Combination vs. placebo improved PFS, where there was improvement in OS as the risk of death was 20% lower but was not significant, in BRAF V600E, the risk of death was reduced by 25%. For BRAF V600E, NCCN recommends using this regimen in the adjuvant setting.
The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis–free survival than placebo among patients with BRAF V600–mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival.
We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis–free survival.
The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan–Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P=0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis–free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports.
After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis–free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.)
I love this trial in that it advances science but also balances cost. Neoadjuvant therapy with ipilimumab + nivolumab (Ipi+Nivo) x 2 followed by surgery followed by adjuvant nivolumab. Patients with a major pathologic response went on to observation alone. Again, intact tumor-immune interactions are key to maximum treatment effectiveness. Another key to these patients is seeing a medical oncologist before surgery.
10-year survival data from Checkmate 067 on Ipi+Nivo, Nivo and Ipi alone in met-melanoma. The OS was twice as long in the Ipi+Nivo group compared to Nivo alone. Of note this was with Nivo-1 + Ipi-3, and most of us use the more tolerable Nivo-3 + Ipi-1 dosing based on Checkmate 511. This remains the SOC for good PFS met-melanoma in my opinion.
This was compared to adjuvant niovolumab for 12 months, patients who did not achieve complete response also received adjuvant nivo. Neoadjuvant therapy was for 2 cycles. 12-month event-free survival was 83.7% in the neoadjuvant group and 57.2% in the adjuvant group. 58% had major pathological response in the neoadjuvant group, less than 5% could not get the surgery. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse.
Interesting study showing a strong difference in EFS with neoadjuvant + adjuvant vs. adjuvant alone for stage III/IV melanoma. All patients had disease that was amenable to surgery; EFS at 24 months was 72% vs. 49% in favor of the neoadjuvant group. The hypothesis is that neoadjuvant therapy functionally inhibits the immune checkpoint before antitumor T-cells are surgically resected. This concept is also developing in other cancers, including NSCLC, breast and bladder cancers. This should affect clinical practice.
More may not always be better. Adjuvant Nivo q2-weeks + Ipi q6-weeks was not better than Nivo q4 weeks in reducing recurrences in fully resected stage III-IV melanoma.
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