Clinical Trials

Date: 2016-10-08

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the European League Against Rheumatism Annual Congress (EULAR 2015)

Company: Novartis (Switzerland)

Product: combination of dabrafenib and trametinib

Action mechanism:

• kinase inhibitor/RAF kinase inhibitor/MEK (MAP kinase) inhibitor. Dabrafenib is an investigational, orally bioavailable inhibitor of the BRAF protein. 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.
• Tafinlar and Mekinist target different kinases within the serine/threonine kinase family - BRAF and MEK1/2, respectively - in the RAS/RAF/MEK/ERK pathway, which is implicated in NSCLC and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone.
• In April 2014, Novartis  has acquired GSK oncology products including dabrafenib and trametinib. In 2015, as part of its purchase of oncology products from GSK, Novartis obtained the worldwide exclusive rights granted by Japan Tobacco  to develop, manufacture, and commercialize trametinib. Japan Tobacco retains co-promotion rights in Japan.
• In August 2015, the European Commission approved the combination of Tafinlar™ + Mekinist™ for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. In July 2015, the FDA granted priority review for an application to obtain regular approval of the Tafinlar + Mekinist combination in BRAF V600E/K mutation-positive metastatic melanoma. Since January 2014, the combination of Tafinlar + 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 V600E/K mutation.

Disease: metastatic melanoma with BRAF V600 mutations

Therapeutic area: Cancer - Oncology

Country: US, Europe, Canada, Russia, Ukraine, Israel, Argentina, Brazil, Korea, New Zealand, Taiwan, Australia

Trial details:

• COMBI-d (GSK study MEK115306 - NCT01584648) is a Phase III, randomised, double-blinded study comparing the combination of the BRAF inhibitor, dabrafenib, and the MEK inhibitor, trametinib, to dabrafenib and placebo as first-line therapy in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The primary endpoint of the study is progression-free survival and patients will be followed for overall survival. The study seeks to enrol about 340 patients from investigative sites in the US, Europe, Canada, Russia, Ukraine, Argentina, and Australia. COMBI-v (GSK study MEK116513 - NCT01597908) is a Phase III, randomised, open-label study comparing the combination of the BRAF inhibitor, dabrafenib, and the MEK inhibitor, trametinib, to the BRAF inhibitor vemurafenib in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The primary endpoint of the study is overall survival. The study seeks to enrol about 690 patients from investigative sites in the US, Europe, Canada, Russia, Ukraine, Israel, Argentina, Brazil, Korea, New Zealand, Taiwan, and Australia.

Latest news:

• • On October 8, 2016, Novartis announced data from the Phase III COMBI-v study demonstrating an overall survival (OS) and a progression-free survival benefit for patients with BRAF V600 mutation-positive advanced melanoma when treated first-line with the combination of Tafinlar® (dabrafenib) + Mekinist® (trametinib) compared to vemurafenib monotherapy. The results of this study, which was conducted in 704 patients, are being presented at the European Society for Medical Oncology (ESMO) 2016 Congress in Copenhagen. Results from the COMBI-v study found the estimated three-year survival rate to be 45% of patients receiving the combination of Tafinlar + Mekinist (95% CI, 39.1%-49.8%) compared with 31% of patients who received vemurafenib monotherapy (95% CI, 26.1%-36.4%). There were 34 patients who crossed over from the vemurafenib monotherapy arm to the combination arm after the combination demonstrated a significant OS benefit in a prior analysis. Additionally, the estimated three-year progression-free survival rate was 24% (95% CI, 19.4%-28.8%) for the combination arm and 10% (95% CI, 5.9%-14.5%) for the vemurafenib monotherapy arm. At three years of follow up, the combination of Tafinlar + Mekinist continued to demonstrate a benefit on the measures of duration of response (DoR) and overall response rate (ORR), in line with results seen at the two-year follow up analysis. The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for vemurafenib monotherapy; no new safety concerns were observed.
• * On September 28, 2015, Novartis announced updated data from the Phase III COMBI-v study showing a significant overall survival benefit for patients with BRAF V600E/K mutation-positive metastatic melanoma when treated with the combination of Tafinlar® (dabrafenib) + Mekinist® (trametinib) compared to vemurafenib monotherapy. The combination also demonstrated significant health-related quality of life improvements in the trial, including overall health, physical and social functioning. Results are being presented at the European Cancer Congress 2015 in Vienna (Robert C. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Abstract #3301. 18th ECCO - 40th ESMO European Cancer Congress, September 2015, Vienna, Austria). In the COMBI-v study, the combination of Tafinlar + Mekinist achieved a statistically significant overall survival (OS) benefit compared to vemurafenib monotherapy (median for the combination 25.6 months vs 18.0 months; HR 0.66 [95% CI, 0.53-0.81], p<0.001). The rate of OS at two years was 51% for those receiving the Tafinlar + Mekinist combination and 38% for those receiving vemurafenib monotherapy[3]. In addition, the median overall response rate (ORR) was 65.6% in patients receiving the Tafinlar + Mekinist combination compared to 52.8% for those receiving vemurafenib monotherapy. The safety results from this study were consistent with the profile observed to date for the combination; no new safety concerns were observed. Results from the COMBI-v study showed that the combination of Tafinlar + Mekinist achieved a statistically significant OS benefit compared to vemurafenib monotherapy (median for the combination 25.6 months vs 18.0 months; HR 0.66 [95% CI, 0.53-0.81], p<0.001). A statistically significant reduction of 34% in the risk of death among patients receiving combination therapy was observed in the study. The analysis reported median progression free survival (PFS) of 12.6 months, ORR of 65.6%, and median duration of response (DoR) of 13.8 months for the Tafinlar + Mekinist combination arm compared to PFS of 7.3 months, ORR of 52.8%, and median DoR of 8.5 months for the vemurafenib monotherapy arm. The most frequent adverse events in the Tafinlar + Mekinist combination arm (>=30%) were pyrexia, nausea, diarrhea, and chills. More patients had AEs leading to dose modifications in the combination arm compared to the vemurafenib monotherapy arm. For the combination group compared to the vemurafenib group, there was a lower incidence of rash, 22% (n=76) vs 43% (n=149); photosensitivity reaction, 4% (n=13) vs 22% (n=78); hand-foot syndrome, 4% (n=14) vs 25% (n=87); skin papillomas, 2% (n=6) vs 23% (n=80); squamous-cell carcinomas and keratoacanthomas, 1% (n=5) vs 18% (n=63); and hyperkeratosis, 4% (n=15) vs 25% (n=86). Adverse events occurring more frequently in the combination arm compared with the vemurafenib monotherapy arm included pyrexia, 53% (n=184) vs 21% (n=73), respectively, and bleeding events, 18% (n=62) vs 7% (n=25), respectively. Discontinuation of treatment due to adverse events was similar between the treatment groups: 13% (n=44) for the combination group compared to 12% (n=41) for the monotherapy group[3]. Results from an analysis of the COMBI-v study of the patients' health-related quality of life showed statistically significant and clinically meaningful improvements among those receiving the combination of Tafinlar + Mekinist, compared to those receiving vemurafenib monotherapy. Overall health, physical and social functioning, and specific symptoms such as pain, insomnia, and loss of appetite were all improved in the group receiving combination therapy. * On November 16, 2014, GSK announced that results have been published in the New England Journal of Medicine show that treatment with the combination of trametinib (Mekinist™) and dabrafenib (Tafinlar™) significantly improved overall survival (OS) compared to vemurafenib monotherapy in previously untreated patients with BRAF V600E/K mutation-positive metastatic melanoma, without increased overall toxicity. The COMBI-v study demonstrated a 31 per cent decrease in the risk of death for patients treated with the trametinib and dabrafenib combination compared to vemurafenib (Hazard Ratio [HR] 0.69; 95% Confidence Interval [CI] 0.53, 0.89; two-sided P=0.005). Median OS for the vemurafenib arm was 17.2 months; median OS for the combination arm had not been reached. At 12 months, the rate of OS was 72 per cent for the combination arm and 65 per cent for the vemurafenib arm. Treatment with the combination increased median progression-free survival to 11.4 months compared to 7.3 months for the vemurafenib arm. Overall, treatment with the combination resulted in a 44 per cent reduction in risk of disease progression or death (HR, 0.56; 95% CI 0.46, 0.69; two-sided P-value <0.001) compared to vemurafenib. The objective response rate was 64 per cent (95% CI 59.1%, 69.4%) for the combination and 51 per cent (95% CI 46.1%, 56.8%) for vemurafenib (P<0.001); the median duration of response was 13.8 months (95% CI 11.0, not reached) vs. 7.5 months (95% CI 7.3, 9.3), respectively. Additionally, 13 per cent of patients treated with the combination achieved a complete response, compared to 8 per cent of patients in the vemurafenib arm. Dr. Rafael Amado, Head of Oncology R&D at GSK, said: “COMBI-v is the first phase III study that demonstrated a statistically significant improvement in overall survival for a combination of targeted MEK and BRAF therapies compared to a single agent in patients with BRAF V600-mutant melanoma. The data published reinforce our confidence in the efficacy of this combination treatment. We are thankful to the patients, caregivers and investigators for their participation in this study.” Overall the frequency of adverse events (AEs) (98% for the combination and 99% for vemurafenib), severe (grade 3 or 4) adverse events (52% for the combination vs. 63% for vemurafenib group), study drug discontinuations (13% for the combination vs. 12% for vemurafenib) and AEs leading to dose reduction (33% for the combination and 39% for vemurafenib) were comparable in both COMBI-v study arms. The most frequent AEs in the trametinib and dabrafenib combination arm were pyrexia (53%), nausea (35%), diarrhoea (32%), chills (31%), fatigue (29%), headache (29%) and vomiting (29%). Pyrexia was more frequent in the combination arm compared with the vemurafenib arm (53% vs. 21%, respectively). In the vemurafenib arm, the most frequent AEs were arthralgia (51%), rash (43%), alopecia (39%), nausea (36%), diarrhoea (38%) and fatigue (33%). Skin AEs were more frequent in the vemurafenib arm compared with the trametinib and dabrafenib combination arm, in particular rash (43% vs. 22%), photosensitivity reaction (22% vs. 4%), hand-foot syndrome (25% vs. 4%), skin papillomas (23% vs. 2%), skin squamous cell carcinomas and keratoacanthomas (18% vs. <1%) and hyperkeratosis (25% vs. 4%).
• • On July 17, 2014, GSK announced that the Independent Data Monitoring Committee (IDMC) recommended COMBI-v (MEK116513), a phase III study of its MEK inhibitor, trametinib (Mekinist™), in combination with its BRAF inhibitor, dabrafenib (Tafinlar™), compared to vemurafenib in patients with BRAF V600E or V600K mutation-positive unresectable or metastatic cutaneous melanoma be stopped early. This IDMC recommendation is based on an interim analysis which demonstrated an overall survival benefit for the trametinib and dabrafenib combination compared to vemurafenib that crossed the pre-specified efficacy stopping boundary. The safety profile of the trametinib and dabrafenib arm was consistent with the safety profile of the combination observed to date.The IDMC recommendation is based on headline data; further analysis of safety and efficacy data is underway and will be completed in the coming months. Eligible study patients who were randomised to the vemurafenib arm will be allowed to cross over to receive treatment with the trametinib and dabrafenib combination.
• • On January 24, 2014, GSK has announced that a Phase III study of the combination of Tafinlar® (dabrafenib) and Mekinist® (trametinib), compared to single agent therapy with Tafinlar in patients with BRAF V600 E or K mutation positive unresectable or metastatic melanoma, met its primary endpoint of Progression Free Survival (PFS) (p<0.05).This follows the recent accelerated approval of the combined therapy in the USA. PFS, response rate and interim overall survival results for the combination arm were consistent with those seen in the Phase I/II study. In this Phase III study, PFS observed among patients in the single agent dabrafenib arm was greater than that seen in previous single agent dabrafenib studies, leading to a more modest difference in PFS between treatment arms than was observed in the Phase I/II study. In the combination arm, the most commonly reported (>20%) adverse events were pyrexia, fatigue, nausea, headache, chills, diarrhoea, arthralgia, rash, hypertension, and vomiting. Full study results will be presented at an upcoming scientific meeting. These results are from COMBI-d (NCT01584648) a Phase III, randomised, double-blinded study comparing the combination of the BRAF inhibitor, dabrafenib and the MEK inhibitor, trametinib to dabrafenib and placebo as first-line therapy in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma.  The primary endpoint of the study is progression-free survival and patients will be followed for overall survival.  The study randomised 423 patients from investigative sites in Australia, Europe, North and South America.
• COMBI-v (NCT01597908) is a Phase III, randomised, open-label study comparing the combination of the BRAF inhibitor, dabrafenib and the MEK inhibitor, trametinib to the BRAF inhibitor vemurafenib in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma.  The primary endpoint of the study is overall survival and results are anticipated in 2014.
• • On May 29, 2012, GSK has announced the start of a Phase III programme evaluating the combination of dabrafenib, its BRAF inhibitor, and trametinib, its MEK inhibitor, in patients with BRAF mutation-positive metastatic cutaneous melanoma. The studies comprising the programme are:
• • COMBI-d (Combination of MEK and BRAF Inhibitors versus dabrafenib), a Phase III trial of the combination of its MEK inhibitor, trametinib, and its BRAF inhibitor, dabrafenib, in patients with BRAF V600E or V600K mutation-positive metastatic cutaneous melanoma. This global trial will evaluate whether combining the two investigational agents is better than dabrafenib single-agent therapy in stopping or slowing the progression of metastatic melanoma (Progression Free Survival).
• • COMBI-v (Combination of MEK and BRAF Inhibitors versus vemurafenib), a Phase III trial of the combination of its MEK inhibitor, trametinib, and its BRAF inhibitor, dabrafenib, in patients with BRAF V600E or V600K mutation-positive metastatic cutaneous melanoma. This global trial will evaluate whether combining the two investigational agents is better than single-agent therapy with vemurafenib, an approved BRAF inhibitor, in improving the overall survival of patients with metastatic melanoma (Overall survival).
• • Both studies will evaluate the safety profile of the dabrafenib-trametinib combination.

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