A prospective, two-arm, two-step, open-label, randomised phase III DREAMseq study shows that in patients with unresectable stage III or IV melanoma containing a BRAFV600E/K mutation a sequence of treatment starting with nivolumab/ipilimumab followed by dabrafenib/trametinib is associated with greater 2-year overall survival (OS) than the inverse sequence. In all clinical subgroups examined and stratified by age, sex, ECOG performance status, LDH level, or disease stage at least a trend toward better 2-year OS for the nivolumab/ipilimumab initial sequence was seen.
According to Prof. Michael B. Atkins of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, US and colleagues, who published the study results on 27 October 2022 in the Journal of Clinical Oncology, in this population with an oncogene-driven tumour and effective targeted therapy available, nivolumab/ipilimumab combination followed by BRAF/MEK inhibitor, if necessary, should be the preferred treatment sequence.
BRAFV600 mutations are present in approximately 50% of patients with metastatic melanoma. Combination PD1/CTLA4 blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Dual BRAF/MEK inhibition tends to produce high tumour shrinkage rates and to prolong median progression-free survival (PFS), whereas nivolumab/ipilimumab tends to have major impact on response duration, 2-year and beyond PFS and OS rates, and treatment-free survival, complicating cross-trial comparisons.
Several non-randomised retrospective comparisons of either matched study data or real-world data suggested improved clinical outcomes and cost-effectiveness of immune checkpoint inhibitors combination as initial treatment. However, these studies were subject to selection biases that could not be controlled for, as well as inconsistent availability and use of second-line treatments. Little prospective data exist to guide the choice of either initial or treatment sequence in this population. Marketing data showed that in 2021, half of all patients in the US with metastatic BRAF-mutated melanoma received dual BRAF/MEK inhibition and only one quarter received nivolumab/ipilimumab combination as initial treatment.
DREAMseq was conducted to determine which initial treatment or treatment sequence produce the best efficacy. Patients with treatment-naïve BRAFV600-mutated unresectable melanoma were randomly assigned to receive either nivolumab/ipilimumab combination (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate treatment, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary endpoint was 2-year OS. Secondary endpoints were 3-year OS, objective response rate (ORR), response duration, PFS, crossover feasibility, and safety.
A total of 265 patients were enroled, with 73 going into step 2, of whom 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 endpoint being achieved. The 2-year OS for those starting on arm A was 71.8% (95% confidence interval [CI] 62.5 to 79.1) and 51.5% in arm B (95% CI 41.7 to 60.4; log-rank p = 0.010).
Step 1 PFS favoured arm A (p = 0.054). ORR rates were 46.0% in arm A, 43.0% in arm B, 47.8% in arm C, and 29.6% in arm D. Median duration of response was not reached for arm A and 12.7 months for arm B (p < 0.001). Crossover occurred in 52% of patients with documented disease progression.
Nivolumab/ipilimumab was administered safely and effectively in this cooperative group trial setting with toxicity profile similar to what has been previously reported including two deaths from immune-related adverse events (irAEs). Although toxicity profiles differ greatly between the two regimens, in the DREAMseq study, the incidence of grade ≥ 3 toxicities were similar between treatment arms, as well as within each treatment approach whether used in the frontline or second-line.
Although severe toxicities from immune checkpoint inhibitors frequently required early treatment cessation, they were not associated with more treatment-related mortality and most importantly, did not appear to negatively affect patient OS. In fact, several analyses suggest that irAEs to nivolumab/ipilimumab are associated with better efficacy. The study team commented that these findings should encourage physicians and patients to consider nivolumab/ipilimumab as the preferred immunotherapy in patients with BRAF-mutated melanoma and be confident that even when treatment needs to be held or stopped because of toxicity, there remains a realistic likelihood of sustained melanoma control.
The authors commented that the study limitations include slow accrual and the crossover rate of only 52%. The sequencing conclusions of this study may not apply to patients treated with other immunotherapy regimens or to patients who have received adjuvant anti-PD1, anti-CTLA4 or BRAF/MEK inhibitors.
The study was supported by the ECOG-ACRIN Cancer Research Group and by the US National Cancer Institute of the National Institutes of Health awards.
The study findings were previously presented at the inaugural ASCO Virtual Plenary Session on 16 November 2021 and in part on 5 June at the 2022 ASCO Annual Meeting in Chicago, IL, US.
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. JCO; Published online 27 October 2022. DOI: 10.1200/JCO.22.01763