Adjuvant encorafenib and binimetinib in stage IIB/IIC melanoma

Design

phase 3 randomised, placebo-controlled trial, terminated early with the primary endpoint amended from recurrence-free survival to safety

Population

110 adults with resected stage IIB/IIC BRAF V600E/K-mutated cutaneous melanoma (planned 815); 79% V600E, 35% stage IIC

Primary outcome

safety after amendment; recurrence-free survival became secondary

Effect

grade 3+ treatment-related adverse events 24%, permanent discontinuation 33%; 12-month RFS 86% (95% CI 65-95) versus 70% (46-85)

Resected stage IIB and IIC melanoma recurs often enough that adjuvant therapy is an open question, and BRAF/MEK inhibition already has a role in stage III. COLUMBUS-AD set out to randomise 815 patients with resected stage IIB/IIC BRAF V600E/K-mutated disease to a year of encorafenib 450 mg daily plus binimetinib 45 mg twice daily, or placebo, with recurrence-free survival as the primary endpoint.

It did not get there. Accrual was terminated early, and with 110 patients randomised the protocol was amended to make safety the primary endpoint and recurrence-free survival secondary. Among the 54 who started the combination, grade 3 or worse treatment-related adverse events occurred in 24%, and 33% stopped permanently because of an adverse event. Recurrence-free survival at twelve months was 86% (95% CI 65-95) on treatment and 70% (46-85) on placebo; distant metastasis-free survival was 92% versus 82%.

Those efficacy numbers are the part to hold most lightly. Median follow-up was 12 months in the treatment arm and 7 in the placebo arm, the confidence intervals overlap substantially, and the trial was no longer powered for the comparison. What the study does establish is a tolerability profile in an adjuvant population who feel well: a third of patients could not complete a year of therapy. That is the figure to quote to a patient weighing an adjuvant option, and it is why anti-PD-1 remains the adjuvant approach with the evidence behind it in this stage.

• Do not treat this as evidence that BRAF/MEK inhibition works in stage IIB/IIC — the trial closed before it could tell
• One in three who started the combination stopped for toxicity, in patients who were disease-free
• BRAF testing still matters in resected stage II disease for trial eligibility and for planning at recurrence
• Adjuvant anti-PD-1 remains the option with randomised evidence at this stage
• In India, adjuvant therapy in stage II is rarely funded — an honest discussion of cost belongs in the same conversation as benefit

The statistics, in plain English

A recurrence-free survival of 86% (65-95) against 70% (46-85) looks like a gap, but the intervals overlap across most of their range, which means the data are compatible with a large benefit, no benefit, or harm. With 110 patients instead of 815 the study has roughly an eighth of its planned information. The unequal follow-up, 12 months against 7, biases the comparison further, because events accrue with time. Safety figures from 54 treated patients are the most reliable numbers in the paper, and even those carry wide uncertainty.

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