Adjuvant Targeted Therapy Proves Beneficial in Resected Stage III BRAF-Mutant Melanoma

Georgina V. Long, AO, PhD, MBBS, BSc

Targeted therapy use in melanoma has been extended beyond just metastatic disease to now include adjuvant therapy for patients with resected stage III melanoma.

Adjuvant targeted therapy use in melanoma has had the most impact thus far on BRAF-mutant disease, as approximately 35% to 40% of melanoma cases are BRAF mutant. The majority of these mutations are V600E and are found in younger patients with melanoma, explained Georgina V. Long, AO, PhD, MBBS, BSc, in a presentation during the 10th World Congress of Melanoma & 17th EADO Congress held virtually in April.^1,2 In addition, approximately 20% of patients with melanoma harbor BRAF V600K mutations.

The seminal trial that showed benefit for adjuvant targeted therapy in BRAF-mutant melanoma was the phase 3 COMBI-AD trial (NCT01682083). It looked at the use of adjuvant dabrafenib (Tafinlar) and trametinib (Mekinist) in comparison with placebo in patients with stage IIIA-IIIC resected cutaneous melanoma harboring a BRAF V600E/K mutation.

In the primary analysis, the relapse-free survival (RFS) rate at 3 years was 58% with dabrafenib/trametinib and 39% with placebo (HR, 0.47; 95% CI, 0.39-0.58; P < .00001).3 The 5-year analysis for the trial showed that RFS benefit persisted over time, with a 5-year RFS rate of 52% versus 36% for dabrafenib/trametinib and placebo, respectively (HR, 0.51; 95% CI, 0.42-0.61).⁴

“Twelve months of treatment gives us a 50% reduction in risk of recurrence,” noted Long, co–medical director and chair of melanoma medical oncology and translational research at Melanoma Institute Australia at the University of Sydney and Royal North Shore Hospital. This reduction was greater than the risk reduction seen with either adjuvant nivolumab (Opdivo; HR, 0.67) or pembrolizumab (Keytruda; HR, 0.57).^5,6

The RFS benefit with dabrafenib/trametinib also was seen across all subgroups at both time points.

The distant metastasis-free survival rate was 71% in the dabrafenib/trametinib arm at 3 years and 65% at 5 years. In the placebo arm, the distant metastasis-free survival rate at 3 years was 57% and 54% at 5 years.^3,4

“We know that anti–PD-1 therapy has also been examined in the adjuvant setting. However, what we don’t know is whether we need to treat now or whether we could wait until stage IV,” Long said. “At the moment, the standard is to resect the disease and treat with 12 months of adjuvant therapy. But what if we resected the disease, watched, and only treated when patients had a recurrence or were stage IV? Do we actually end up with the same overall survival and quality of life?”

Long pointed out that the adjuvant combination of dabrafenib and trametinib was the only FDA-approved adjuvant regimen to provide a suggestion of overall survival (OS) benefit in melanoma. In the COMBI-AD study, the 3-year OS rate with the combination was 86% and 77% with placebo (HR, 0.57; 95% CI, 0.42-0.79; P = .0006). However, the P value did not cross the prespecified significance threshold.

The investigators found that with tumor mutational burden (TMB) and interferon-γ (IFN-γ) gene expression signatures, all groups, except for patients with high TMB and low IFN-γ scores, benefited more from the combination of dabrafenib/trametinib than from placebo.⁷ Long suggested this was because these patients had many mechanisms of resistance to targeted therapy but without the immune engagement that leads to a better prognosis.

When patients in the study had a recurrence, 54% in the placebo arm developed a distant recurrence. In the dabrafenib/trametinib arm, however, 62% of patients had a distant recurrence. Long noted that investigators are seeking to determine whether this is related to more brain metastases with adjuvant targeted therapy compared with adjuvant immunotherapy or if this is just related to the characteristics of the disease.

Adjuvant Targeted Therapy Versus Immunotherapy

Long compared the RFS rates from the COMBI-AD trial with that of the CheckMate 238 trial (NCT02388906) to compare adjuvant targeted therapy with immunotherapy. At 1 year, the RFS rates were 86% with dabrafenib/trametinib, 72% with nivolumab, 62% with ipilimumab (Yervoy), and 51% with no therapy.^3,5 She commented that the curves were similar to what is seen in stage IV melanoma as well.

At 2 years, however, the RFS rate for dabrafenib/trametinib drops slightly below that of nivolumab (63% vs 64%, respectively). Long cautioned that not all patients in the CheckMate 238 trial had a BRAF mutation.

In the KEYNOTE-054 study (NCT02362594) of adjuvant pembrolizumab versus placebo in patients with resected stage III melanoma, among patients with BRAF V600E/K–mutated melanoma, the 3-year RFS rate was 62.0% with pembrolizumab and 37.1% with placebo (HR, 0.51; stratified log-rank P < .001).⁸ This compared similarly with the RFS curves in the COMBI-AD trial. In patients with BRAF wild-type disease, however, the difference was narrower at 61.8% versus 46.5% for pembrolizumab and placebo, respectively (HR, 0.66; stratified log-rank P = .003).

“Let’s watch this space,” Long stressed. “We can’t really make a decision [yet] about how we will compare these therapies, but we must remember to compare similar patients.”

_References:

_{1. Long GV. Adjuvant targeted therapy in melanoma. Presented at: 10th World Congress of Melanoma & 17th EADO Congress; April 15-17, 2021; virtual.}

_{2. Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18(12):3242-3249. doi:10.1158/10780432.CCR-12-0052}

_{3. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813-1823. doi:10.1056/NEJMoa1708539}

_{4. Dummer R, Hauschild A, Santinami M, et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma. N Engl J Med. 2020;383(12):1139-1148. doi:10.1056/NEJMoa2005493}

_{5. Weber J, Mandala M, Del Vecchio M, et al; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824-1835. doi:10.1056/NEJMoa1709030}

_{6. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789-1801. doi:10.1056/NEJMoa1802357}

_{7. Dummer R, Brase JC, Garrett J, et al. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAF V600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Lancet Oncol. 2020;21(3):358-372. doi:10.1016/ S1470-2045(20)30062-0}

_{8. Eggermont AM, Blank CU, Mandala M, et al. Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: new recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up. J Clin Oncol. 2020;38(suppl 15):10000. doi:10.1200/JCO.2020.38.15_suppl.10000}