- Given the high risk of recurrence for patients with clinical regional lymphadenopathy or resectable distant metastasis and the effectiveness of systemic therapies:
- Neoadjuvant therapy is being actively pursued in several clinical trials and is increasingly employed in the clinical setting for patients who present with clinical regional lymphadenopathy
- Neoadjuvant therapy:
- Provides the opportunity to examine disease biology in response to therapy, reduce the morbidity of surgical resection, and potentially tailor the need for and approach to adjuvant therapy based on extent of response
- For BRAF V600 mutant patients:
- A single-center (MD Anderson), open-label phase II randomized neoadjuvant therapy trial with neoadjuvant BRAF / MEK combination inhibitor therapy dabrafenib + trametinib for 8 weeks followed by surgery versus surgery with adjuvant dabrafenib + trametinib (for patients in both study arms) in patients with resectable clinical stage IIIB / C or stage IV oligometastatic disease
- The trial enrolled 14 patients to the neoadjuvant arm and 7 patients to the adjuvant arm
- It was stopped early at a prespecified interim safety analysis after noting significantly longer event-free survival in the neoadjuvant arm:
- 71% [10 of 14 patients] vs. 0% [0 of 7 patients]
- Median event-free survival:
- 19.7 vs. 2.9 months; HR 0.016; 95% CI, 0.00012 to 0.14; P < .0001
- There were no grade 4 adverse events in the neoadjuvant group, and importantly, they observed a pathologic complete response (pCR) in 58% of patients treated on the neoadjuvant arm
- The trial was continued as a single-arm neoadjuvant study
- The results were replicated in the phase II, single-arm NeoCombi study conducted in Australia:
- Which found a 49% pCR in the cohort of 35 patients receiving neoadjuvant dabrafenib + trametinib
- Leveraging advances in the immunotherapy arena:
- Several trials (OpACIN, OpACIN-Neo, Amaria et al., 2018) have investigated various regimens of nivolumab with or without ipilimumab, and one trial from the University of Pennsylvania investigated neoadjuvant single-dose pembrolizumab (Huang et al.):
- A recent meta-analysis of these four studies by Menzies et al. found that 38% (n = 51) of patients had a pCR:
- Which correlated with improved RFS (100% vs. 72%, P < .001):
- No patients with a pCR had thus far died
- Which correlated with improved RFS (100% vs. 72%, P < .001):
- In addition, in patients with pCR, near pCR, or partial pathologic response following neoadjuvant immunotherapy:
- The 2-year RFS was 96%, with very few relapses observed
- Of note, the optimal dose from OpACIN-Neo appeared to be ipilimumab 1 mg/kg and nivolumab 3 mg/kg, which was also better tolerated than the ipilimumab 3 mg/kg and nivolumab 1 mg/kg employed in the metastatic setting
- A recent meta-analysis of these four studies by Menzies et al. found that 38% (n = 51) of patients had a pCR:
- Several trials (OpACIN, OpACIN-Neo, Amaria et al., 2018) have investigated various regimens of nivolumab with or without ipilimumab, and one trial from the University of Pennsylvania investigated neoadjuvant single-dose pembrolizumab (Huang et al.):
- The ongoing PRADO trial (NCT02977052), based on an expansion cohort from OpACIN-Neo, is investigating whether CLND can be safely omitted in patients with a major pathologic response in the excised index lymph node after two cycles of neoadjuvant ipilimumab + nivolumab
- The role of neoadjuvant therapy in patients with melanoma continues to rapidly evolve
- When considered, this approach should be discussed in the context of a multidisciplinary care team, preferably in the context of a clinical trial
Rodrigo Arrangoiz MS, MD, FACS, FSSO 