Adjuvant Dabrafenin plus Trametinib in BRAF mutant Stage III Melanoma

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The incidence of cutaneous melanoma is increasing in the last few years. In the early stage surgical resection is the standard of care with 5-years survival rate for Stage I and II of 98% and 90%, respectively[1]. However, in the stage III, after surgery, the risk of relapse is high making it suitable for adjuvant therapy. Unfortunately, the role of adjuvant therapy is still controversial. In fact, Interferon alpha the only approved drug for adjuvant treatment of melanoma in Europe has very low efficacy considering reduction in risk relapse with several side effects [3]. For these reasons new adjuvant treatments are needed.

More recently, in the EORTC 18071 study, Ipilimumab at the high dose of 10 mg/kg has shown a significant improvement in terms of Relapse Free Survival and Overall Survival for stage III melanoma patients with a significant cost in terms of immune-related toxicities. In fact, the study has met its primary endpoint after a median follow up of 5.3 years, with a significant improvement in RFS, that was significantly improved with ipilimumab (40.8%) compared with placebo, (30.3%; HR 0.76, CI: 95%, 0.64–0.89). As expected, adjuvant ipilimumab at 10 mg/kg was associated with significant toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration. The most important grade 3/4 adverse events were gastrointestinal (16%), hepatic (11%), and endocrine (8%). Furthermore, 5 patients died as a result of immune-related adverse events after treatment with ipilimumab. Based on these results the drug was subsequently approved by the U.S. Food and Drug Administration (FDA) as adjuvant therapy for stage III melanoma [5]. Based on these data ipilimumab could be able to cure 11% of patients in this setting. This is an important improvement in the melanoma treatment. However, more than one out of two patients (53.3%) discontinued treatment because of toxic effects; 38.6% of patients did so during the induction phase. Taken together, these data emphasize the need to discuss the risks and benefits of this therapy with each patient.

Recently results of two-phase three trails have been presented at ESMO 2017 congress, the first one, Checkmate 238, shows the superiority of adjuvant Nivolumab vs Ipilimumab; the second one (main argument of the article), COMBI-AD, compares target therapy vs placebo. COMBI-AD, published by Long et al. on NEJM on 10 September 2017, is the first phase III double blind clinical trial of combined targeted therapies for adjuvant treatment of stage III melanoma. All patients had a BRAF mutation (91% V600E and 9% V600K mutation).

As discussed in the NEJM paper, a total of 870 patients were randomly assigned to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy), or two matched placebo tablets for 12 months [2-4]. The primary endpoint was RFS. Secondary end points included OS, DMFS (Distant Metastasis Free Survival), freedom from relapse, and safety. The trial met its primary endpoint. At a median follow-up of 2.8 years, the combination therapy had significantly reduced the risk of disease recurrence or death by 53% compared to placebo (HR 0.47; CI: 95 %, 0.39-0.58). The RFS benefit with the combination therapy was observed across all patients subgroup. The combination treatment also showed a benefit in secondary endpoints: the estimated rate of OS was 97% at 1 year, 91% at 2 years, and 86% at 3 years in the combination-therapy group, as compared with rates of 94%, 83%, and 77% respectively, in the placebo group (HR 0.57; CI: 95%, 0.42-0.79; P = 0.0006). The estimated rates of RFS were 88% at 1 year, 67% at 2 years, and 58% at 3 years in the combination-therapy group, as compared with rates of 56%, 44%, and 39%, respectively, in the placebo group (HR, 0.47; CI: 95%, 44.5 to not reached). Finally, for distant metastases-free survival, the estimated rate was, at the time of the analysis, 25% in the combination-therapy group as compared with 35% in the placebo group (HR 0.51; CI: 95%, 0.40-0.65; P<0.001).

Regarding adverse events, 97% of patients in the combination-therapy group had an adverse event of any kind and 41% had serious (grade 3/4) adverse events, compared to 88% and 14% in the placebo group, respectively. Around one-quarter (26%) of patients in the combination-therapy group had to stop treatment due to adverse events versus 3% in placebo group. The number of treatment discontinuations was a little higher than in trials on stage IV melanoma patients. This could be because 90% of patients had no progressive disease and were treated for the scheduled full year.
Finally, this trial has shown the efficacy of targeted therapy in stage III Melanoma as adjuvant treatment, with reduction of risk of death and relapse. Moreover, the therapy has shown to have a really acceptable profile of side effect. In fact, no toxic deaths have been reported with very low grade 3 or 4 toxicities.  

Compared with nivolumab [6] (not discussed in this article) in the same setting and in the BRAF mutated patients, what adjuvant therapy would you choose today?

 References

  1. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence based changes in the eighth edition American Joint Committee on Cancer (AJCC) Cancer Staging Manual. CA Cancer J Clin (in press)
  2. Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010; 102: 493-501
  3. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014; 371: 1877-8
  4. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372: 30-9.
  5. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016; 375: 1845-55.
  6. Weber J, Grob J, Margolin KA, et al. A phase III study (CheckMate 238) of adjuvant immunotherapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage IIIb/c or stage IV melanoma (MEL) in patients (pts) at high risk for recurrence. J Immunother Cancer 2015; 2: 3. abstract.

Pasquale Vitale has no actual, potential, real or apparent interest to declare. He has no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated.

Adjuvant Dabrafenin plus Trametinib in BRAF mutant Stage III Melanoma
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