Prescription Drug Information: Tafinlar (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with dabrafenib have not been conducted. TAFINLAR increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials.

Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay, and was not clastogenic in an in vivo rat bone marrow micronucleus test.

In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended dose based on AUC).

Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended dose based on AUC, respectively.

13.2 Animal Toxicology and/or Pharmacology

Adverse cardiovascular effects were noted in dogs at dabrafenib doses of 50 mg/kg/day (approximately five times the human exposure at the recommended dose based on AUC) or greater, when administered for up to 4 weeks. Adverse effects consisted of coronary arterial degeneration/necrosis and hemorrhage, as well as cardiac atrioventricular valve hypertrophy/hemorrhage.

14 CLINICAL STUDIES

14.1 BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma – TAFINLAR Administered as a Single Agent

In Trial 1, the safety and efficacy of TAFINLAR as a single agent were demonstrated in an international, multicenter, randomized (3:1), open-label, active-controlled trial conducted in 250 patients with previously untreated BRAF V600E mutation-positive, unresectable or metastatic melanoma. Patients with any prior use of BRAF inhibitors or MEK inhibitors were excluded. Patients were randomized to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 63). Randomization was stratified by disease stage at baseline [unresectable Stage III (regional nodal or in-transit metastases), M1a (distant skin, subcutaneous, or nodal metastases), or M1b (lung metastases) versus M1c melanoma (all other visceral metastases or elevated serum LDH)]. The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. In addition, an independent radiology review committee (IRRC) assessed the following efficacy outcome measures in pre-specified supportive analyses: PFS, confirmed objective response rate (ORR), and duration of response.

The median age of patients in Trial 1 was 52 years. The majority of the trial population was male (60%), White (99%), had an ECOG performance status of 0 (67%), M1c disease (66%), and normal LDH (62%). All patients had tumor tissue with mutations in BRAF V600E as determined by a clinical trial assay at a centralized testing site. Tumor samples from 243 patients (97%) were tested retrospectively, using an FDA-approved companion diagnostic test, THxID™-BRAF assay.

The median durations of follow-up prior to initiation of alternative treatment in patients randomized to receive TAFINLAR was 5.1 months and in the dacarbazine arm was 3.5 months. Twenty-eight (44%) patients crossed over from the dacarbazine arm at the time of disease progression to receive TAFINLAR.

Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with TAFINLAR. Table 7 and Figure 1 summarize the PFS results.

Table 7. Investigator-Assessed Progression-Free Survival and Confirmed Objective Response Results in Trial 1

Investigator-Assessed Endpoints

TAFINLAR

N = 187

Dacarbazine

N = 63

Progression-Free Survival

Number of Events (%)

78 (42%)

41 (65%)

Progressive Disease

76

41

Death

2

0

Median, months (95% CI)

5.1 (4.9, 6.9)

2.7 (1.5, 3.2)

HRa (95% CI)

0.33 (0.20, 0.54)

P
-valueb

P <0.0001

Confirmed Tumor Responses

Objective Response Rate

52%

17%

(95% CI)

(44, 59)

(9, 29)

CR, n (%)

6 (3%)

0

PR, n (%)

91 (48%)

11 (17%)

Duration of Response
Median, months (95% CI)

5.6 (5.4, NR)

NR (5.0, NR)

CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached.
a Pike estimator, stratified by disease state.
b Stratified log-rank test.

Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival in Trial 1

Figure 1
(click image for full-size original)

In supportive analyses based on IRRC assessment and in an exploratory subgroup analysis of patients with retrospectively confirmed V600E mutation-positive melanoma with the THxID™-BRAF assay, the PFS results were consistent with those of the primary efficacy analysis.

The activity of TAFINLAR for the treatment of BRAF V600E mutation-positive melanoma, metastatic to the brain was evaluated in a single-arm, open-label, two-cohort multicenter trial. All patients received TAFINLAR 150 mg twice daily. Patients in Cohort A (n = 74) had received no prior local therapy for brain metastases, while patients in Cohort B (n = 65) had received at least one local therapy for brain metastases, including, but not limited to, surgical resection, whole brain radiotherapy, or stereotactic radiosurgery such as gamma knife, linear-accelerated-based radiosurgery, or charged particles. In addition, patients in Cohort B were required to have evidence of disease progression in a previously treated lesion or an untreated lesion. Additional eligibility criteria were at least one measurable lesion of 0.5 cm or greater in largest diameter on contrast-enhanced MRI, stable or decreasing corticosteroid dose, and no more than two prior systemic regimens for treatment of metastatic disease. The primary outcome measure was estimation of the overall intracranial response rate (OIRR) in each cohort.

The median age of patients in Cohort A was 50 years, 72% were male, 100% were White, 59% had a pre-treatment ECOG performance status of 0, and 57% had an elevated LDH value at baseline. The median age of patients in Cohort B was 51 years, 63% were male, 98% were White, 66% had a pre-treatment ECOG performance status of 0, and 54% had an elevated LDH value at baseline. Efficacy results as determined by an independent radiology review committee, masked to investigator response assessments, are provided in Table 8.

Table 8. Efficacy Results in Patients with BRAF V600E Melanoma Brain Metastases

IRRC-assessed Endpoints

Cohort A

n = 74

Cohort B

n = 65

Overall Intracranial Response Rate (OIRR)

% (95% CI)

18 (9.7, 28.2)

18 (9.9, 30.0)

Duration of OIRR

(n = 13)

(n = 12)

Median, months (95% CI)

4.6 (2.8, NR)

4.6 (1.9, 4.6)

IRRC = Independent radiology review committee; CI = Confidence interval; NR = Not reached.

14.2 BRAF V600E or V600K Unresectable or Metastatic Melanoma – TAFINLAR Administered with Trametinib

The safety and efficacy of TAFINLAR administered with trametinib were evaluated in two international, randomized, active-controlled trials: one double-blind trial (Trial 2) and one open-label trial (Trial 3).

Trial 2 compared TAFINLAR and trametinib to TAFINLAR and placebo as first-line therapy for patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive TAFINLAR 150 mg twice daily and trametinib 2 mg once daily or TAFINLAR 150 mg twice daily plus matching placebo. Randomization was stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) vs. ≤ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR).

Trial 3 compared TAFINLAR and trametinib to vemurafenib as first-line treatment therapy for patients with unresectable (Stage IIIc) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive TAFINLAR 150 mg twice daily and trametinib 2 mg once daily or vemurafenib 960 mg twice daily. Randomization was stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) vs. ≤ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome measure was overall survival. Additional efficacy outcome measures were PFS and ORR as assessed by investigator per RECIST v1.1.

In Trial 2, 423 patients were randomized to TAFINLAR plus trametinib (n = 211) or TAFINLAR plus placebo (n = 212). The median age was 56 years (range: 22 to 89 years), 53% were male, >99% were White, 72% had ECOG performance status of 0, 4% had Stage IIIc, 66% had M1c disease, 65% had a normal LDH, and 2 patients had a history of brain metastases. All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing, 85% with BRAF V600E mutations and 15% with BRAF V600K mutations.

In Trial 3, 704 patients were randomized to TAFINLAR plus trametinib (n = 352) or single-agent vemurafenib (n = 352). The median age was 55 years (range: 18 to 91 years), 96% were White, and 55% were male, 6% percent of patients had Stage IIIC, 61% had M1c disease, 67% had a normal LDH, 70% had ECOG performance status of 0, 89% had BRAF V600E mutation-positive melanoma, and one patient had a history of brain metastases.

Trial 2 and Trial 3 demonstrated statistically significant improvements in OS and PFS (see Table 9 and Figures 2 and 3).

Table 9. Efficacy Results in Patients with BRAF V600E or V600K Melanomaa

Endpoint

Trial 2

Trial 3

TAFINLAR plus Trametinib

N=211

TAFINLAR

plus Placebo

N=212

TAFINLAR plus Trametinib

N=352

Vemurafenib

N=352

Overall Survival

Number of deaths (%)

99 (47%)

123 (58%)

100 (28%)

122 (35%)

Median, months
(95% CI)

25.1

(19.2, NR)

18.7

(15.2, 23.1)

NR

(18.3, NR)

17.2

(16.4, NR)

HR (95% CI)

0.71 (0.55, 0.92)

0.69 (0.53, 0.89)

P
value (log-rank test)

0.01

0.005a

Progression-Free Survival (PFS) b

Number of events (%)

102 (48%)

109 (51%)

166 (47%)

217 (62%)

Median, months
(95% CI)

9.3

(7.7, 11.1)

8.8

(5.9, 10.9)

11.4

(9.9, 14.9)

7.3

(5.8, 7.8)

HR (95% CI)

0.75 (0.57, 0.99)

0.56 (0.46, 0.69)

P
value (log-rank test)

0.035

<0.001

Overall Response Rate (ORR) b

ORR, %
(95% CI)

66

(60, 73)

51

(44, 58)

64

(59, 69)

51

(46, 56)

P
value

<0.001

<0.001

CR, %

10

8

13

8

PR, %

56

42

51

43

Median duration of response, months (95% CI)

9.2

(7.4, NR)

10.2

(7.5, NR)

13.8

(11.0, NR)

7.5

(7.3, 9.3)

CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached.
a P-value is comparing with the allocated alpha of 0.021 for the interim analysis based on 77% information.

b PFS and ORR were assessed by investigator.

Figure 2. Kaplan-Meier Curves for Overall Survival in Trial 2

Figure 2
(click image for full-size original)

Figure 3. Kaplan-Meier Curves for Overall Survival in Trial 3

Figure 3
(click image for full-size original)

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