VIENNA—For patients with metastatic melanoma, adding a MEK inhibitor to a BRAF inhibitor lowered the odds of progression or death by 61 percent at 12 months, compared with use of a BRAF-inhibitor alone, according to the results of a Phase II study reported here at the European Society for Medical Oncology Congress and published simultaneously online in the New England Journal of Medicine (DOI: 10.1056/NEJMoa1210093).
The median progression-free survival (PFS) time was 9.4 months for patients treated with the BRAF inhibitor dabrafenib (150 mg bid) and the MEK inhibitor trametinib (2 mg) vs. 5.8 months for patients who received only dabrafenib at that dosage.
The combination also significantly improved the response rate and duration of response, said the principal investigator, Georgina Long, BSc, PhD, MBBS, a clinical researcher at Melanoma Institute Australia and Westmead Hospital in Sydney.
In addition, combination therapy caused less cutaneous toxicity (particularly squamous cell carcinoma) than dabrafenib monotherapy, although overall adverse events (particularly pyrexia, nausea, vomiting, and neutropenia), dose reductions, and drug discontinuations were much higher with the combination.
“Never ever before have we combined drugs and seen a reduction in toxicity,” she said. “Significant toxicity was not increased with the combination vs. the single agent.”
The study involved patients with metastatic melanoma harboring the V600E or V600K BRAF mutations, which occur in about 50 percent of all melanomas.
Long explained that in earlier studies, BRAF inhibitors shrank melanoma tumors, but the benefit didn't last because the tumors developed resistance. Since resistance is associated with reactivation of the MEK pathway, typically after five to seven months of treatment, scientists theorized that adding the selective MEK inhibitor trametinib would delay that resistance, thus prolonging response.
The current analysis, which was funded by GlaxoSmithKline, involved 162 patients randomized to receive dabrafenib (150 mg bid) alone or with 1 or 2 mg of the MEK inhibitor as well as 85 patients who were included in an open-label assessment of the safety and pharmacokinetics of various doses of dabrafenib and trametinib.
In the randomized phase of the trial, the median progression-free survival time was 9.4 months with higher-dose trametinib, 9.2 months with lower-dose trametinib, and 5.8 months for dabrafenib alone. The higher dose led to a significantly higher objective response rate of 76 percent vs. 54 percent for monotherapy.
While overall survival data are not yet mature, “the 12-month survival in the full-combination group was 79 percent. We have never seen a 12-month survival of that level in metastatic melanoma,” she said.
The high-dose combination was associated with a lower incidence of squamous-cell skin cancer—seven vs. nine percent—but the difference did not reach statistical significance. The incidence was two percent among patients who received the lower-dose combination, which was significantly lower than with dabrafenib monotherapy.
The most common adverse event was pyrexia, which occurred in 67 percent of patients in the high-dose arm, with five percent having Grade 3 or higher severity. Pyrexia requiring hospitalization occurred in 19 and 25 percent of the 1-mg and 2-mg combination arms, respectively, versus two percent of the monotherapy group.
Long said that the pyrexia is generally manageable, with most of it occurring in the first six weeks. However, it was associated with acute renal failure and hypernatremia due to dehydration is some patients: “We found that corticosteroids were an effective prophylactic to prevent fever in these patients,” she said.
Rash occurred in 20 and 27 percent of the low-dose and high-dose trametinib groups compared with 36 percent of patients in the monotherapy arm. A decrease in ejection fraction occurred in nine percent and four percent of patients in the high-dose and low-dose arms, respectively, with no cases in the monotherapy arm. Alopecia occurred in substantially more patients in the monotherapy arm (34% vs. 9% and 5%).
Other adverse events that occurred more often in the combination therapy included fatigue, nausea, vomiting, and diarrhea.
The session moderator said that two things stood out in terms of toxicity: (1) the pyrexia, which does not appear to be an issue with other BRAF/MEK combinations; and (2) the 35 percent rate of vomiting with the high—i.e., full—dose.
Long responded, “The vomiting was all Grades 1 and 2 and usually associated with fever. It is easily managed and not a big problem. The pyrexia was easily managed. Once we knew how to manage it, we could prevent it with corticosteroids. And the majority of patients have a single episode.
“You stop the drug for 24 to 48 hours, and patients don't have another episode. We are looking at the mechanism. We don't know why it occurs, but we are exploring that. There is not a single drug we have in any cancer that has no toxicity. It is about how you manage it, education, and having a proper plan for managing the pyrexia, which is what we have done through our experience with this trial,” she said.
Asked by a member of the audience how the ejection fraction decrease was managed, Long said, “It was measured by serial echos. It is completely reversible on cessation, and it is no higher than single-agent trametinib. We did try to re-introduce it in several cases, and the patients were fine.”
The Discussant for the study, Reinhard Dummer, MD, PhD, Professor of Dermatology at the University of Zurich Hospital, said, “We are very impressed by the responses. Every patient responded. That is hard to believe. I've never seen something like this.”
Two Phase III studies are ongoing: COMBI-d (Combination of MEK and BRAF Inhibitors versus dabrafenib) and COMBI-v (Combination of MEK and BRAF Inhibitors versus vemurafenib), both looking at the combination of trametinib and dabrafenib in patients with BRAF V600E or V600K mutation-positive metastatic cutaneous melanoma.
Vemurafenib + GDC-0973 Safe
At the same session, researchers reported the results of a Phase Ib dose-escalation and dose-expansion study in 44 patients with advanced/unresectable or metastatic BRAFV600-positive melanoma. The study showed that the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor GDC-0973 is safe, with a maximum tolerated dose of 960 mg twice a day, and a reasonable response rate.
Patients had either not received prior treatment or had disease progression on vemurafenib. They were given vemurafenib alone, GDC-0973 alone, or a combination of the two.
The researcher, Rene Gonzalez, MD, Professor of Medicine and Dermatology and Director of Melanoma Research Clinics at the University of Colorado Comprehensive Cancer Center, said that as of July, six of the 10 dose cohorts had been declared safe. There was one dose-limiting toxicity: a Grade 3 QT prolongation that was determined to be related to vemurafenib 960 mg, and that patient had the drug therapy discontinued.
Gonzalez reviewed the most common and most serious adverse events seen with the combination therapy: Non-acneiform rash, diarrhea, photosensitivity, nausea, ALT elevation, and cutaneous squamous cell carcinoma.
Because he pooled the results rather than reporting how each arm compared, it is not clear whether the combination causes more or less toxicity, except that there were no more dose reductions/interruptions/discontinuations with combination therapy.
“The vast majority of adverse events were very mild and not all related to the drug,” he said. “Discontinuations were very low—less than five percent.”
Waterfall plots of change in tumor size in patients suggested that the combination has activity in both vemurafenib-naïve and vemurafenib-refractory patients.
“Melanoma has been the graveyard of many drugs,” he said. “Preliminary anti-tumor activity in vemurafenib-naïve patients is encouraging.”
Roche helped fund the study, and Gonzalez said a Phase III study is being initiated.
Dummer, who was Discussant for both studies, said that combining a BRAF inhibitor with a MEK inhibitor is “a very exciting development that is really science based. One of the reasons [this progress has been made so quickly] is that it is science-driven.”
So, what do the combinations mean for future treatment of melanoma? “I am fully convinced that resistance mechanisms vary from patient to patient, and we can't predict the resistance mechanism at initiation of toxicity,” he said.
“I'm now convinced the combination of BRAF/MEK will be the first choice for BRAF-mutant patients in the near future. But then, resistance will occur. It will definitely be later, but it will come, and then what are the next steps? I'm sure you can get longer PFS, but you have to make individual solutions.”
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