Dabrafenib/Trametinib Improves Overall Survival in Advanced Melanoma

Caroline Robert, MD

Caroline Robert, MD

Dabrafenib (Tafinlar), in combination with trametinib (Mekinist), improved overall survival (OS) by 7.6 months, compared to the single-agent vemurafenib (Zelboraf) in patients who have unresectable or metastaticBRAFV600E/K-mutant melanoma, according to a 2-year analysis of a phase II COMBI-v study that was presented at this year’s European Cancer Congress.

At the longer analysis, the median OS with dabrafenib/trametinib was 25.6 months compared with 18 months for vemurafenib (HR, 0.66; 95% CI, 0.53-0.81;P<.001). The estimated 2-year OS rate was 51% for the combination, compared with 38% for vemurafenib monotherapy.

&ldquo;We observed a statistically significant reduction of 34% in the risk of death among patients receiving the combination therapy,&rdquo; said lead investigator Caroline Robert, MD, a medical oncologist at Gustave Roussy Institute in Villejuif, France, in a statement. &ldquo;The increased survival among these patients is remarkable, and this median overall survival of more than two years is the longest in this category of patients in a phase III randomized trial.&rdquo;

The COMBI-v trial randomized 704 patients to receive the combination of the MEK inhibitor trametinib and the BRAF inhibitor dabrafenib (n = 352), or monotherapy with the BRAF inhibitor vemurafenib (n = 352). In the combination arm, dabrafenib was administered at 150 mg twice daily with trametinib at 2 mg once daily. Vemurafenib was administered at 960 mg twice daily.

Baseline characteristics were well balanced between the two groups, except for gender. The combination arm contained 59% men, compared with 51% in the vemurafenib arm. The median duration of treatment following progression was similar between arms. Nine percent of patients received the combination for 6 to 12 months, compared with 1% in the vemurafenib arm.

The primary endpoint of the trial was OS, with secondary endpoints focused on progression-free survival (PFS), response, and safety. As a result of a recommendation given by an Independent Data Monitoring Committee, the study ended early, following the demonstration of benefit at an interim analysis (P<.0214). Crossover from the combination arm to vemurafenib was not allowed.

At the updated analysis, the median PFS was 12.6 months with the combination versus 7.3 months for vemurafenib (HR, 0.61; 95% CI, 0.51-0.73;P<.001). &ldquo;The 12.6 months of progression-free survival for patients on the combination treatment is the longest achieved in a randomized study for patients with the BRAFV600 mutation to date,&rdquo; Robert commented.

In the earlier analysis of the study, conducted on less mature data, the median OS had not yet been reached, compared with 17.2 months for vemurafenib (HR = 0.69;P= .002).²At this time, the 1-year OS rate was 72% versus 65% for the combination and monotherapy, respectively. The median PFS was 11.4 months with the combination versus 7.3 months with the single-agent (HR, 0.56; 95% CI, 0.46-0.69;&nbsp;P<.001)

The most frequently reported adverse events (AEs) for the combination, compared with vemurafenib, respectively, were pyrexia (53% vs 21%), chills (31% vs 8%), and vomiting (29% vs 15%). Discontinuation of treatment due to AEs was similar between the treatment groups (13% vs 12%).

A number of events were lower with the combination, specifically the incidence of rash (22% vs 43%), particularly grade 3 rash (1% vs 9%). Additionally, AEs were less frequent with the combination versus single-agent for photosensitivity reaction (4% vs 22%), hand-foot syndrome (4% vs 25%), skin papillomas (2% vs 23%), squamous-cell carcinomas and keratoacanthomas (1% vs 18%), and hyperkeratosis (4% vs 25%).

&ldquo;This combination therapy is already available in the US and now also in Europe as a result of the European Commission&rsquo;s decision to approve its use," added Robert. "This long-term benefit in terms of overall survival confirms the major potential of this combination in patients with metastatic melanoma."

In September 2015, the combination of dabrafenib and trametinib was approved by the European Commission for unresectable or metastaticBRAF-mutant melanoma. In the United States, the combination was granted an accelerated approval forBRAF-mutant melanoma in January 2014. An application for full approval was submitted to the FDA in July 2015, based on findings from the COMBI-v and COMBI-d studies.

In the phase III COMBI-d trial, 423 patients withBRAFV600E/K-mutant melanoma were randomized to receive dabrafenib with trametinib (n = 211) or placebo (n = 212). In a final analysis of the study presented at the 2015 ASCO Annual Meeting,³the combination demonstrated a median OS of 25.1 months compared with 18.7 months with dabrafenib alone (HR, 0.71; 95% CI, 0.55-0.92;&nbsp;P= .011). The 2-year OS rate with the combination was 51% versus 42% with the single-agent.

"A further question to investigate is the combination treatment versus new immunotherapies or combined with them," concluded Robert.

A phase III study being conducted by the National Cancer Institute is looking at dabrafenib and trametinib followed by ipilimumab and nivolumab or the reverse sequence in patients with stage III/IVBRAF-mutant melanoma (NCT02224781). Additionally, a study will be opened soon at the University of Pittsburgh, and it will explore nivolumab in combination with dabrafenib and/or trametinib (NCT02357732).

Outside of melanoma, the combination of dabrafenib and trametinib continues to be explored across a number of settings. In July 2015, the FDA granted a breakthrough therapy designation to the combination for patients with non—small cell lung cancer (NSCLC). Additionally, as a single-agent, dabrafenib was granted a breakthrough designation for NSCLC in January 2014.

References:

1. Robert C, Karaszewska B, Schachter J, et al. 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. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 3301.
2. Robert C, Karaszewska B, Schachter J, et al. Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib.N Engl J Med. 2015; 372:30-39.
3. Long GV, Stroyakovsky DK, Gogas H, et al. COMBI-d: a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma.J Clin Oncol.2015;33 (suppl; abstr 102).