Data for COMBI-v Study Now Published
11/17/2014
Data demonstrating 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, are now published. Findings from the COMBI-v study appear in the New England Journal of Medicine.
In the COMBI-v study there was a 31% 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% for the combination arm and 65% 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% 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% (95% CI 59.1%, 69.4%) for the combination and 51% (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% of patients treated with the combination achieved a complete response, compared to 8% of patients in the vemurafenib arm.
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%).
About COMBI-v: This phase III, randomised (1:1), open-label study compared the combination of dabrafenib and trametinib to vemurafenib in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. COMBI-v enrolled 704 patients from investigative sites in the USA, Europe, Canada, Russia, Ukraine, Israel, Argentina, Brazil, Korea, New Zealand, Taiwan and Australia.
The primary objective of the study was to evaluate dabrafenib and trametinib combination therapy vs. vemurafenib with respect to OS. Secondary objectives evaluated and compared dabrafenib and trametinib combination therapy versus vemurafenib with respect to progression-free survival, overall response rate and duration of response. The safety of dabrafenib and trametinib combination therapy, including incidences of squamous cell carcinoma and other proliferative skin diseases, was also evaluated.
These interim analysis for the trametinib and dabrafenib combination—performed after 77% of the total number of expected events—crossed the pre-specified interim-stopping boundary (P<0.0214). As a result, in July 2014, an independent data monitoring committee recommended that the study be stopped early, therefore this data represents the final analysis. At that time, eligible study patients randomised to the vemurafenib arm were allowed to cross over to receive treatment with the trametinib and dabrafenib combination.
About cutaneous melanoma: Cutaneous melanoma is the most aggressive form of all skin cancers. Worldwide, it is expected that over 132,000 people will be diagnosed with melanoma each year and more than 37,000 people are expected to die of this tumour disease annually. In the U.S. and most countries of the Western World including Australia, the incidence of melanoma continues to rise faster than any other type of cancer in men and the annual increase in the incidence of melanoma in women is second only to lung cancer.1,2
About trametinib (Mekinist) and dabrafenib (Tafinlar): Combination use of trametinib and dabrafenib in patients with unresectable or metastatic melanoma who have BRAF V600E or K mutation is approved only in the U.S. and Australia.
Trametinib was in-licensed by GSK in 2006 from Japan Tobacco Inc. (JTI). GSK holds the worldwide exclusive rights to develop, manufacture, and commercialise trametinib, while JTI retains co-promotion rights in Japan.
Tafinlar and Mekinist are registered trademarks of the GSK group of companies.
1 Linos E, Swetter SM, Cockburn MG, et al. Increasing burden of melanoma in the United States. J Invest Dermatol. 2009; 129 (7): 1666-1674.
2 Ries LAG, Melbert D, Krapcho M et al (eds). SEER cancer statistics review1975-2005: National Cancer Institute, Bethesda MD, http://seer.cancer.gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER web site, 2008.
In the COMBI-v study there was a 31% 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% for the combination arm and 65% 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% 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% (95% CI 59.1%, 69.4%) for the combination and 51% (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% of patients treated with the combination achieved a complete response, compared to 8% of patients in the vemurafenib arm.
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%).
About COMBI-v: This phase III, randomised (1:1), open-label study compared the combination of dabrafenib and trametinib to vemurafenib in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. COMBI-v enrolled 704 patients from investigative sites in the USA, Europe, Canada, Russia, Ukraine, Israel, Argentina, Brazil, Korea, New Zealand, Taiwan and Australia.
The primary objective of the study was to evaluate dabrafenib and trametinib combination therapy vs. vemurafenib with respect to OS. Secondary objectives evaluated and compared dabrafenib and trametinib combination therapy versus vemurafenib with respect to progression-free survival, overall response rate and duration of response. The safety of dabrafenib and trametinib combination therapy, including incidences of squamous cell carcinoma and other proliferative skin diseases, was also evaluated.
These interim analysis for the trametinib and dabrafenib combination—performed after 77% of the total number of expected events—crossed the pre-specified interim-stopping boundary (P<0.0214). As a result, in July 2014, an independent data monitoring committee recommended that the study be stopped early, therefore this data represents the final analysis. At that time, eligible study patients randomised to the vemurafenib arm were allowed to cross over to receive treatment with the trametinib and dabrafenib combination.
About cutaneous melanoma: Cutaneous melanoma is the most aggressive form of all skin cancers. Worldwide, it is expected that over 132,000 people will be diagnosed with melanoma each year and more than 37,000 people are expected to die of this tumour disease annually. In the U.S. and most countries of the Western World including Australia, the incidence of melanoma continues to rise faster than any other type of cancer in men and the annual increase in the incidence of melanoma in women is second only to lung cancer.1,2
About trametinib (Mekinist) and dabrafenib (Tafinlar): Combination use of trametinib and dabrafenib in patients with unresectable or metastatic melanoma who have BRAF V600E or K mutation is approved only in the U.S. and Australia.
Trametinib was in-licensed by GSK in 2006 from Japan Tobacco Inc. (JTI). GSK holds the worldwide exclusive rights to develop, manufacture, and commercialise trametinib, while JTI retains co-promotion rights in Japan.
Tafinlar and Mekinist are registered trademarks of the GSK group of companies.
1 Linos E, Swetter SM, Cockburn MG, et al. Increasing burden of melanoma in the United States. J Invest Dermatol. 2009; 129 (7): 1666-1674.
2 Ries LAG, Melbert D, Krapcho M et al (eds). SEER cancer statistics review1975-2005: National Cancer Institute, Bethesda MD, http://seer.cancer.gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER web site, 2008.
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