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Date: 2017-12-22

Type of information: Acceptation for review of a sNDA

Product name: trametinib (Mekinist®) in combination with dabrafenib (Tafinlar®)

Compound: trametinib in combination with dabrafenib

Therapeutic area: Cancer - Oncology

Action mechanism:

  • kinase inhibitor/RAF kinase inhibitor/MEK (MAP kinase) inhibitor. Dabrafenib is a selective inhibitor of BRAF protein kinase carrying V600E mutation. This orally bioavailable inhibitor of B-raf protein binds to and inhibits the activity of B-raf, which may inhibit the proliferation of tumor cells which contain a mutated BRAF gene. B-raf belongs to the the raf/mil family of serine/threonine protein kinases and plays a role in regulating the MAP kinase/ERKs signaling pathway, which may be constitutively activated due to BRAF gene mutations. Dabrafenib was discovered and developed at GSK.
  • Trametinib is an investigational, orally bioavailable inhibitor of the MEK protein discovered by Japan Tobacco, Inc and in-licensed by GSK in 2006.
  • • On April 22, 2014, Novartis has announced that it has acquired GSK oncology pipeline. As part of its purchase of oncology products from GlaxoSmithKline, Novartis obtained the worldwide exclusive rights granted by Japan Tobacco to develop, manufacture, and commercialize trametinib. Japan Tobacco retains co-promotion rights in Japan.

Company: Novartis (Switzerland)

Disease:

  • unresectable or metastatic melanoma with a BRAF V600 mutation
  • adjuvant treatment of patients with stage III melanoma with BRAF V600E or V600K mutations

Latest news:

  • • On December 22, 2017, Novartis announced the FDA has accepted the Company's supplemental New Drug Application (sNDA) for filing, and granted Priority Review designation for Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) for the adjuvant treatment of patients with stage III melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, following complete resection. Priority Review designation is based on results from COMBI-AD, a Phase III study evaluating Tafinlar + Mekinist in patients with stage III BRAF V600E/K mutation-positive melanoma after complete resection. The study met its primary endpoint by significantly reducing the risk of disease recurrence or death by 53% versus placebo (hazard ratio [HR]: 0.47 [95% confidence interval (CI): 0.39-0.58]). The combination treatment group also showed an improvement in the key secondary endpoint of OS (HR: 0.57 [95% CI: 0.42-0.79] p=0.0006, which did not cross the predefined interim analysis boundary of p=0.000019 to claim statistical significance). Other secondary endpoints where the combination demonstrated a clinically meaningful benefit include DMFS (HR: 0.51 [95% CI: 0.40-0.65]), and FFR (HR: 0.47 [95% CI: 0.39-0.57]).
  • Tafinlar in combination with Mekinist is currently approved in the US for patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation as detected by an FDA-approved test and non-small cell lung cancer (NSCLC) with a BRAF V600E mutation.      
  • • On October 23, 2017, Novartis announced that the FDA has granted Breakthrough Therapy Designation for Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) for the adjuvant treatment of patients with stage III melanoma with a BRAF V600 mutation following complete resection. Tafinlar in combination with Mekinist is in development to become the first adjuvant treatment specifically for melanoma patients with a BRAF V600 mutation.
  • The designation is based on results from COMBI-AD, a Phase III study of 870 patients with stage III BRAF V600E/K mutation-positive melanoma after complete surgical resection treated with Tafinlar + Mekinist. Patients received the Tafinlar (150 mg BID) + Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432)[1]. After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. Treatment with the combination therapy significantly reduced the risk of disease recurrence or death by 53% vs. placebo (HR: 0.47 [95% CI: 0.39-0.58]; median not reached vs. 16.6 months, respectively; p<0.001). The RFS benefit among the combination arm was observed across all patient subgroups, including stage III A, B and C. These results were recently presented at the European Society for Medical Oncology Congress (ESMO) and published in the New England Journal of Medicine.,Adverse events (AEs) were consistent with other Tafinlar + Mekinist studies, and no new safety signals were reported[1]. Of patients treated with the combination, 97% experienced an AE; 41% had grade 3/4 AEs and 26% had AEs leading to treatment discontinuation (vs. 88%, 14% and 3%, respectively, with placebo).
  • • On July 24, 2015, Novartis announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for the combination of Tafinlar® (dabrafenib) and Mekinist® (trametinib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. The Company also announced that the FDA has granted priority review for the same patient population. The CHMP positive opinion is based on results from the Phase III COMBI-d and COMBI-v studies. The COMBI-d study showed that the combination of Tafinlar® and Mekinist® achieved a statistically significant overall survival (OS) benefit compared to Tafinlar® monotherapy (median of 25.1 months vs 18.7 months; Hazard Ratio [HR] 0.71 [95% Confidence Interval (CI), 0.55-0.92], p=0.011). In those who received Tafinlar® in combination with Mekinist®, OS was 74% at 1 year and 51% at 2 years versus 68% and 42% for those who received Tafinlar® only, respectively. The COMBI-v study showed that the combination of Tafinlar® and Mekinist® achieved a statistically significant OS benefit compared to vemurafenib monotherapy (median for the combination not reached vs 17.2 months; HR 0.69 [95% CI, 0.53-0.89], p=0.005). In the COMBI-v study, the rate of OS at 1 year was 72% with the combination of Tafinlar® and Mekinist® and 65% for those receiving vemurafenib only. The safety results from these studies were consistent with the profile observed to date for the combination; no new safety concerns were observed. The most common adverse reactions seen for combination therapy in both studies at >=20% include pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, arthralgia, vomiting, hypertension, and cough. Adverse events or toxicities were generally manageable with appropriate intervention, as described in the product labelling submitted with the application. The European Commission will review the CHMP recommendation and is expected to deliver its final decision within three months. The decision will be applicable to all 28 EU member states plus Iceland, Norway and Liechtenstein.The  FDA granted Priority Review in metastatic melanoma for the supplemental New Drug Application (sNDA) for the combination of Tafinlar® and Mekinist®, which included data from the COMBI-d and COMBI-v studies. Since January 2014, the combination of Tafinlar and Mekinist has been approved for use in the US in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma as detected by an FDA-approved test. The combination was approved through the FDA's Accelerated Approval program and reviewed under a Priority Review designation. The approval was contingent on the results of the COMBI-d study, which was designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma with a BRAF V600 mutation. A PDUFA date is in November 2015.
  • • On March 26, 2014, GSK has announced that it has withdrawn its Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for the use of Mekinist® (trametinib) in combination with the previously approved BRAF inhibitor Tafinlar® (dabrafenib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. The application for the use of Mekinist® as a single agent in the same patient population, submitted simultaneously with the MAA for the combination, is still undergoing review by the EMA. The Committee for Medicinal Products for Human Use (CHMP) of the EMA has indicated that the data provided to date by GSK did not allow the Committee to conclude on a positive benefit-risk balance of the combination. GSK intends to re-submit the MAA for the combined use of Tafinlar® and Mekinist® when additional data from the ongoing Phase III programme become available.The regulatory submission for the combination was based on the results from an open-label randomised three-arm phase II study, provided to EMA in 2012. The study aimed to assess the safety and efficacy of dabrafenib in combination with two different doses of trametinib compared to dabrafenib monotherapy in patients with unresectable or metastatic BRAF V600 E or K mutation-positive melanoma.Additional data from the randomised, double-blind Phase III study (COMBI-d) comparing the combination of dabrafenib and trametinib to dabrafenib and placebo as first-line therapy in the same patient population were also provided to EMA earlier this year.
  • • On January 10, 2014, GSK has announced that the 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. 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. The combination was approved through the FDA’s Accelerated Approval programme and reviewed under a Priority Review designation. 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. 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). 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 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%).
  • In May 2013, the FDA approved both drugs as single agents to treat patients with unresectable or metastatic melanoma. 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.
  • • On September 16, 2013, GSK has announced that the FDA has granted Priority Review designation to its supplemental New Drug Applications (sNDAs) for combined use of Tafinlar® (dabrafenib) and Mekinist® (trametinib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 E or K mutation. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target date of 8 January 2014 for the Mekinist® (trametinib) supplement and 9 January 2014 for the Tafinlar® (dabrafenib) supplement. The applications are based on data from a randomised Phase I/II study comparing combination therapy with dabrafenib and trametinib to dabrafenib monotherapy in adult patients with BRAF V600E and V600K mutation positive metastatic melanoma. Use of dabrafenib and trametinib in combination is investigational and not approved anywhere in the world.
• On July 9, 2013, GSK has announced submission of supplemental New Drug Applications (NDAs) to the FDA for use of dabrafenib, a BRAF inhibitor, in combination with trametinib, a MEK inhibitor. Supplemental applications were submitted to each of the currently approved NDAs for the use of each drug in combination with the other, for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 E or K mutation. The applications are based on data from a randomised Phase I/II study comparing dabrafenib monotherapy to combination therapy with dabrafenib and trametinib in patients with BRAF V600E and V600K mutation positive metastatic melanoma. European review of the MAA submission for trametinib, both as monotherapy and in combination with dabrafenib, is ongoing. CHMP has reverted from the accelerated assessment review process to standard timelines to allow sufficient time for review of the submission.
• On February 7, 2013, GSK has announced submission of a Marketing Authorisation Application to the European Medicines Agency (EMA) for trametinib (MEK) as monotherapy and in combination with dabrafenib (BRAF) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. The EMA’s Committee for Medicinal Products for Human Use (CHMP) has granted GSK’s request for accelerated assessment of this application. The application includes data from a randomised, Phase III study of trametinib monotherapy compared to dacarbazine monotherapy in patients with BRAF V600 mutation positive metastatic melanoma, as well as data from a randomised Phase I/II study comparing dabrafenib monotherapy to combination therapy with dabrafenib and trametinib in patients with BRAF V600 mutation positive metastatic melanoma.
The ongoing Phase III development programme for the combination in BRAF V600 mutation positive melanoma comprises three randomised trials: two trials in the metastatic setting (NCT01584648 and NCT01597908) and one trial in the adjuvant setting (NCT01682083). In August 2012, GSK announced regulatory submissions for dabrafenib monotherapy as a treatment for BRAF V600 metastatic melanoma in the EU and US as well as a US submission for trametinib monotherapy as a treatment for BRAF V600 metastatic melanoma.

Patents:

Submission of marketing authorization application USA : 2013-07-09/2017-12-22

Submission of marketing authorization application UE: 2013-02-07

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2014-01-10

UE authorization: 2015-08-25

Favourable opinion UE: 2015-07-23

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

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