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Melanoma Adjuvant Targeted Therapy
My Thoughts on Adjuvant Targeted Therapy for BRAF V600E/K, High-Risk, Resected Melanoma

Released: October 19, 2020

Expiration: October 18, 2021

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During the past decade, major advances have transformed the treatment of melanoma, both in patients with unresectable/metastatic disease and in high-risk patients with resected disease who receive adjuvant therapy. Effective targeted therapies blocking mutated BRAF and monoclonal antibodies that stimulate T-cells against melanoma are now available in each of these settings. In an era of multiple clinically active agents, identifying the most optimal sequences of therapies is now a major goal.

Adjuvant Therapy
Stage III melanoma is an incredibly heterogeneous population of patients, with a recurrence risk ranging from <10% for low-risk stage IIIa to > 80% for high-risk stage IIId. Given the recurrence risk, developing effective adjuvant therapies has been a major priority. Historically, interferon-α and high-dose ipilimumab have had relatively modest benefit in relapse-free survival (RFS) and/or OS and have caused substantial and highly morbid toxicities. More recently, the availability of BRAF and MEK inhibitors, specifically dabrafenib and trametinib, and the PD-1 inhibitors nivolumab and pembrolizumab have provided more robust benefit with, generally speaking, a more palatable toxicity profile.

Adjuvant BRAF/MEK Inhibition
The combination of dabrafenib and trametinib (D plus T) was approved for adjuvant therapy based on the COMBI-AD study. This study randomized 870 patients with resected stage III, BRAF V600E or V600K–mutated melanoma to either D plus T or 2 matched placebos for up to 12 months. Prolonged follow-up has now shown an improvement for D plus T vs placebo in terms of RFS (52% vs 36%, respectively, at 5 years; HR: 0.51) and distant metastasis–free survival (65% vs 54%, respectively; HR: 0.55). OS follow-up data remain immature and have not been analyzed yet. Toxicities observed were largely consistent with those seen with these agents in the metastatic setting and included fevers (63%; grade 3/4: 5%), fatigue (47%), and nausea (40%). The largest relative benefit to D plus T was observed at 1 year on treatment (88% vs 56%, respectively, 1-year RFS, for an absolute difference of 32%) and has declined at each additional timepoint (23% at 2 years, 19% at 3 years, 17% at 4 years, 16% at 5 years). The largest decline, however, was between 1 and 2 years, and RFS does appear to be stabilizing with prolonged follow-up.

When to Use Adjuvant BRAF/MEK Inhibition?
D plus T can be strongly considered in patients with resected stage III melanoma with BRAF V600E/K mutations, consistent with the FDA label. Patients with resected stage IV melanoma, and patients with less common BRAF V600 mutations (such as V600R, V600G, V600D) may also be considered for off-label therapy. Observation may be chosen instead of adjuvant therapy in some patients, since OS benefit has yet to be demonstrated—although most melanoma-focused physicians, including myself, presume that a benefit will be eventually shown. In particular, patients with low-risk stage IIIA disease may consider opting for observation due to their low absolute risk of recurrence.

BRAF/MEK or Anti–PD-1?
A major topic of debate currently is whether to choose D plus T or single agent anti–PD-1 for adjuvant therapy in patients with BRAF mutations. In some patients, the choice is obvious. For example, patients with severe autoimmune disease, organ transplant, or strong desire to avoid IV therapy should receive D plus T rather than anti–PD-1. On the other hand, patients with depressed cardiac ejection fraction or retinal comorbidities should receive anti–PD-1 therapy. For most other patients, however, it comes down to physician and patient preference in the absence of a direct comparison. I will briefly “make the case” for each option.

The argument for D plus T is as follows: BRAF/MEK inhibition given in the adjuvant setting (with only microscopic disease present) does appear to cure some patients, given the sustained benefit observed in RFS even at 5 years. Conventional wisdom suggests that BRAF/MEK inhibition is not curative in the metastatic setting, whereas anti–PD-1 may still produce durable responses even when used for metastatic disease. Thus, the opportunity for potentially curative therapy with D plus T should be taken while still present (that is, in the adjuvant setting). Furthermore, the toxicities, although nontrivial, are reversible and not generally permanent. By contrast, toxicities from anti–PD-1 such as hypothyroidism or arthritis may be persistent and even irreversible. 

The case for anti–PD-1 is the following: Immunotherapy benefit is generally more durable; therefore, the more sustained benefit should be gained upfront. The RFS curve for anti–PD-1 also appears to have a more stable separation, without evidence of convergence, in contrast to D plus T. In addition, BRAF/MEK therapy does appear to have truly durable responses in the metastatic setting in some patients (~ 15% 5-year PFS rate), suggesting that this option may still be curative in some patients. Finally, although selected adverse events may be long-lasting, the day-to-day toxicities associated with anti–PD-1 are subjectively less problematic than the fevers, arthralgias, and fatigue occurring with BRAF/MEK inhibition.

Additional insight is needed to select the optimal therapeutic strategy. Biomarkers could be one approach to choose among these options. An exploratory biomarker analysis from the COMBI-AD performed an exhaustive search for markers of RFS for D plus T. Signs of immune activation, identified through IFN-γ signaling signatures, correlated with improved RFS for both D plus T and placebo. On the other hand, patients with lower tumor mutational burden (TMB) had substantially more benefit from combination therapy compared with placebo. One could consider using lower TMB to shift the selection to D plus T and higher TMB to drive the selection of anti–PD-1 therapy, but this approach remains somewhat experimental and is based on a subset analysis. 

Ultimately, treatment with D plus T is a very appropriate treatment option for patients with resected stage III/IV melanoma with a BRAF V600 mutation. There will likely continue to be vigorous debate about the choice of D plus T or anti–PD-1 therapy for this population, and there will likely never be a direct prospective comparison. Biomarkers may help guide therapy selections in the future but remain exploratory at this stage.

What’s Your Take?
What factors do you consider when selecting adjuvant therapy for your patients? Join the discussion by leaving a comment below.

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What is your preferred adjuvant therapy for your patients with stage III, high-risk, resected melanoma with BRAF mutations?
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