and desmethyl-dabrafenib were also shown to be moderate inhibitors of human breast cancer resistance protein (BCRP); however, based on clinical exposure, the risk of a drug-drug interaction is minimal.
Effect of food on dabrafenib
Patients should take dabrafenib at least one hour prior to or two hours after a meal due to the effect of food on dabrafenib absorption (see section 5.2).
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Women of chilbearing potential/Contraception in females
Women of childbearing potential must use effective methods of contraception during therapy and for 4 weeks following discontinuation. Dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception should be used (see section 4.5).
There are no data from the use of dabrafenib in pregnant women. Animal studies have shown reproductive toxicity and embryofoetal developmental toxicities, including teratogenic effects (see section 5.3). Dabrafenib should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus. If the patient becomes pregnant while taking dabrafenib, the patient should be informed of the potential hazard to the foetus.
It is not known whether dabrafenib is excreted in human milk. Because many medicinal products are excreted in human milk, a risk to the breast-feeding child cannot be excluded. A decision should be made whether to discontinue breastfeeding or discontinue dabrafenib, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
There are no data in humans. Dabrafenib may impair male and female fertility as adverse effects on male and female reproductive organs have been seen in animals (see section 5.3). Male patients should be informed of the potential risk for impaired spermatogenesis, which may be irreversible.
4.7 Effects on ability to drive and use machines
Dabrafenib has minor influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of dabrafenib should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills. Patients should be made aware of the potential for fatigue and eye problems to affect these activities.
4.8 Undesirable effects
Summary of the safety profile
The safety profile is based on data from five clinical monotherapy studies and included 578 patients with melanoma. The most frequently occurring adverse drug reactions (ADRs) (≥ 15 %) reported with dabrafenib were hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea, papilloma, alopecia, rash and vomiting.
Tabulated summary of adverse reactions
ADRs which were reported are listed below by MedDRA body system organ class and by frequency. The following convention has been utilised for the classification of frequency:
≥ 1/100 to < 1/10
≥ 1/1,000 to < 1/100
≥ 1/10,000 to < 1/1,000
(cannot be estimated from the available data)
Table 3: Adverse reactions reported in melanoma trials
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.imb.ie; e-mail: firstname.lastname@example.org
the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Description of selected adverse reactions
Fever has been reported in clinical trials. In 1 % of patients in clinical trials, serious non-infectious febrile events were identified as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency or pre-renal origin in subjects with normal baseline renal function. The onset of these serious non-infectious febrile events was typically within the first month of therapy. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care (see sections 4.2 and 4.4).
Cutaneous squamous cell carcinoma
Cutaneous squamous cell carcinomas (including those classified as keratoacanthoma or mixed keratoacanthoma subtype) occurred in 9 % of patients treated with dabrafenib. Approximately 70 % of events occurred within the first 12 weeks of treatment with a median time to onset of 8 weeks. Ninety-six percent of patients who developed cuSCC continued on treatment without dose modification.
New primary melanoma
New primary melanomas have been reported in clinical trials with dabrafenib. Cases were managed with excision and did not require treatment modification (see section 4.4).
Activation of MAP-kinase signalling in BRAF wild type cells which are exposed to BRAF inhibitors may lead to increased risk of non-cutaneous malignancies, including those with RAS mutations (see section 4.4). Cases of RAS-driven malignancies have been seen with dabrafenib. Patients should be monitored as clinically appropriate.
One subject in the integrated safety population experienced a QTcB > 500 ms and only 3 % experienced worst-case QTc prolongation of > 60 msec.
Decreased LVEF has been reported in 1 % of patients with most cases being asymptomatic and reversible. Patients with LVEF lower than the institutional lower limit of normal were not included in clinical trials with dabrafenib.
Arthralgia was reported very commonly in clinical trials with dabrafenib (25 %) although these were mainly grade 1 and 2 in severity with Grade 3 occurring uncommonly (< 1 %) and no Grade 4 occurrences being reported.
Hypophosphataemia has been reported commonly in clinical trials with dabrafenib (7 %). It should be noted that approximately half of these occurrences (4 %) were Grade 3 in severity.
Pancreatitis has been reported in dabrafenib-treated subjects. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when re-starting dabrafenib after an episode of pancreatitis (see section 4.4).
Renal failure due to pyrexia-associated pre-renal azotaemia or granulomatous nephritis was uncommon; however dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN). Caution should be used in this setting (see section 4.4).
Of the total number of patients in clinical studies of dabrafenib (N = 578), 22 % were 65 years of age and older, and 6 % were 75 years of age and older. Compared with younger subjects (< 65), more subjects ≥ 65 years old had adverse reactions that led to study drug dose reductions (22 % versus 12 %) or interruptions (39 % versus 27 %). In addition, older patients experienced more serious adverse reactions compared to younger patients (41 % versus 22 %). No overall differences in efficacy were observed between these subjects and younger subjects.
There is no specific treatment for an overdose of dabrafenib. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE23
Mechanism of action
Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway. BRAF mutations have been identified at a high frequency in specific cancers, including approximately 50 % of melanoma. The most commonly observed BRAF mutation is V600E which accounts for approximately 90 % of the BRAF mutations that are seen in melanoma.
Preclinical data generated in biochemical assays demonstrated that dabrafenib inhibits BRAF kinases with activating codon 600 mutations (Table 4).
Table 4: Kinase inhibitory activity of dabrafenib against RAF kinases
In subjects with BRAF V600 mutation positive melanoma, administration of dabrafenib resulted in inhibition of tumour phosphorylated ERK relative to baseline.
Determination of BRAF mutation status
Before taking dabrafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test. In the Phase II and III clinical trials, screening for eligibility required central testing for BRAF V600 mutation using a BRAF mutation assay conducted on the most recent tumour sample available. Primary tumour or tumour from a metastatic site was tested with an investigational use only assay (IUO). The IUO is an allele-specific polymerase chain reaction (PCR) assay performed on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue. The assay was specifically designed to differentiate between the V600E and V600K mutations. Only subjects with BRAF V600E or V600K mutation positive tumors were eligible for study participation.
Subsequently, all patient samples were re-tested using the bioMerieux (bMx) THxID BRAF validated assay, which has CE marking. The bMx THxID BRAF assay is an allele-specific PCR performed on DNA extracted from FFPE tumour tissue. The assay was designed to detect the BRAF V600E and V600K mutations with high sensitivity (down to 5 % V600E and V600K sequence in a background of wild-type sequence using DNA extracted from FFPE tissue). Non-clinical and clinical studies with retrospective bi-directional Sanger sequencing analyses have shown that the test also detects the less common BRAF V600D mutation and V600E/K601E mutation with lower sensitivity. Of the specimens from the non-clinical and clinical studies (n = 876) that were mutation positive by the THxID BRAF assay and subsequently were sequenced using the reference method, the specificity of the assay was 94 %.
Clinical efficacy and safety
The efficacy of dabrafenib in the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma has been evaluated in 3 studies (BRF113683 [BREAK-3], BRF113929 [BREAK-MB], and BRF113710 [BREAK-2]) including patients with BRAF V600E and/or V600K mutations.
Included in these studies were in total 402 subjects with BRAF V600E and 49 subjects with BRAF V600K mutation. Patients with melanoma driven by BRAF mutations other than V600E were excluded from the confirmatory trial and with respect to patients with the V600K mutation in single arm studies the activity appears lower than in V600E tumours.
No data is available in patients with melanoma harbouring BRAF V600 mutations others than V600E and V600K. Efficacy of dabrafenib in subjects previously treated with a protein kinase inhibitor has not been investigated.
Previously untreated patients (Results from the Phase III study [BREAK-3])
The efficacy and safety of dabrafenib were evaluated in a Phase III randomized, open-label study [BREAK 3] comparing dabrafenib to dacarbazine (DTIC) in previously untreated patients with BRAF V600E mutation positive advanced (unresectable Stage III) or metastatic (Stage IV) melanoma. Patients with melanoma driven by BRAF mutations other than V600E were excluded.
The primary objective for this study was to evaluate the efficacy of dabrafenib compared to DTIC with respect to progression-free survival (PFS) per investigator assessment. Patients on the DTIC arm were allowed to cross over to dabrafenib after independent radiographic confirmation of initial progression. Baseline characteristics were balanced between treatment groups. Sixty percent of patients were male and 99.6 % were Caucasian ; the median age was 52 years with 21 % of patients being ≥ 65 years, 98.4 % had ECOG status of 0 or 1, and 97 % of patients had metastatic disease.
At the pre-specified analysis with a 19 December 2011 data cut, a significant improvement in the primary endpoint of PFS (HR = 0.30; 95 % Cl 0.18, 0.51; p < 0.0001) was achieved. Efficacy results from the primary analysis and a post-hoc analysis with 6-months additional follow up are summarized in Table 5. Overall survival data from a further post-hoc analysis based on a 18 December 2012 data cut are shown in Figure 1.
Table 5: Efficacy in previously untreated patients (BREAK-3 Study, 25 June 2012)
a. Defined as confirmed complete +partial response.
As of 25 June 2012 cut-off, thirty five subjects (55.6 %) of the 63 randomized to DTIC had crossed over to dabrafenib and 63 % of subjects randomised to dabrafenib and 79 % of subjects randomised to DTIC had progressed or died. Median PFS after cross-over was 4.4 months.
Table 6: Survival data from the primary analysis and post-hoc analyses
Overall survival data from a further post-hoc analysis based on the 18 December 2012 data cut demonstrated a 12 month OS rate of 63 % and 70 % for DTIC and dabrafenib treatments respectively.
Figure 1: Kaplan-Meier curves of overall survival (BREAK-3) (18 December 2012)
Patients with brain metastases (Results from the Phase II study (BREAK-MB)
a - Confirmed response.
简介： 2013年9月3日，葛兰素史克（GSK）黑色素瘤新药Tafinlar（dabrafenib）已获欧盟委员会（EC）批准，作为一种口服靶向药物，用于携带BRAF V600E突变的手术不可切除性黑色素瘤或转移性黑色素瘤成人患者的治 ...