Researchers say they have discovered the optimal sequence of treatment for BRAF-mutant, advanced melanoma — first-line nivolumab plus ipilimumab followed by dabrafenib plus trametinib at disease progression.

First-line nivolumab-ipilimumab with second-line dabrafenib-trametinib resulted in superior outcomes, compared with first-line dabrafenib-trametinib with second-line nivolumab-ipilimumab, the researchers found. 

These results, from the phase 3 DREAMseq trial (ClinicalTrials.gov Identifier: NCT02224781), were published in the Journal of Clinical Oncology.


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The trial enrolled 265 patients with BRAFV600-mutant, stage III-IV unresectable melanoma. They were randomly assigned to receive first-line treatment with nivolumab-ipilimumab (n=133) or dabrafenib-trametinib (n=132). 

There were 73 patients whose disease progressed on first-line therapy, and they were switched to the alternate treatment. A total of 27 patients received second-line dabrafenib-trametinib, and 46 received second-line nivolumab-ipilimumab.

The primary endpoint was overall survival (OS) at 2 years. Study accrual was halted early due to a clinically meaningful difference in OS between treatment arms. At that time, patients in the first-line dabrafenib-trametinib arm were given the option to receive second-line nivolumab-ipilimumab without disease progression.

The 2-year OS rate was 71.8% for patients who received nivolumab-ipilimumab upfront and 51.5% for those who received dabrafenib-trametinib upfront (P =.010). The 3-year OS rate was 66.2% and 42.8%, respectively. 

The median progression-free survival (PFS) was 11.8 months with nivolumab-ipilimumab upfront and 8.5 months with dabrafenib-trametinib upfront (P =.054). The 2-year PFS rate was 41.9% and 19.2%, respectively. 

Among patients whose disease progressed, the median PFS was 9.9 months for those who received second-line dabrafenib-trametinib and 2.9 months for those who received second-line nivolumab-ipilimumab.

The objective response rate (ORR) was similar in the first-line setting, at 46.0% with nivolumab-ipilimumab upfront and 43.0% with dabrafenib-trametinib upfront. After disease progression, the ORR was 47.8% with second-line dabrafenib-trametinib and 29.6% with second-line nivolumab-ipilimumab.

The median duration of response was not reached for patients treated with nivolumab-ipilimumab upfront and was 12.7 months for those who received dabrafenib-trametinib upfront (P <.001).

The rate of grade 3 or higher treatment-related adverse events was similar across the treatment groups. It was 59.5% with nivolumab-ipilimumab upfront, 53.1% with dabrafenib-trametinib upfront, 53.8% with second-line dabrafenib-trametinib, and 50.0% with second-line nivolumab-ipilimumab. 

“The optimal sequence of targeted molecular therapy vs checkpoint inhibitor immunotherapy as first-line treatment for patients with BRAFV600 mutant metastatic melanoma has represented a major therapeutic challenge,” the researchers noted. “This study addresses this issue and settles this question by showing that immunotherapy should precede targeted therapy as the first-line treatment for patients with BRAFV600 metastatic disease.” 

Disclosures: This study was supported by the National Cancer Institute. Study drugs were provided by Bristol-Myers Squibb and Novartis. The study authors did not provide disclosures.

Reference

Atkins MB, Lee SJ, Chmielowski B, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: The DREAMseq Trial – ECOG-ACRIN EA6134. J Clin Oncol. Published online September 27, 2022. doi:10.1200/JCO.22.01763

This article originally appeared on Cancer Therapy Advisor