Press Release: Practice-changing trial results for advanced skin cancer

Philadelphia, November 16, 2021 — Determining the optimal treatment sequence for patients with BRAF V600 mutant metastatic melanoma was the focus of the DREAMseq phase 3 clinical trial. The combination of nivolumab and ipilimumab, followed by dabrafenib and trametinib if there was disease progression, led to a significant improvement in estimated 2-year overall survival from the start of treatment (72%) when compared to the opposite treatment sequence (52%). The findings were presented today at the Inaugural American Society of Clinical Oncology Virtual Plenary Series. The trial was sponsored by the National Cancer Institute, part of the National Institutes of Health.

"We found a 20% increase in two-year survival with a treatment sequence that begins with immunotherapy followed by targeted drugs if disease progression occurred versus beginning with targeted therapy," said lead author Michael B. Atkins, MD, a medical oncologist and deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

“Even though the current practice for many physicians is to start treatment with targeted therapy for patients with melanoma that has the BRAF gene mutation, the DREAMseq trial provides strong evidence that immunotherapy is the better initial approach,” said Dr. Atkins.

The DREAMseq (EA6134) trial sought to improve survival for patients found with stage 3 or 4 skin cancer that had spread beyond its local area and could not be removed by surgery. To be eligible, patients needed to have BRAF V600 mutations in the tumor cells. These mutations drive cancer growth and are present in roughly 40% - 50% of melanomas. As a result, BRAF testing is recommended for patients with metastatic melanoma.

“Beginning with immunotherapy also led to longer durations of response and more ongoing responses than the treatment beginning with the targeted drugs,” said Dr. Atkins.

Melanoma can be highly aggressive, and existing treatments often stop working.

"After years of research, we have many exciting and effective new combination treatment regimens. As a result, patients with advanced melanoma and their physicians often find themselves with multiple treatment options but few answers to questions surrounding how and when to use these new approaches,” said Dr. Atkins. “The DREAMseq trial provides the first prospective data on what sequence of these treatments best extends the lives of our patients."

The DREAMseq trial enrolled 265 out of a proposed 300 patients between July 2015 and July 16, 2021 (cut-off date for data). At the fourth interim analysis in September 2021, with 59% of patients being two years from enrollment, the ECOG-ACRIN Data Safety Monitoring Committee noted a clinically meaningful efficacy benefit in favor of the treatment sequence beginning with immunotherapy that emerged around ten months. Therefore, the committee recommended stopping patient enrollment in the trial. On September 30, 2021, ECOG-ACRIN and the National Cancer Institute's Cancer Therapy Evaluation Program notified physicians and patients.

"These results are practice-changing and establish nivolumab and ipilimumab followed by targeted therapy if progression is observed as the preferred treatment approach for the vast majority of patients with BRAF V600 mutant metastatic melanoma," said Dr. Atkins.

DREAMseq is a randomized trial design. Half of the patients (133) were randomly assigned to begin treatment with the combination of nivolumab and ipilimumab immunotherapy. If the medicine stopped working and the disease became worse, patients received a second, different treatment of two other drugs, dabrafenib and trametinib. Dabrafenib and trametinib, given together, block the signaling pathway of abnormal BRAF molecules. This action slows or stops the out-of-control cell growth.

For the other half of the patients (132), the scenario was reversed. They were randomly assigned to begin treatment with the two molecularly targeted drugs. If those drugs stopped working and the disease became worse, they were treated with the immunotherapy combination.

The trial's primary endpoint was two-year overall survival. Researchers continue to follow patients and will report three-year overall survival in the future, along with the results of other secondary and correlative endpoints.

The latest Annual Report to the Nation on the Status of Cancer 2021 states that melanoma death rates declined between 2014 and 2018 in both men and women. The trend reflects a significant increase in survival due to improved treatment options, among other factors.

The National Cancer Institute (NCI) provided ECOG-ACRIN with primary funding support for this trial. ECOG-ACRIN received additional funding support from Bristol-Myers Squibb, the manufacturer of ipilimumab (brand name Yervoy®) and nivolumab (Opdivo®), and from Novartis Pharmaceuticals, the company that commercializes dabrafenib (Tafinlar®) and trametinib (Mekinist®). The NCI is sponsoring the trial under its clinical collaborative agreements with Bristol-Myers Squibb for ipilimumab and nivolumab and Cooperative Research and Development Agreements with Novartis Pharmaceuticals for dabrafenib and trametinib.

ClinicalTrials.gov Identifier: NCT02224781. DREAMSeq: Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAF V600 Melanoma (EA6134)

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