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Administering an immunotherapy combination before targeted agents in previously untreated patients with advanced BRAF V600-positive melanoma achieved greater overall survival (OS) than the reverse order, a phase III study found.

Results from the DREAMseq trial, which was halted early due to the findings, demonstrated an absolute OS improvement of 20% at the 2-year mark for the group assigned to initial treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy), followed by dabrafenib (Tafinlar) and trametinib (Mekinist) at disease progression, reported Michael B. Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., and colleagues.

The 2-year OS rates were:

• 72% (95% CI 62-81%) with nivolumab-ipilimumab first
• 52% (95% CI 42-62%) with dabrafenib-trametinib first

The superior OS with immunotherapy upfront became evident after 10 months of treatment, and the approach demonstrated a longer duration of response, as well as more ongoing responses, the investigators found.

Initial overall response rates (ORRs) were 46% with nivolumab-ipilimumab (median duration of response not reached) and 43% with dabrafenib-trametinib (median duration 12.7 months).

The results were conclusive enough that the trial's data and safety monitoring committee and the NCI Cancer Therapy Evaluation Program recommended halting accrual and releasing the data, which will be presented on Tuesday during a session of the inaugural .

"The drug combinations tested in this trial all improve survival compared to prior standards of care, but we now know which combination should be administered first to achieve maximum benefit for the vast majority of our patients," Atkins said in a press release. "This trial should provide clearer guidance."

While immune checkpoint inhibitors and BRAF/MEK inhibitors have both demonstrated antitumor efficacy and an OS benefit in patients with BRAF V600-mutant metastatic melanoma, no prospective data were available to indicate the optimal treatment sequence for these drugs, noted Atkins and colleagues.

"The study results from DREAMseq answer one of the most important clinical questions in our care of patients with advanced melanoma," commented Lynn Schuchter, MD, of the University of Pennsylvania in Philadelphia, in an ASCO press release. "For patients with melanoma with [a] BRAF V600 mutation who have not received prior therapy, the results clearly show better overall survival when combination immunotherapy is selected first. In an era of remarkable advances for patients with melanoma, this study is an important addition to understanding the best approach to provide the very best care."

Although this trial focused on melanoma, Atkins suggested it could have "significant implications for the treatment of other forms of cancer where immunotherapies are increasingly part of treatment regimens."

Starting in 2015, the DREAMseq study enrolled 265 patients (median age 61 years, 63% male) with treatment-naive BRAF V600-mutant metastatic melanoma (stratified by performance status 0 or 1, and lactate dehydrogenase level).

Patients were randomized 1:1 to receive step 1 treatment: nivolumab-ipilimumab (arm A) or dabrafenib-trametinib (arm B). Upon disease progression these patients were enrolled in step 2, which involved the alternate combination: switch to targeted therapies (arm C) or switch to immunotherapy (arm D). The primary endpoint of the trial was 2-year OS.

At a median follow-up of 27.7 months, there were 100 deaths in the trial, with 38 occurring in patients who started on nivolumab-ipilimumab first and 62 in those who started on the targeted therapies first. Progression-free survival showed a trend favoring the group that started on immunotherapy first.

At data cutoff, 37 of 42 assessed patients (88%) in the immunotherapy-first group remained in response, as compared to 19 of 37 patients (51%) from the targeted therapy-first group.

With regard to responses to second-line treatment following progression, ORRs were 48% with dabrafenib-trametinib for patients who initially started on the immunotherapy, and 30% for nivolumab-ipilimumab for the group who started on targeted agents.

For safety, grade ≥3 toxicity was slightly higher with the immunotherapy-first strategy, at 60% versus 52% with the targeted therapy-first approach. There were three treatment-related deaths among patients who started on immunotherapy first, two during the nivolumab-ipilimumab phase and one after switching to the targeted combination.

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