2013年9月3日讯 /生物谷BIOON/ --葛兰素史克（GSK）9月2日宣布，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疗。
Dabrafenib是一种激酶抑制剂，靶向于BRAF蛋白，这是机体内一个生物信号通路中的关键元件，该信号通路调节细胞的正常生长和死亡，包括皮肤细胞。
今年5月，Tafinlar及另一种黑色素瘤新药Mekinist（trametinib）均获得了FDA的批准。Tafinlar为BRAF抑制剂，作为一种单药口服胶囊，适用于携带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疗。Mekinist为首个MEK抑制剂，作为一种单药口服片剂，适用于携带BRAF V600E或V600K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疗。
转移性黑色素瘤中，约有一半携带BRAF突变，该异常突变能促使黑色素瘤生长和扩散，其中BRAF V600E突变约占转移性黑色素瘤所有BRAF V600突变的85%，BRAF V600K突变约占转移性黑色素瘤所有BRAF V600突变的10%。
TAFINLAR
Pharmacological Class:
Kinase inhibitor.

Active Ingredient(s):
Dabrafenib 50mg, 75mg; caps.

Company
GlaxoSmithKline Pharmaceuticals
Indication(s):
Treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation, as detected by an FDA-approved test. Limitation of use: not indicated for the treatment of patients with wild-type BRAF melanoma.

Pharmacology:
Dabrafenib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.

Clinical Trials:
The safety and efficacy of Tafinlar 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 were randomized to receive Tafinlar 150mg twice daily (N = 187) or dacarbazine 1000mg/m2 IV every 3 weeks (N = 63). The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. All patients had tumor tissue with mutations in BRAF V600E as determined by a clinical trial assay. Tumor samples from 243 patients (97%) were tested retrospectively, using an FDA-approved companion diagnostic test, THxID-BRAF assay.

The study demonstrated a statistically significant increase in PFS in the patients treated with Tafinlar. In terms of PFS, the Tafinlar treatment arm showed a lower number of events (disease progression or death), in terms of percentage, compared to the dacarbazine treatment arm (42% [78/187] vs. 65% [41/63], respectively). Also, the Tafinlar treatment arm showed a longer median PFS compared to the dacarbazine treatment arm (5.1 months vs. 2.7 months), respectively (HR 0.33, [95% CI: 0.20, 0.54], P<0.0001). For confirmed tumor responses, the Tafinlar treatment arm showed a higher objective response rate compared to the dacarbazine arm (52% [95% CI: 44, 59] vs. 17% [95% CI: 9, 29], respectively), with 6 patients from the Tafinlar arm achieving complete response and no complete responses from the dacarbazine arm.

For more information on clinical trials, see full labeling.

Legal Classification:
Rx

Adults:
Confirm presence of BRAF V600E mutation prior to initiation. Swallow whole. Take at least 1 hour before or 2 hours after a meal. 150mg twice daily, about 12 hours apart until disease progression or unacceptable toxicity. Dose modifications or reductions: see full labeling.

Children:
Not established.

Warnings/Precautions:
Increased incidence of new primary cutaneous malignancies; perform skin eva luation prior to initiation, every 2 months during therapy, and up to 6 months after discontinuation. Withhold if fever ≥101.3°F or any serious febrile drug reaction occurs and eva luate for infection; prophylaxis with antipyretics may be needed when resuming. Pre-existing diabetes or hyperglycemia; monitor serum glucose levels. Monitor for visual signs/symptoms of uveitis. Closely monitor patients with G6PD deficiency for signs of hemolytic anemia. Males (risk of infertility). Embryo-fetal toxicity. Females of reproductive potential should use highly effective non-hormonal contraception during and for 4 weeks after treatment. Pregnancy (Category D). Nursing mothers: not recommended.

Interaction(s)
Concomitant strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of CYP3A4 or CYP2C8: not recommended; if unavoidable, monitor closely. Drugs that affect gastric pH (eg, PPIs, H2-blockers, antacids) may decrease dabrafenib exposure. May antagonize effects of CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT, transporters, or other substrates (eg, midazolam, warfarin, dexamethasone, hormonal contraceptives).

Adverse Reaction(s)
Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia syndrome.

How Supplied:
Caps—120

LAST UPDATED:
9/20/2013