这是FDA批准用于不可切除性或转移性BRAF V600E或V600K阳性黑色素瘤的首个口服靶向组合疗法。
Tafinlar和Mekinist是GSK开发的2种黑色素瘤新药，均于2013年5月获得了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。Tafinlar不适用于野生型BRAF黑色素瘤患者的治疗。Mekinist不适用于既往接受过BRAF抑制剂疗法的患者的治疗。
该组合疗法，是FDA通过一项优先审查资格认定审查，并通过加速审批程序批准。该组合的获批，是基于一项I/II期研究中响应率和响应持续时间。目前尚未证实该组合疗法对疾病相关症状及总生存期的改善。
英文原文：GSK gains accelerated FDA approval for combination use of Mekinist® (trametinib) and Tafinlar® (dabrafenib)
- First approved combination of oral targeted therapies for unresectable or metastatic melanoma with BRAF V600E or V600K mutations[i]
GlaxoSmithKline plc [LSE/NYSE: GSK ] announced today that the U.S. Food and Drug Administration (FDA) has approved Mekinist® (trametinib) for use in combination with Tafinlar® (dabrafenib) for the treatment of patients with unresectable melanoma (melanoma that cannot be removed by surgery) or metastatic melanoma (melanoma which has spread to other parts of the body) with BRAF V600E or V600K mutations. These mutations must be detected by an FDA-approved test.1 Tafinlar is not indicated for treatment of patients with wild-type BRAF melanoma.[ii]
The approval of the combination is based on the demonstration of response rate and median duration of response in a Phase I/II study. Improvement in disease-related symptoms or overall survival has not been demonstrated for Mekinist in combination with Tafinlar.1 The combination was approved through the FDA’s Accelerated Approval programme and reviewed under a Priority Review designation.[iii] This accelerated approval is contingent on the results of the ongoing Phase III trial (referred to as MEK115306 or Combi-D), which is designed to evaluate the clinical benefit of the combination in this patient population.
“This approval marks another key moment in what continues to be a rapid evolution of the treatment landscape for metastatic melanoma patients. Combining agents that target different mechanisms regulating the growth of cancer cells is one of the promising areas in cancer research,” said Dr. Paolo Paoletti, President of Oncology, GSK. “We are proud that the first approved combination of targeted therapies in metastatic melanoma is Mekinist and Tafinlar, and our hope is that it will become part of the new standard of care for appropriate patients with BRAF V600E or V600K mutation-positive metastatic melanoma.”
The results from the randomised Phase II part of the Phase I/II open-label study, which evaluated the combination of trametinib and dabrafenib at the recommended dose (150/2mg) (N=54) and single-agent dabrafenib (150mg) (N=54)1, were as follows：
The investigator-assessed overall response rate (ORR) (main efficacy endpoint) was 76% (95% CI, 62, 87) for patients treated with the combination, and 54% (95% CI, 40, 67) for patients treated with single-agent dabrafenib. The median duration of response was 10.5 months (95% CI, 7, 15) for patients treated with the combination, and 5.6 months (95% CI, 5, 7) for patients treated with single-agent dabrafenib.
Data analyses of the blinded independent radiologic review committee (IRRC) supported the investigator results. The IRRC-assessed ORR was 57% (95% CI, 43, 71) for patients treated with the combination, and 46% (95% CI, 33, 60) for patients receiving single-agent dabrafenib. The median duration of response as assessed by the IRRC was 7.6 months (95% CI, 7, NR) for patients treated with the combination, and 7.6 months (95% CI, 6, NR) for patients treated with single-agent dabrafenib.
Trametinib in combination with dabrafenib can cause serious side effects, some of which can be life threatening, including: new primary cutaneous malignancies (new skin cancers); tumour promotion in wild-type BRAF melanoma; haemorrhagic events (symptomatic bleeding in a critical area or organ); venous thromboembolic events (blood clots); cardiomyopathy (heart problems, including heart failure); ocular (eye-related) toxicities; interstitial lung disease (ILD); serious febrile drug reactions (severe fevers); serious skin toxicity (rash); hyperglycaemia (blood sugar problems); haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; and embryofoetal toxicity (potential harm to the unborn baby in pregnant women).1,2
The most frequently occurring adverse reactions at the recommended dose of trametinib 2mg once daily in combination with dabrafenib 150mg twice daily (all grades in more than 20% of patients) in the randomised part of Phase I/II study included: pyrexia (fever) (71%), chills (58%), fatigue (53%), rash (45%), nausea (44%), vomiting (40%), diarrhoea (36%), abdominal pain (33%), oedema peripheral (swelling of tissues, usually in the lower limbs) (31%), cough (29%), headache (29%), arthralgia (27%), night sweats (24%), decreased appetite (22%), constipation (22%) and myalgia (muscular pain) (22%). The most common (≥2%) Grade 3 or 4 adverse events observed in the combination group in this study were: renal failure (7%), pyrexia (5%), back pain (5%), haemorrhage (5%), fatigue (4%), chills (2%), nausea (2%), vomiting (2%), diarrhoea (2%), abdominal pain (2%), myalgia (2%) and urinary tract infection (2%).
Details Behind the Trametinib and Dabrafenib Combination Clinical Data
The safety of trametinib (2mg once daily) in combination with dabrafenib (150mg twice daily) was evaluated in 202 patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma enrolled in a Phase I/II study. FDA approval of the combination therapy was based on the demonstration of response rate and median duration of response in a multicentre, open-label, randomised, active-controlled, dose-ranging part of the Phase I/II study enrolling patients with histologically-confirmed Stage IIIC or IV melanoma determined to be BRAF V600E or V600K mutation-positive. No more than one prior chemotherapy regimen and/or interleukin-2 were permitted. Patients with prior exposure to BRAF inhibitors or MEK inhibitors were ineligible. The main efficacy outcome measure was investigator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration of response, IRRC-assessed ORR, and IRRC-assessed duration of response.
Trametinib was in-licensed by GSK in 2006. GSK holds the worldwide exclusive rights to develop, manufacture and commercialise Mekinist, while Japan Tobacco retains co-promotion rights in Japan.The PDUFA date for the update to the Tafinlar label is 9 January 2014.
