J Clin Oncol 2022 Sep 27
Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced -Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134.
Abstract
Purpose
Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy.
Patients and methods
In a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety.
Results
A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A (P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B (P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated.
Conclusion
Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.
Related Questions
For a patient with metastatic melanoma with small, asymptomatic brain mets what is your preferred systemic therapy?
In this scenario, I default to using a combination of ipilimumab plus nivolumab. We know from prior clinical trials that have looked at this combination of patients with asymptomatic brain metastases that immunotherapy seems to work similarly well intracranially as it does extracranially. This was e...
When would you offer nivolumab/relatlimab to a metastatic melanoma patient following progression on BRAF/MEK targeted therapy?
It depends on what previous therapies have been used. If this patient has already progressed on anti-PD1 monotherapy and BRAF/MEK inhibitor, then TIL therapy should be explored. I would use IPI-3 and NIVO-1 as a bridge in that scenario, after harvest (can start before harvest as well if a date is no...
In what scenario would you consider dual IO and TKI therapy in advanced stage melanoma?
Triplet therapy with the combination of vemurafenib, cobimetinib, and atezolizumab provides a new treatment option for patients with advanced BRAF-mutated melanoma. However, given the lack of survival benefit thus far and increased toxicity, I currently do not routinely employ this as frontline ther...
If a BRAF-mutated melanoma patient developed metastatic disease progression on adjuvant anti-PD-1 monotherapy, do you recommend switching to BRAF/MEK targeted therapy or combination immunotherapy?
The developing pre-clinical and clinical data is clear on this and I believe it becomes even more clear with time. While the DREAMseq study did not enroll patients following adjuvant therapy as the patient in the case, the overall evidence clearly shows that BRAF/MEK inhibitor resistant melanomas ar...