Stage III High-Risk Melanoma Benefits With Dabrafenib–Trametinib, Pembrolizumab

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Updated analyses for high-risk stage III melanoma studies have been reported at the virtual 2020 ASCO Annual Meeting, demonstrating recurrence-free survival (RFS) benefits with dabrafenib plus trametinib for BRAF-mutated disease and pembrolizumab for PD-L1-positive tumours. 

The 5-year COMBI-AD analysis was presented by Axel Hauschild, from University Hospital Schleswig-Holstein in Kiel, Germany, while the 3-year findings for the EORTC 1325-MG/KEYNOTE-054 study were reported by Alexander Eggermont, from the Princess Máxima Center in Utrecht, the Netherlands. 

For COMBI-AD, patients with completely resected cutaneous stage IIIA–C melanoma with BRAF V600E or V600K mutations were randomly assigned to receive dabrafenib 150 mg twice daily plus trametinib 2 mg/day (n=438) or placebo (n=432) and followed up for a median 60 and 58 months, respectively. 

At 60 months, RFS was achieved by 52% of the combination arm versus 36% of controls, with median RFS values unreached and 16.6 months, respectively. This gave a significant hazard ratio (HR) for recurrence of 0.51. 

A significant RFS benefit was found in patients with stage IIIB (55 vs 34%, HR=0.50) and stage IIIC (45 vs 29%, HR=0.48) disease. Although the benefit in stage IIIA patients did not reach significance (65 vs 58%, HR=0.61), the presenter commented that this group was “relatively small” and relapse occurred in only about a third of these patients. 

When the results were translated into the new AJCC 8th edition melanoma classifications, the stage IIIB, IIIC and IIID groups showed a significant RFS benefit, with HRs of 0.51, 0.50 and 0.34, but the HR of the smaller stage IIIA group was 0.83 and again did not reach significance. 

At 60 months, 65% of patients in the combination arm were free from distant metastasis as a first relapse compared with 54% of controls (HR=0.55). Overall, 34% and 47% of the groups went on to receive a further systemic anticancer treatment. The impact of immunotherapy and additional BRAF or MEK inhibitor combination therapy in these patients will be followed up, the presenter said. 

Summing up the analysis, Axel Hauschild said that for patients with stage III BRAF-mutated melanoma “there is more than 50% 5-year relapse-free survival, and relapse-free survival curves for both treatment arms appear to be reaching a plateau, which is a good sign if we’re talking about cure.” He added that the overall survival and safety findings will be updated in the future. 

Alexander Eggermont presented updated results for the EORTC 1325-MG/KEYNOTE-054 phase III trial that built on the interim analysis at a median 1.25 years, which suggested a significant RFS benefit compared with placebo for the overall and PD-L1-positive patients in the study given pembrolizumab 200 mg every 3 weeks for a year. Pembrolizumab was given to patients in both study arms at time of progression. 

The latest RFS analysis, after a median 3 years of follow-up, gave a HR of 0.56 for recurrence that significantly favoured the pembrolizumab-treated patients versus controls, with RFS achieved by 63.7% and 44.1%, respectively. 

Alexander Eggermont said that the “sustained RFS benefit” with pembrolizumab translated to a “clinically meaningful improvement consistent across subgroups”. 

This included patients with PD-L1-positive (65.3 vs 52.2%, HR=0.57) and PD-L1-negative tumours (56.9 vs 33.3%, HR=0.45), and patients with stage IIIA (81.2 vs 66.3%, HR=0.50), stage IIIB (65.7 vs 47.0%, HR=0.56) and stage IIIC (54.3 vs 32.3%, HR=0.57) disease. 

Both patients with BRAF-mutated and BRAF-wild-type disease experienced a significant RFS benefit with pembrolizumab, with HRs of 0.51 and 0.66, respectively, said Alexander Eggermont, noting that this was “similar” to the improvement in the BRAF-mutated patients found in the COMBI-AD trial. 

Finally, distant metastasis as a first recurrence occurred in 22.3% of the pembrolizumab arm and 37.3% of controls, giving a significant HR of 0.55 in favour of the PD-1 inhibitor. 

The presenter also highlighted a higher incidence of immune-related adverse events (irAEs) during pembrolizumab than placebo therapy, with grade 1–5 irAEs reported in 37.7% and 9.0%, and grade 3–5 irAEs reported in 7.7% versus 0.6% of patients.  

Among pembrolizumab-treated patients, irAEs were linked to significantly longer RFS (HR=0.61) but no association was found between irAEs and RFS in the placebo arm. 

Furthermore, when compared with the placebo arm, the reduction in the risk of recurrence or death in the pembrolizumab arm was significantly higher after irAE onset than before or without an irAE, with HRs of 0.37 versus 0.62. 

This “means that you can console your patients with irAEs a little bit by telling them that this might be, actually, a good sign”, the presenter suggested. 

References  

Hauschild A, Dummer R, Santinami M, et al. Long-term benefit of adjuvant dabrafenib + trametinib (D+T) in patients (pts) with resected stage III BRAF V600-mutant melanoma: Five-year analysis of COMBI-AD. J Clin Oncol 38: suppl; abstr 10001. DOI: 10.1200/JCO.2020.38.15_suppl.10001.

Eggermont AM, Blank CU, Mandalà 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 38: suppl; abstr 10000. DOI: 10.1200/JCO.2020.38.15_suppl.10000.