Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, B-Raf serine- threonine kinase (BRAF) inhibitors, ATC code: L01EC02

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 11).

Table 11. Kinase inhibitory activity of dabrafenib against RAF kinases 
Kinase                           Inhibitory concentration 50 (nM)
BRAF V600E                                       0.65
BRAF V600K                                       0.50
BRAF V600D                                        1.8
BRAF WT                                          3.2
CRAF WT                                          5.0

Dabrafenib demonstrated suppression of a downstream pharmacodynamic biomarker (phosphorylated ERK) and inhibited cell growth of BRAF V600 mutant melanoma cell lines, 
in vitro and in animal models.

In subjects with BRAF V600 mutation-positive melanoma, administration of dabrafenib resulted in inhibition of tumour phosphorylated ERK relative to baseline.

In the setting of BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors (see section 4.1).

Combination with trametinib

Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity.
MEK proteins are components of the extracellular signal-related kinase (ERK) pathway.

Thus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore the combination provides concomitant inhibition of the pathway. The combination of dabrafenib with trametinib has shown anti-tumour activity in BRAF V600 mutation- positive melanoma cell lines in vitro and delays the emergence of resistance in vivo in BRAF V600 mutation-positive melanoma xenografts.

Determination of BRAF mutation status

Before taking dabrafenib or combination with trametinib, 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 tumours 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 trials 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 trials (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

Unresectable or metastatic melanoma
•    Dabrafenib in combination with trametinib

Treatment-naïve patients
The efficacy and safety of the recommended dose of trametinib (2 mg once daily) in combination with dabrafenib (150 mg twice daily) for the treatment of adult patients with 
unresectable or metastatic melanoma with a BRAF V600 mutation was studied in two Phase III trials and one supportive Phase I/II study.

MEK115306 (COMBI-d):
MEK115306 was a Phase III, randomised, double-blinded study comparing the combination of dabrafenib and trametinib to dabrafenib and placebo in first-line therapy for subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The primary endpoint of the study was progression-free survival (PFS), with a key secondary endpoint of overall survival (OS). Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K).

A total of 423 subjects were randomised 1:1 to either combination (N=211) or dabrafenib (N=212). Most subjects were Caucasian (>99%) and male (53%), with a median age of 56 years (28% were ≥65 years). The majority of subjects had Stage IVM1c disease (67%).
Most subjects had LDH ≤ULN (65%), Eastern Cooperative Oncology Group (ECOG) performance status of 0 (72%), and visceral disease (73%) at baseline. The majority of subjects had a BRAF V600E mutation (85%). Subjects with brain metastases were not included in the trial.

Median OS and estimated 1-year, 2-year 3-year, 4 year and 5-year survival rates are presented in Table 12. From an OS analysis at 5 years, the median OS for the combination arm was approximately 7 months longer than for dabrafenib monotherapy (25.8 months versus 18.7 months) with 5-year survival rates of 32% for the combination versus 27% for dabrafenib monotherapy (Table 12, Figure 1). The Kaplan-Meier OS curve appears to stabilise from 3 to 5 years (see Figure 1). The 5-year overall survival rate was 40% (95% CI: 31.2, 48.4) in the combination arm versus 33% (95% CI: 25.0, 41.0) in the dabrafenib monotherapy arm for patients who had a normal lactate dehydrogenase level at baseline, and 16% (95% CI: 8.4, 26.0) in the combination arm versus 14% (95% CI: 6.8, 23.1) in the dabrafenib monotherapy arm for patients with an elevated lactate dehydrogenase level at baseline.

Table 12.       Overall Survival results for Study MEK115306 (COMBI-d) 
OS analysis                     5-year OS analysis
(data cut-off: 12-Jan-2015)         (data cut-off: 10-Dec-2018)
Dabrafenib +       Dabrafenib +     Dabrafenib +      Dabrafenib +
Trametinib          Placebo         Trametinib          Placebo
(n=211)           (n=212)           (n=211)           (n=212)
Number of patients
Died (event), n
99 (47)             123 (58)            135 (64)           151 (71)
(%)
Estimates of OS (months)
Median (95%           25.1                 18.7               25.8               18.7 CI)                (19.2, NR)          (15.2, 23.7)        (19.2, 38.2)       (15.2, 23.1) Hazard ratio                     0.71                                    0.80 (95% CI)                     (0.55, 0.92)                            (0.63, 1.01) p-value                         0.011                                    NA Overall survival
Dabrafenib + Trametinib                    Dabrafenib + Placebo estimate, %
(n=211)                               (n=212)
(95% CI)
At 1 year                   74 (66.8, 79.0)                         68 (60.8, 73.5) At 2 years                  52 (44.7, 58.6)                         42 (35.4, 48.9) At 3 years                  43 (36.2, 50.1)                         31 (25.1, 37.9) At 4 years                 35 (28.2, 41.8)                                                        29 (22.7, 35.2) At 5 years                 32 (25.1, 38.3)                                                        27 (20.7, 33.0) NR = Not reached, NA = Not applicable

Figure 1        Kaplan-Meier overall survival curves for Study MEK115306 (ITT population)

1.0
Dabrafenib + Trametinib
Dabrafenib + Placebo
Estimated Survival Function


0.8


0.6


0.4


0.2


0.0
0        6      12    18     24    30    36   42     48     54   60     66      72         78 Time since Randomisation (Months)
Subjects at Risk:
Dabrafenib + Trametinib 211                               188     145   113    98    86    79   71     63     60   57     54      12         0 Dabrafenib + Placebo    212                               175     137   104    84    69    60   56     54     51   50     46      10         0 

Improvements for the primary endpoint of PFS were sustained over a 5 year timeframe in the combination arm compared to dabrafenib monotherapy. Improvements were also observed for overall response rate (ORR) and a longer duration of response (DoR) was observed in the combination arm compared to dabrafenib monotherapy (Table 13).



Table 13.          Efficacy results for Study MEK115306 (COMBI-d)

Primary analysis (data cut-             Updated analysis (data cut-            5-year analysis (data cut- off: 26-Aug-2013)                       off: 12-Jan-2015)                      off: 10-Dec-2018) Endpoint                 Dabrafenib         Dabrafenib          Dabrafenib          Dabrafenib          Dabrafenib Dabrafenib +                  +                   +                   +                   +               + Trametinib          Placebo            Trametinib           Placebo            Trametinib       Placebo (n=211)            (n=212)             (n=211)             (n=212)             (n=211)         (n=212) PFSa
Progressive                102 (48)           109 (51)            139 (66)            162 (76)               160 (76)         166 (78) disease or death,
n (%)
Median PFS                  9.3                 8.8                11.0                 8.8                10.2                 8.8 (months) (95%            (7.7, 11.1)         (5.9, 10.9)         (8.0, 13.9)          (5.9, 9.3)         (8.1, 12.8)          (5.9, 9.3) CI)
Hazard Ratio                           0.75                                   0.67                                    0.73 (95% CI)                           (0.57, 0.99)                           (0.53, 0.84)                            (0.59, 0.91) P value                       0.035                                 <0.001 f                                  NA ORRb                         67                  51                  69                 53                   69                   54 % (95% CI)               (59.9, 73.0)        (44.5, 58.4)        (61.8,74.8)        (46.3, 60.2)        (62.5, 75.4)         (46.8, 60.6) ORR difference                         15e                                     15e                                      NA (95% CI)                           (5.9, 24.5)                             (6.0, 24.5) P value                           0.0015                                  0.0014f                                    NA DoRc (months)
Median                       9.2d               10.2d                12.9               10.6                12.9                10.2 (95% CI)                  (7.4, NR)           (7.5, NR)           (9.4,19.5)         (9.1, 13.8)         (9.3, 18.4)         (8.3, 13.8) a – Progression-free survival (investigator assessed) b – Overall Response Rate = Complete Response + Partial Response c – Duration of response d - At the time of the reporting the majority (≥59%) of investigator-assessed responses were still ongoing e – ORR difference calculated based on the ORR result not rounded f
– Updated analysis was not pre-planned and the p-value was not adjusted for multiple testing NR = Not reached
NA = Not applicable

MEK116513 (COMBI-v):
Study MEK116513 was a 2-arm, randomised, open-label, Phase III study comparing dabrafenib and trametinib combination therapy with vemurafenib monotherapy in BRAF V600 mutation-positive unresectable or metastatic melanoma. The primary endpoint of the study was OS with a key secondary endpoint of PFS. Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K).

A total of 704 subjects were randomised 1:1 to either combination or vemurafenib. Most subjects were Caucasian (>96%) and male (55%), with a median age of 55 years (24% were ≥65 years). The majority of subjects had Stage IV M1c disease (61% overall). Most subjects had LDH ≤ULN (67%), ECOG performance status of 0 (70%), and visceral disease (78%) at Baseline. Overall, 54% of subjects had <3 disease sites at baseline. The majority of subjects had BRAF V600E mutation-positive melanoma (89%). Subjects with brain metastases were not included in the trial.

Median OS and estimated 1-year, 2-year, 3-year, 4-year and 5-year survival rates are presented in Table 14. From an OS analysis at 5 years, the median OS for the combination arm was approximately 8 months longer than the median OS for vemurafenib monotherapy (26.0 months versus 17.8 months) with 5-year survival rates of 36% for the combination 
versus 23% for vemurafenib monotherapy (Table 14, Figure 2). The Kaplan-Meier OS curve appears to stabilise from 3 to 5 years (see Figure 2). The 5-year overall survival rate was 46% (95% CI: 38.8, 52.0) in the combination arm versus 28% (95% CI: 22.5, 34.6) in the vemurafenib monotherapy arm for patients who had a normal lactate dehydrogenase level at baseline, and 16% (95% CI: 9.3, 23.3) in the combination arm versus 10% (95% CI: 5.1, 17.4) in the vemurafenib monotherapy arm for patients with an elevated lactate dehydrogenase level at baseline.

Table 14.       Overall Survival results for Study MEK116513 (COMBI-v) 
OS analysis                           5-year OS analysis data cut-off: 13-Mar-2015)               (data cut-off: 08-Oct-2018)
Dabrafenib +                             Dabrafenib +
Vemurafenib                                 Vemurafenib
Trametinib                               Trametinib
(n=352)                                     (n=352)
(n=352)                                  (n=352)
Number of patients
Died (event), n
155 (44)                    194 (55)          216 (61)                  246 (70) (%)
Estimates of OS (months)
Median (95% CI)
25.6                   18.0                 26.0                   17.8 (22.6, NR)              (15.6, 20.7)         (22.1, 33.8)           (15.6, 20.7) Adjusted hazard                       0.66                                        0.70 ratio (95% CI)                   (0.53, 0.81)                                (0.58, 0.84) p-value                        <0.001                                        NA Overall survival
Dabrafenib + Trametinib                         Vemurafenib estimate, % (95%
(n=352)                                   (n=352)
CI)
At 1 year                          72 (67, 77)                                65 (59, 70) At 2 years                        53 (47.1, 57.8)                           39 (33.8, 44.5) At 3 years                        44 (38.8, 49.4)                           31 (25.9, 36.2) At 4 years                        39 (33.4, 44.0)                           26 (21.3, 31.0) At 5 years                        36 (30.5, 40.9)                           23 (18.1, 27.4) NR = Not reached, NA = Not applicable



Figure 2                                      Kaplan-Meier overall survival curves for Study MEK116513 
1.0
Dabrafenib + Trametinib

Estimated Survival Function
Vemurafenib
0.8


0.6


0.4


0.2


0.0
0   6    12    18   24    30    36    42    48    54       60      66      72    78 
Time since Randomisation (Months)
Subjects at Risk:
Dabrafenib + Trametinib 352     311     246                       201   171   151   140   130   118   109      104     49      4     0 Vemurafenib 352      287     201                       154   120   104   94    86    78    72       65      30      1     0 

Improvements for the secondary endpoint of PFS were sustained over a 5 year timeframe in the combination arm compared to vemurafenib monotherapy. Improvements were also observed for ORR. and a longer DoR was observed in the combination arm compared to vemurafenib monotherapy (Table 15).



Table 15. Efficacy results for Study MEK116513 (COMBI-v)

Primary analysis (Data cut-off:         5-year analysis (Data cut-off: 08- 17-Apr-2014)                               Oct-2018)
Endpoint            Dabrafenib +     Vemurafenib             Dabrafenib +      Vemurafenib Trametinib        (n=352)                Trametinib          (n=352)
(n=352)                                  (n=352)
PFSa
Progressive            166 (47)              217 (62)           257 (73)             259 (74) disease or death, n (%)
Median PFS               11.4                   7.3               12.1                 7.3 (months)              (9.9, 14.9)            (5.8, 7.8)        (9.7, 14.7)          (6.0, 8.1) (95% CI)
Hazard Ratio                        0.56                                     0.62 (95% CI)                        (0.46, 0.69)                             (0.52, 0.74) P value                   <0.001                                     NA ORRb                     64                   51                  67                   53 %(95% CI)            (59.1, 69.4)         (46.1, 56.8)        (62.2, 72.2)         (47.2, 57.9) ORR                                   13                                     NA difference                        (5.7, 20.2)
(95% CI)
P value                     0.0005                                   NA DoRc (months)
Median                   13.8d                  7.5 d            13.8                  8.5 (95% CI)              (11.0, NR)             (7.3, 9.3)       (11.3, 18.6)          (7.4, 9.3) a – Progression-free survival (investigator assessed) b – Overall Response Rate = Complete Response + Partial Response c – Duration of response d – At the time of the reporting the majority (59% of dabrafenib+trametinib and 42% of vemurafenib) of investigator-assessed responses were still ongoing
NR = Not reached
NA = Not applicable

Prior BRAF inhibitor therapy
There are limited data in patients taking the combination of dabrafenib with trametinib who have progressed on a prior BRAF inhibitor.

Part B of study BRF113220 included a cohort of 26 patients that had progressed on a BRAF inhibitor. The trametinib 2 mg once daily and dabrafenib 150 mg twice daily combination demonstrated limited clinical activity in patients who had progressed on a BRAF inhibitor.
The investigator-assessed confirmed response rate was 15% (95% CI: 4.4, 34.9) and the median PFS was 3.6 months (95% CI: 1.9, 5.2). Similar results were seen in the 45 patients who crossed over from dabrafenib monotherapy to the trametinib 2 mg once daily and dabrafenib 150 mg twice daily combination in Part C of this study. In these patients a 13% (95 CI: 5.0, 27.0) confirmed response rate was observed with a median PFS of 3.6 months (95% CI: 2, 4).

Patients with brain metastases
The efficacy and safety of dabrafenib in combination with trametinib in patients with BRAF mutation-positive melanoma that has metastasised to the brain was studied in a non- randomised, open-label, multicentre, Phase II study (COMBI-MB study). A total of 125 patients were enrolled into four cohorts:
•       Cohort A: patients with BRAF V600E mutant melanoma with asymptomatic brain metastases without prior local brain-directed therapy and ECOG performance status of 0 or 1.
•       Cohort B: patients with BRAF V600E mutant melanoma with asymptomatic brain metastases with prior local brain-directed therapy and ECOG performance status of 0 or1.
•       Cohort C: patients with BRAF V600D/K/R mutant melanoma with asymptomatic brain metastases, with or without prior local brain-directed therapy and ECOG performance status of 0 or 1.
•       Cohort D: patients with BRAF V600D/E/K/R mutant melanoma with symptomatic brain metastases, with or without prior local brain-directed therapy and ECOG performance status of 0 or 1 or 2.

The primary endpoint of the study was intracranial response in Cohort A, defined as the percentage of patients with a confirmed intracranial response assessed by the investigator using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Intracranial response assessed by the investigator in Cohorts B, C and D were secondary endpoints of the study. Due to small sample size reflected by wide 95% CIs, the results in Cohorts B, C, and D should be interpreted with caution. Efficacy results are summarised in Table 16.

Table 16. Efficacy data by investigator assessment from COMBI-MB study 
All treated patients population
Endpoints/                                          Cohort Cohort Cohort        Cohort assessment                                              A        B      C         D N=76     N=16   N=16        N=17
Intracranial response rate, % (95 % CI)
59%      56%    44%         59%
(47.3,   (29.9, (19.8,      (32.9,
70.4)    80.2)  70.1)       81.6)
Duration of intracranial response, median, months (95% CI)
6.5      7.3    8.3        4.5
(4.9,    (3.6,  (1.3,      (2.8,
8.6)   12.6)  15.0)       5.9)
Overall response rate, % (95% CI)
59%      56%    44%         65%
(47.3,   (29.9, (19.8,      (38.3,
70.4)    80.2)  70.1)       85.8)
Progression-free survival, median, months (95% CI)
5.7      7.2    3.7        5.5
(5.3,    (4.7,  (1.7,      (3.7,
7.3)   14.6)    6.5)      11.6)
Overall survival, median, months (95% CI)
10.8     24.3   10.1       11.5
(8.7,    (7.9,  (4.6,      (6.8,
17.9)     NR)   17.6)       22.4)
CI = Confidence Interval, NR = Not reached


•       Dabrafenib monotherapy

The efficacy of dabrafenib in the treatment of adult patients with BRAF V600 mutation- 
positive unresectable or metastatic melanoma has been evaluated in 3 clinical trials (BRF113683 [BREAK-3], BRF113929 [BREAK-MB], and BRF113710 [BREAK-2]) including patients with BRAF V600E and/or V600K mutations.

Included in these clinical trials 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 clinical trials 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 randomised, 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 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 summarised in Table 17. OS data from a further post-hoc analysis based on a 18 December 2012 data cut are shown in Figure 3.

Table 17. Efficacy in previously untreated patients (BREAK-3 Study, 25 June 2012) 
Data as of                            Data as of
December 19, 2011                        June 25, 2012
Dabrafenib             DTIC              Dabrafenib         DTIC
N=187               N=63                N=187            N=63
Progression-free survival
Median, months      5.1 (4.9, 6.9)     2.7 (1.5, 3.2)        6.9 (5.2,9.0)      2.7 (1.5,3.2) (95% CI)
HR (95% CI)               0.30 (0.18, 0.51)                       0.37 (0.24, 0.58) P < 0.0001                              P < 0.0001
Overall responsea
% (95% CI)       53 (45.5, 60.3) 19 (10.2, 30.9)         59 (51.4, 66.0)     24 (14, 36.2) Duration of response
Median, months          N=99               N=12                N=110               N=15 (95% CI)            5.6 (4.8, NR)     NR (5.0, NR)          8.0 (6.6, 11.5)     7.6 (5.0, 9.7) Abbreviations: CI: confidence interval; DTIC: dacarbazine; HR: hazard ratio; NR: not reached a
Defined as confirmed complete + partial response.


As of 25 June 2012 cut-off, thirty five subjects (55.6%) of the 63 randomised 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 18. Survival data from the primary analysis and post-hoc analyses 
Cut-off date            Treatment       Number of          Hazard ratio (95% CI) deaths (%)
December 19, 2011       DTIC              9 (14%)          0.61 (0.25, 1.48) (a) dabrafenib        21 (11%)
June 25, 2012            DTIC              21 (33%)        0.75 (0.44, 1.29) (a) dabrafenib        55 (29%)
December 18, 2012       DTIC              28 (44%)        0.76 (0.48, 1.21) (a) dabrafenib        78 (42%)
(a)
Patients were not censored at the time of cross-over

OS 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 3         Kaplan-Meier curves of overall survival (BREAK-3) (18 December 2012) 


Patients with brain metastases (results from the Phase II study (BREAK-MB) BREAK-MB was a multicentre, open-label, two-cohort, Phase II study designed to evaluate the intracranial response of dabrafenib in subjects with histologically confirmed (Stage IV) BRAF mutation-positive (V600E or V600K) melanoma metastatic to the brain. Subjects were enrolled into Cohort A (subjects with no prior local therapy for brain metastasis) or Cohort B (subjects who received prior local therapy for brain metastasis).

The primary endpoint of the study was overall intracranial response rate (OIRR) in the V600E patient population, as assessed by investigators. The confirmed OIRR and other efficacy results per investigator assessment are presented in Table 19.
Table 19. Efficacy data in patients with brain metastases (BREAK-MB Study) 
All Treated Subjects Population
BRAF V600E (Primary)                      BRAF V600K
Cohort A            Cohort B        Cohort A       Cohort B
N=74                N=65             N=15          N=18 a
Overall intracranial response rate,% (95% CI)
39% (28.0, 51.2)     31% (19.9, 43.4)     7% (0.2,      22% (6.4,
P < 0.001b          P < 0.001b          31.9)         47.6)
Duration of intracranial response, median, months (95% CI)
N=29                N=20             N=1            N=4
4.6 (2.8, NR)       6.5 (4.6, 6.5)  2.9 (NR, NR) 3.8 (NR, NR)
Overall response,% (95% CI)a
38% (26.8, 49.9)     31% (19.9, 43.4)    0 (0, 21.8)    28% (9.7,
53.5)
Duration of response, median, months (95% CI)
N=28                N=20              NA            N=5
5.1 (3.7, NR)       4.6 (4.6, 6.5)                 3.1 (2.8, NR)
Progression-free survival, median, months (95% CI)
3.7 (3.6, 5.0)      3.8 (3.6, 5.5)  1.9 (0.7, 3.7) 3.6 (1.8, 5.2)
Overall survival, median, months (95% CI)
Median,              7.6 (5.9, NR)       7.2 (5.9, NR)   3.7 (1.6, 5.2) 5.0 (3.5, NR) months
Abbreviations: CI: confidence interval; NR: not reached; NA: not applicable a
Confirmed response.
b
This study was designed to support or reject the null hypothesis of OIRR ≤10% (based on historical results) in favour of the alternative hypothesis of OIRR ≥ 30% in BRAF V600E mutation-positive subjects.

Patients who were previously untreated or failed at least one prior systemic therapy (results from the Phase II [BREAK-2])
BRF113710 (BREAK-2) was a multicentre, single-arm study that enrolled 92 subjects with metastatic melanoma (Stage IV) with confirmed BRAF V600E or V600K mutation-positive melanoma.

The investigator assessed confirmed response rate in patients with BRAF V600E metastatic melanoma (n=76) was 59% (95% CI: 48.2, 70.3) and the median DoR was 5.2 months (95% CI: 3.9, not calculable) based on a median follow-up time of 6.5 months. In patients with BRAF V600K mutation-positive metastatic melanoma (n=16) the response rate was 13% (95% CI: 0.0, 28.7) with a median DoR of 5.3 months (95% CI: 3.7, 6.8). Although limited by the low number of patients, median OS appeared consistent with data in patients with BRAF V600E mutation-positive tumours.

Adjuvant treatment of Stage III melanoma

BRF115532 (COMBI-AD)
The efficacy and safety of dabrafenib in combination with trametinib were studied in a Phase III, multicentre, randomised, double-blind, placebo-controlled study in patients with Stage III (Stage IIIA [lymph node metastasis >1 mm], IIIB, or IIIC) cutaneous melanoma with a BRAF V600 E/K mutation, following complete resection.

Patients were randomised 1:1 to receive either combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg once daily) or two placebos for a period of 12 months. Enrollment 
required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomisation. Any prior systemic anti-cancer treatment, including radiotherapy, was not allowed. Patients with a history of prior malignancy, if disease-free for at least 5 years, were eligible. Patients presenting with malignancies with confirmed activating RAS mutations were not eligible. Patients were stratified by BRAF mutation status (V600E versus V600K) and stage of disease prior to surgery using the American Joint Committee on Cancer (AJCC) 7th edition Melanoma Staging System (by Stage III sub-stage, indicating different levels of lymph node involvement and primary tumour size and ulceration). The primary endpoint was investigator-assessed relapse-free survival (RFS), defined as the time from randomisation to disease recurrence or death from any cause. Radiological tumour assessment was conducted every 3 months for the first two years and every 6 months thereafter, until first relapse was observed. Secondary endpoints include overall survival (OS; key secondary endpoint), freedom from relapse (FFR) and distant metastasis-free survival (DMFS).

A total of 870 patients were randomised to the combination therapy (n=438) and placebo (n=432) arms. Most patients were Caucasian (99%) and male (55%), with a median age of 51 years (18% were ≥65 years). The study included patients with all sub-stages of Stage III disease prior to resection; 18% of these patients had lymph node involvement only identifiable by microscope and no primary tumour ulceration. The majority of patients had a BRAF V600E mutation (91%).

The median duration of follow-up at the time of the primary analysis was 2.83 years in the dabrafenib and trametinib combination arm and 2.75 years in the placebo arm.

Results for the primary analysis of RFS are presented in Table 20. The study showed a statistically significant difference for the primary outcome of investigator-assessed RFS between treatment arms, with a median RFS of 16.6 months for the placebo arm and not yet reached for the combination arm (HR: 0.47; 95% confidence interval: (0.39, 0.58); p=1.53×10-14). The observed RFS benefit was consistently demonstrated across subgroups of patients including age, sex and race. Results were also consistent across stratification factors for disease stage and BRAF V600 mutation type.

Table 20. Investigator-assessed RFS results for Study BRF115532 (COMBI-AD primary analysis)

Dabrafenib + Trametinib              Placebo
RFS parameter                                                    N=438                        N=432 Number of events, n (%)                                        166 (38%)                    248 (57%) Recurrence                                               163 (37%)                    247 (57%) Relapsed with distant metastasis                 103 (24%)                    133 (31%) Death                                                     3 (<1%)                      1 (<1%) Median (months)                                                    NE                          16.6 (95% CI)                                                 (44.5, NE)                  (12.7, 22.1) Hazard ratio[1]                                                                 0.47 (95% CI)                                                              (0.39, 0.58) p-value[2]                                                             1.53×10-14 1-year rate (95% CI)                                        0.88 (0.85, 0.91)            0.56 (0.51, 0.61) 2-year rate (95% CI)                                        0.67 (0.63, 0.72)            0.44 (0.40, 0.49)
3-year rate (95% CI)                                        0.58 (0.54, 0.64)            0.39 (0.35, 0.44) Hazard ratio is obtained from the stratified Pike model.
[1]

P-value is obtained from the two-sided stratified log-rank test (stratification factors were disease stage – IIIA [2]
 vs. IIIB vs. IIIC – and BRAF V600 mutation type – V600E vs. V600K) NE = not estimable

Based on updated data with an additional 29 months of follow-up compared to the primary analysis (minimum follow-up of 59 months), the RFS benefit was maintained with an estimated HR of 0.51 (95% CI: 0.42, 0.61) (Figure 4). The 5-year RFS rate was 52% (95% CI: 48, 58) in the combination arm compared to 36% (95% CI: 32, 41) in the placebo arm.

Figure 4       Kaplan-Meier RFS curves for Study BRF115532 (ITT population, updated results)



At the time of the final OS analysis, the median duration of follow-up was 8.3 years in the combination arm and 6.9 years in the placebo arm. The observed difference in OS was not statistically significant (HR: 0.80; 95% CI: 0.62, 1.01) with 125 events (29%) in the combination arm and 136 events (31%) in the placebo arm. Estimated 5-year OS rates were 79% in the combination arm and 70% in the placebo arm, and estimated 10-year OS rates were 66% in the combination arm and 63% in the placebo arm.

Non-small cell lung cancer

Study BRF113928
The efficacy and safety of dabrafenib in combination with trametinib was studied in a Phase II, three-cohort, multicentre, non-randomised and open-label study in which patients with stage IV BRAF V600E mutant NSCLC were enrolled. The primary endpoint was ORR using the (RECIST 1.1) assessed by the investigator. Secondary endpoints included DoR, PFS, OS, safety and population pharmacokinetics. ORR, DoR and PFS were also assessed by an Independent Review Committee (IRC) as a sensitivity analysis.

Cohorts were enrolled sequentially:
•    Cohort A: Monotherapy (dabrafenib 150 mg twice daily), 84 patients enrolled.
78 patients had previous systemic treatment for their metastatic disease.
•    Cohort B: Combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg once daily), 59 patients enrolled. 57 patients had 1-3 lines of previous systemic treatment for their metastatic disease. 2 patients had no previous systemic treatment and were included in the analysis for patients enrolled in Cohort C.
•    Cohort C: Combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg once daily), 34 patients. All patients received study medicinal product as first-line treatment for metastatic disease.


Among the total of 93 patients who were enrolled in the combination therapy cohorts B and C, most patients were Caucasian (>90%), and similar female versus male (54% versus 46%), with a median age of 64 years in second line or higher patients and 68 years in the first line patients. Most patients (94%) enrolled in the combination therapy treated cohorts had an ECOG performance status of 0 or 1. 26 (28%) had never smoked. The majority of patients had a non-squamous histology. In the previously treated population, 38 patients (67%) had one line of systemic anti-cancer therapy for metastatic disease.

At the time of the primary analysis, the primary endpoint of investigator-assessed ORR in the first line population was 61.1% (95% CI, 43.5%, 76.9%) and in the previously treated population was 66.7% (95% CI, 52.9%, 78.6%). These met the statistical significance to reject the null hypothesis that the ORR of dabrafenib in combination with trametinib for this NSCLC population was less than or equal to 30%. The ORR results assessed by IRC were consistent with the investigator assessment. The efficacy of the combination with trametinib was superior when indirectly compared to dabrafenib monotherapy in Cohort A. The final analysis of efficacy performed 5 years after last subject first dose is presented in Table 21 .

Table 21.       Summary of efficacy in the combination treatment cohorts based on investigator and independent radiology review

Endpoint                   Analysis      Combination 1st line        Combination 2nd line plus N=361                           N=571
Overall confirmed             By Investigator         23 (63.9%)                    39 (68.4%) response n (%)                                  (46.2, 79.2) 23 (63.9%)       (54.8, 80.1)36 (63.2%) (95% CI)                           By IRC             (46.2, 79.2)                  (49.3, 75.6) 
Median DoR                    By Investigator   10.2 (8.3, 15.2)15.2 (7.8,    9.8 (6.9, 18.3)12.6 (5.8, Months (95% CI)                  By IRC                   23.5)                         26.2) Median PFS                    By Investigator   10.8 (7.0, 14.5)14.6 (7.0,    10.2 (6.9, 16.7)8.6 (5.2, Months (95% CI)                  By IRC                   22.1)                        16.8) Median OS                           -               17.3 (12.3, 40.2)             18.2 (14.3, 28.6) Months (95% CI)
1
Data cut-off: 7 January 2021


Other studies - pyrexia management analysis
Study CPDR001F2301 (COMBI-i) and Study CDRB436F2410 (COMBI-Aplus)
Pyrexia is observed in patients treated with dabrafenib and trametinib combination therapy.
The initial registration studies for the combination therapy in the unresectable or metastatic melanoma setting (COMBI-d and COMBI-v; total N=559) and in the adjuvant melanoma setting (COMBI-AD, N=435) recommended to interrupt only dabrafenib in case of pyrexia (fever ≥38.5°C). In two subsequent studies in unresectable or metastatic melanoma (COMBI-i control arm, N=264) and in the adjuvant melanoma setting (COMBI-Aplus, N=552), interruption of both medicinal products when patient’s temperature is ≥38°C (COMBI- Aplus), or at the first symptom of pyrexia (COMBI-i; COMBI-Aplus for recurrent pyrexia) was advised. In COMBI-i and COMBI-Aplus there was a lower incidence of grade 3/4 pyrexia, complicated pyrexia, hospitalisation due to serious pyrexia adverse events of special interest (AESIs), the time spent in pyrexia AESIs, and permanent discontinuations from both medicinal products due to pyrexia AESIs (the latter in the adjuvant setting only) compared to COMBI-d, COMBI-v and COMBI-AD. The COMBI-Aplus study met its primary endpoint with a composite rate of 8.0% (95% CI: 5.9, 10.6) for grade 3/4 pyrexia, hospitalisation due to 
pyrexia, or permanent treatment discontinuation due to pyrexia compared to 20.0% (95% CI: 16.3, 24.1) for the historical control (COMBI-AD).

Anaplastic Thyroid Cancer (ATC)
The safety and efficacy of dabrafenib administered with trametinib was evaluated in an activity estimating, nine-cohort, multi-center, non-randomized, open-label trial (Study BRF117019; NCT02034110) in patients with rare cancers with the BRAF V600E mutation, including locally advanced, unresectable, or metastatic anaplastic thyroid cancer (ATC) with no standard locoregional treatment options. Trial BRF117019 excluded patients who could not swallow or retain the medication; who received prior treatment with BRAF or MEK inhibitors; with symptomatic or untreated CNS metastases; or who had airway obstruction.
Patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The major efficacy outcome measure was overall response rate (ORR) per RECIST v1.1 as assessed by independent review committee (IRC) and DoR.
Thirty-six patients were enrolled and were evaluable for response in the ATC cohort. The median age was 71 years (range 47 to 85); 44% were male, 50% White, 44% Asian; and 94% had ECOG performance status of 0 or 1. Prior anti-cancer treatments included surgery and external beam radiotherapy (83% each), and systemic therapy (67%).
Efficacy results are summarized in Table 22.
Table 22. Efficacy Results in the ATC Cohort Based on Independent Review of Study BRF117019
ATC Cohort Population                                                  N= 36 Overall Response Rate
ORR (95% CI)                                                   53% (35.5%, 69.6%) Complete Response                                                       6% Partial Response                                                       47% Duration of Response                                                    n = 19 Median DoR, months (95% CI)                                         13.6 (3.8, NE) % with DoR ≥6 months                                                    68% % with DoR ≥ 12 months                                                   53% Abbreviations: ATC, anaplastic thyroid cancer; DoR, duration of response; CI = Confidence interval; NE, not estimable; ORR, overall response rate.

BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors
The safety and efficacy of dabrafenib in combination with trametinib for the treatment of BRAF V600E mutation-positive unresectable or metastatic solid tumors were evaluated in Trials BRF117019, NCI-MATCH, and CTMT212X2101, and supported by results in COMBI-d, COMBI-v, and BRF113928. In adult studies, patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The major efficacy outcome measures were ORR per RECIST v1.1, RANO [HGG] or modified RANO [LGG] criteria and duration of response (DoR).
BRF117019 Study and NCI-MATCH Study
Study BRF117019 (NCT02034110) is a multi-cohort, multi-center, non-randomized, open- label trial in adult patients with selected tumors with the BRAF V600E mutation, including high grade glioma (HGG) (n = 45), biliary tract cancer (BTC) (n = 43), low grade glioma (LGG) (n = 13), adenocarcinoma of small intestine (ASI) (n = 3), gastrointestinal stromal 
tumor (GIST) (n = 1), and anaplastic thyroid cancer. Patients were enrolled based on local assessments of BRAF V600E mutation status; a central laboratory confirmed the BRAF mutation in 93 of 105 patients.
Arm H (EAY131-H) of the NCI-MATCH study (NCT02465060) is a single-arm, open-label study that enrolled patients with a BRAF V600E mutation. Patients with melanoma, thyroid cancer, or CRC were excluded. BRAF V600E mutation status for enrollment was determined either by central or local laboratory test. The study included adult patients with solid tumors including gastrointestinal tumors (n = 14), lung tumors (n = 7), gynecologic or peritoneal tumors (n = 6), CNS tumors (n = 4), and ameloblastoma of mandible (n = 1).
Among the 131 patients enrolled in BRF117019 and NCI-MATCH with the tumor types shown in Table 21, the baseline characteristics were: median age of 51 years with 20% age 65 or older; 56% female; 85% White, 9% Asian, 3% Black, 3% Other; and 37% ECOG 0, 56% ECOG 1, and 6% ECOG 2. Of the 131 patients, 90% received prior systemic therapy.
Efficacy results in patients with solid tumors are summarized in Table 23.
Table 23. Efficacy Results Based on Independent Review in Studies BRF117019 and NCI-MATCH Arm H

Objective Response Rate           Duration of Response
Tumor Type     a
N                (ORR)                            (DoR)
%              95% CI              Range (months) b
Biliary tract cancer                         48          46             (31, 61)                 1.8d, 40d High grade gliomac                           48          33             (20, 48)                 3.9, 44 Glioblastoma                          32          25             (12, 43)                 3.9, 27 Anaplastic pleomorphic                                                                     6, 43 6          67             (22, 96) xanthoastrocytoma
Anaplastic astrocytoma                 5          20             (0.5, 72)                   15 Astroblastoma                          2         100            (16, 100)                 15, 23d Undifferentiated                       1          PR            (2.5, 100)                   6 Anaplastic ganglioglioma               1           0                 NA                     NA Anaplastic oligodendroglioma           1           0                 NA                     NA Low grade glioma                             14          50             (23, 77)                  6, 29d Astrocytoma                              4          50              (7, 93)                  7, 23 Ganglioglioma                            4          50              (7, 93)                  6, 13 Pleomorphic xanthoastrocytoma            2          50             (1.3, 99)                   6 Pilocytic astrocytoma                    2           0                 NA                     NA Choroid plexus papilloma                 1          PR            (2.5, 100)                  29d Gangliocytoma/Ganglioglioma              1          PR            (2.5, 100)                  18d Low grade serous ovarian carcinoma            5          80            (28, 100)                 12, 42d Adenocarcinoma small intestine                4          50              (7, 93)                   7, 8 Adenocarcinoma pancreas                       3           0                 NA                     NA Mixed ductal / adenoneuroendocrine            2           0                 NA                     NA carcinoma
Neuroendocrine carcinoma of colon            2           0                NA                    NA Ameloblastoma of mandible                    1          PR            (2.5, 100)                30 Combined small cell-squamous                 1          PR            (2.5, 100)                5 carcinoma of lung
Mucinous-papillary serous                    1          PR            (2.5, 100)                8 adenocarcinoma of peritoneum
Adenocarcinoma of anus                       1           0                NA                    NA Gastrointestinal stromal tumor               1           0                NA                    NA Abbreviations: PR, partial response.
a
Excludes NSCLC (n=6) and ATC (n=36) (previously approved tumor types for dabrafenib in combination with trametinib).
b
Median DoR 9.8 months (95% CI: 5.3, 20.4).
c
Median DoR 13.6 months (95% CI: 5.5, 26.7).
d
Denotes a right-censored DoR.

CTMT212X2101 (X2101) Study
Study X2101 (NCT02124772) was a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors. Part C was a dose escalation of dabrafenib in combination with trametinib in patients with a BRAF V600E mutation. Part D was a cohort expansion phase of dabrafenib in combination with trametinib in patients with LGG with a BRAF V600E mutation. The major efficacy outcome measure was ORR as assessed by independent review committee per RANO criteria.
The efficacy of dabrafenib in combination with trametinib was evaluated in 48 pediatric patients, including 34 patients with LGG and 2 patients with HGG.
For patients with BRAF V600E mutant LGG and HGG in Parts C and D, the median age was 10 years (range: 1-17); 50% were male, 75% White, 8% Asian, 3% Black; and 58% had Karnofsky/Lansky performance status of 100. Prior anti-cancer treatments included surgery (83%), external beam radiotherapy (2.8%), and systemic therapy (92%). The ORR was 25% (95% CI: 12%, 42%). For the 9 patients who responded, DoR was ≥6 months for 78% of patients, and ≥24 months for 44% of patients.


CDRB436G2201 (G2201) Study – High-Grade Glioma Cohort
Study G2201 (NCT02684058) was a multi-center, randomized, open-label, Phase II study of dabrafenib and trametinib in chemotherapy naïve pediatric patients with BRAF V600E mutant low-grade glioma (LGG) and patients with relapsed or progressive BRAF V600E mutant HGG. Patients with HGG were enrolled in a singlearm cohort. The major efficacy outcome measure for the HGG cohort was ORR as assessed by independent review committee per RANO 2010 criteria.
The efficacy of dabrafenib in combination with trametinib was evaluated in 41 pediatric patients with relapsed or progressive HGG.
For patients with BRAF V600E mutant HGG enrolled in the HGG cohort, the median age was 13 years (range: 2 to 17); 56% were female, 61% White, 27% Asian, 2.4% Black and 37% had Karnofsky/Lansky performance status of 100. Prior anti-cancer treatments included surgery (98%), radiotherapy (90%), and chemotherapy (81%). The ORR was 56% (95% CI: 40, 72). The median DoR was not reached (95% CI: 9.2, NE). For the 23 patients who responded in the HGG cohort, DoR was ≥ 6 months for 78% of patients, ≥ 12 months for 48% of patients, and ≥ 24 months for 22% of patients.

BRAF V600E Mutation-Positive Low-Grade Glioma
CDRB436G2201 (G2201) Study – Low-Grade Glioma Cohort
The safety and efficacy of dabrafenib in combination with trametinib for the treatment of BRAF V600E mutation-positive low-grade glioma (LGG) in pediatric patients aged 1 to < 18 years of age were evaluated in the multi-center, open-label trial (Study CDRB436G2201; NCT02684058). Patients with LGG (WHO grades 1 and 2) who required first systemic therapy were randomized in a 2:1 ratio to dabrafenib plus trametinib (D + T) or carboplatin plus vincristine (C + V).
BRAF mutation status was identified prospectively via a local assessment or a central laboratory test. In addition, retrospective testing of available tumor samples by the central laboratory was performed to evaluate BRAF V600E mutation status.
Patients received age- and weight-based dosing of dabrafenib and trametinib until loss of clinical benefit or until unacceptable toxicity. Carboplatin and vincristine were dosed based on body surface area at doses 175 mg/m2 and 1.5 mg/m2 (0.05 mg/kg for patients < 12 kg), respectively, as one 10-week induction course followed by eight 6-week cycles of maintenance therapy.
The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO LGG (2017) criteria. Additional efficacy outcome measures were progression free survival and overall survival. The primary analysis was performed when all patients had completed at least 32 weeks of therapy.
In the LGG cohort, 110 patients were randomized to D + T (n=73) or C + V (n=37). Median age was 9.5 years (range: 1 to 17); 60% were female. Study G2201 showed a statistically significant improvement in ORR and PFS in LGG patients randomized to D + T compared to those randomized to C + V. Efficacy results are shown in Table 24.


Table 24. Efficacy Results Based on Independent Review in Study G2201 (LGG cohort) dabrafenib plus                   Carboplatin plus
Trametinib                        Vincristine
N=73                               N=37
Overall Response Rate
ORR% (95% CI)a                              46.6 (34.8, 58.6)                  10.8 (3.0, 25.4) P value                                                           < 0.001 Complete response (CR), n                         2 (2.7)                           1 (2.7) (%)
Partial response (PR), n (%)                     32 (44)                             3 (8) Duration of Response
Median (95% CI)b, months                     23.7 (14.5, NE)                    NE (6.6, NE) % with observed DoR ≥ 12                            56                               50 months
% with observed DoR ≥ 24                            15                                25 months
Progression-Free Survival
Median (95% CI)b, months                     20.1 (12.8, NE)                 7.4 (3.6, 11.8) Hazard ratio (95% CI)c                                     0.31 (0.17, 0.55) P value                                                        < 0.001 Abbreviations: CI, confidence interval; DoR, duration of response; NE, not estimable; ORR, overall response rate.

a
Based on Clopper-Pearson exact confidence interval.
b
Based on Kaplan-Meier method.
c
Based on proportional hazards model.

Figure 5.    Kaplan-Meier Curves for Progression-Free Survival in Study G2201 (LGG cohort)



At the time of the interim analysis of overall survival (OS), conducted when all patients had completed at least 32 weeks of treatment or had discontinued earlier, there was one death on the C+V arm. The OS results at interim analysis did not reach statistical significance.

QT prolongation

Worst-case QTc prolongation of >60 millisecond (msec) was observed in 3% of dabrafenib- treated subjects (one >500 msec in the integrated safety population). In the Phase III study MEK115306 no patients treated with trametinib in combination with dabrafenib had worst- case QTcB prolongation to >500 msec; QTcB was increased more than 60 msec from baseline in 1% (3/209) of patients. In the Phase III study MEK116513 four patients (1%) treated with trametinib in combination with dabrafenib had a QTcB Grade 3 increase (>500 msec). Two of these patients had a QTcB Grade 3 increase (>500 msec) that was also an increase >60 msec from baseline.

The potential effect of dabrafenib on QT prolongation was assessed in a dedicated multiple dose QT study. A supratherapeutic dose of 300 mg dabrafenib twice daily was administered in 32 subjects with BRAF V600 mutation-positive tumours. No clinically relevant effect of dabrafenib or its metabolites on the QTc interval was observed.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption
Dabrafenib is absorbed orally with median time to achieve peak plasma concentration of 
2 hours post-dose. Mean absolute bioavailability of oral dabrafenib is 95% (90% CI: 81,
110%). Dabrafenib exposure (Cmax and AUC) increased in a dose proportional manner between 12 and 300 mg following single-dose administration, but the increase was less than dose-proportional after repeat twice daily dosing. A decrease in exposure was observed with repeat dosing, likely due to induction of its own metabolism. Mean accumulation AUC Day 18/Day 1 ratios was 0.73. Following administration of 150 mg twice daily, geometric mean Cmax, AUC(0-τ) and predose concentration (Cτ) were 1478 ng/ml, 4341 ng*hr/ml and 26 ng/ml, respectively.

Administration of dabrafenib with food reduced the bioavailability (Cmax and AUC decreased by 51% and 31% respectively) and delayed absorption of dabrafenib capsules when compared to the fasted state.

Distribution

Dabrafenib binds to human plasma protein and is 99.7% bound. The steady-state volume of distribution following intravenous microdose administration is 46 L.

Biotransformation

The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib, which is further oxidised via CYP3A4 to form carboxy-dabrafenib.
Carboxy-dabrafenib can be decarboxylated via a non-enzymatic process to form desmethyl- dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may also be formed in the gut and reabsorbed. Desmethyl-dabrafenib is metabolised by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 10 hrs while the carboxy- and desmethyl-metabolites exhibited longer half-lives (21-22 hours). Mean metabolite-to-parent AUC ratios following repeat-dose administration were 0.9, 11 and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl- dabrafenib are likely to contribute to the clinical activity of dabrafenib while the activity of carboxy-dabrafenib is not likely to be significant.

Medicinal product interactions

Effects of other medicinal products on dabrafenib
Dabrafenib is a substrate of human P-glycoprotein (P-gp) and human BCRP in vitro.
However, these transporters have minimal impact on dabrafenib oral bioavailability and elimination and the risk for clinically relevant drug-drug interactions with inhibitors of P-gp or BCRP is low. Neither dabrafenib nor its 3 main metabolites were demonstrated to be inhibitors of P-gp in vitro.

Effects of dabrafenib on other medicinial products
Although dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib and desmethyl-dabrafenib, were inhibitors of human organic anion transporter (OAT) 1 and OAT3 in vitro and dabrafenib and its desmethyl metabolite were found to be inhibitors of organic cation transporter 2 (OCT2) in vitro,the risk of a drug-drug interaction at these transporters is minimal based on clinical exposure of dabrafenib and its metabolites .

Elimination

Terminal half-life of dabrafenib following an intravenous single microdose is 2.6 hours.
Dabrafenib terminal half-life after a single oral dose is 8 hours due to absorption-limited elimination after oral administration (flip-flop pharmacokinetics). IV plasma clearance is 
12 l/hr.

After an oral dose, the major route of elimination of dabrafenib is metabolism, mediated via CYP3A4 and CYP2C8. Dabrafenib related material is excreted primarily in faeces, with 71% of an oral dose recovered in faeces; 23% of the dose was recovered in urine in the form of metabolites only.

Special patient populations

Hepatic impairment
A population pharmacokinetic analysis indicates that mildly elevated bilirubin and/or AST levels (based on National Cancer Institute [NCI] classification) do not significantly affect dabrafenib oral clearance. In addition, mild hepatic impairment as defined by bilirubin and AST did not have a significant effect on dabrafenib metabolite plasma concentrations. No data are available in patients with moderate to severe hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, administration of dabrafenib should be undertaken with caution in patients with moderate to severe hepatic impairment (see section 4.2).

Renal impairment

A population pharmacokinetic analysis suggests that mild renal impairment does not affect oral clearance of dabrafenib. Although data in moderate renal impairment are limited these data may indicate no clinically relevant effect. No data are available in subjects with severe renal impairment (see section 4.2).

Elderly

Based on the population pharmacokinetic analysis, age had no significant effect on dabrafenib pharmacokinetics. Age greater than 75 years was a significant predictor of carboxy- and desmethyl-dabrafenib plasma concentrations with a 40% greater exposure in subjects ≥75 years of age, relative to subjects <75 years old.

Body weight and gender

Based on the population pharmacokinetic analysis, gender and weight were found to influence dabrafenib oral clearance; weight also impacted oral volume of distribution and distributional clearance. These pharmacokinetic differences were not considered clinically relevant in adult patients.

Pediatric Patients
The pharmacokinetics of dabrafenib were evaluated in 109 pediatric patients after single or repeat weight-adjusted dosing. The pharmacokinetic exposures of dabrafenib at the recommended weight-adjusted dosage in pediatric patients were within range of those observed in adults.

Race

The population pharmacokinetic analysis showed no significant differences in the pharmacokinetics of dabrafenib between Asian and Caucasian patients. There are insufficient data to evaluate the potential effect of other races on dabrafenib pharmacokinetics.