VIENNA, Austria—Dual targeted agent therapy against a specific mutation-driven form of advanced melanoma continues to show improvements in overall survival when compared with single-agent monotherapy, researchers said here at the European Cancer Congress.
After two years of first-line therapy with the combination of dabrafenib and trametinib, the median overall survival of patients with unresectable or metastatic melanoma was 25.6 months, compared with 18.0 months for those receiving single-agent vemurafenib, considered a standard of care for these patients.
Caroline Robert, MD, PhD, Head of Dermatology at Gustave Roussy Institute in France, reported the results of the studies, which were sponsored by GlaxoSmithKline. “Dabrafenib plus trametinib has demonstrated superiority over BRAF monotherapy in two Phase III trials, supporting its use as a standard of care in patients with BRAF V600-mutant melanoma,” she said at an ECC news conference that featured the study.
In almost every category of efficacy, the combination therapy appeared superior to use of vemurafenib alone in the Phase III, randomized trial—specifically:
- More patients receiving dabrafenib/trametinib achieved a complete response—59 of 351 patients (17%), versus 36 of 350 patients (10%) taking vemurafenib;
- The trend for patients achieving an objective partial response was similar: 172 patients (49%) of those on dual therapy compared with 150 (43%) of those on monotherapy;
- Overall, 66 percent of patients on the dual-agent therapy had an objective response compared with 53 percent of patients assigned to vemurafenib; and
- The duration of response was 13.8 months with dabrafenib/trametinib compared with 8.5 months for vemurafenib.
While combination treatment would intuitively seem to be the way to go to improve efficacy, Robert noted that there are numerous studies that show that dual agents add little efficacy to treatment, while adding considerable adverse events: “We wanted to see if the additional time showed signals of adverse events with the dual-therapy treatment, but we did not observe that. The rates of adverse events were quite similar—about 12 percent of patients on the combination treatment permanently discontinued treatment due to adverse events compared with 10 percent of the patients on vemurafenib.”
Proto-oncogene BRAF V600E/K Mutation
In the trial, researchers screened 1,645 patients with melanoma. seeking individuals whose tumors expressed the proto-oncogene BRAF V600E/K mutation, the target of the agents used in the study. The patients were eligible for the study if they were diagnosed with stages IIIC or IV cutaneous melanoma and had not been treated for advanced or metastatic melanoma.
The patients were required to be in good ECOG performance status (0-1), and had to be free of brain metastases upon entry into the study, or those brain metastases had to be under treatment.
Patients were stratified by the type of mutation and by their levels of lactate dehydrogenase, which is a marker of tissue injury.
A total of 704 patients were eventually enrolled in the study, with 352 assigned to each treatment arm. The patients were treated with dabrafenib at 150 mg twice a day plus trametinib at 2 mg once daily, or with vemurafenib at 960 mg twice a day.
Baseline characteristics were well balanced between the two groups, except for gender. The combination arm had contained 59 percent men, compared with 51 percent in the vemurafenib arm. The median duration of treatment following progression was similar between the two arms of the study. Nine percent of patients received the combination for six to 12 months, compared with one percent in the vemurafenib arm.
“What is quite promising,” she said, “is that 98 patients in the combination arm remain on treatment compared with just 33 patients on vemurafenib therapy after two years. We hope this means that these patients are still responding to treatment.”
Trial Truncated for Efficacy
In April 2014, the independent data monitoring committee recommended that the trial be truncated for efficacy. Patients receiving vemurafenib were permitted to cross over to the dual-agent arm of the trial. At that point, the researchers reported that at 18 months, about 60 percent of the patients on dual therapy were alive compared with 50 percent of those on vemurafenib.
In the updated analysis that includes an additional 11 months of follow-up (March 2015 cut-off), Robert reported that 51 percent of the patients on dual therapy remained alive compared with 38 percent of the patients who had been assigned to vemurafenib.
“We observed a statistically significant reduction of 34 percent in the risk of death among patients receiving the combination therapy. 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. 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.”
The moderator of the news conference, Peter Naredi, MD, Professor and Chairman of Surgery at Sahlgrenska Academy of the University of Gothenburg in Sweden, said: “We have been using medications for treating advanced melanoma for many years, but in the last six or seven years we have found more effective drugs. Today we have heard about a combination that really makes a difference in the clinic.
“This is not the only way to make a difference, because we also have immunotherapy we can use in these patients. This has changed clinical practice. Every time we hear of these new data, we are so amazed at how we have improved outcomes for these patients.”
Robert demonstrated that treatment with the combination had an even more pronounced impact over the monotherapy arm when the patients were stratified by lactate dehydrogenase (LDH) levels: Patients with lower levels of LDH who received vemurafenib had a median overall survival of 21.5 months, versus a median overall survival out to more than 30 months and not yet reached for patients on the dual-treatment arm.
In an analysis of progression-free survival based on LDH levels, the median time to progression was 17.5 months with the dual-treatment regimen compared with 9.2 months for those on vemurafenib, Robert said. “The treatment of patients with high lactate dehydrogenase levels continues to be an area of unmet need.” The treatments available now do not markedly help this subgroup of patients.
“This combination therapy is already available in the U.S. and now also in Europe as a result of the European Commission's decision to approve its use,” she added. “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 use in patients with unresectable or metastatic BRAF-mutant melanoma. In the United States, the combination was granted an accelerated approval for BRAF-mutant melanoma in January 2014 (OT 2/10/14 issue), and an application for full approval was submitted to the FDA in July 2015.
A Phase III study being conducted by the National Cancer Institute is now looking at dabrafenib and trametinib followed by ipilimumab and nivolumab or the reverse sequence in patients with stage III/IV BRAF-mutant melanoma. Additionally, a study will be opened soon at the University of Pittsburgh to explore nivolumab in combination with dabrafenib and/or trametinib.
All the abstracts from the meeting are available at: http://bit.ly/ECC2015-search