Neoadjuvant therapy may benefit patients with high-risk melanoma
medwireNews: Receiving neoadjuvant plus adjuvant dabrafenib and trametinib significantly improves event-free survival compared with standard care in patients with high-risk melanoma, phase II study findings indicate.
“The large difference in event-free survival necessitated early closure of the trial, which potentially limited the generalisability of the results, but they provided important proof-of-concept and data for future studies,” Jennifer Wargo (University of Texas MD Anderson Cancer Center, Houston, USA) and co-authors remark.
The researchers found that after a median 18.6 months of follow-up, 10 (71%) of the 14 patients in the neoadjuvant plus adjuvant dabrafenib and trametinib treatment group were still alive and without disease progression compared with none of the seven patients given upfront surgery and possible adjuvant therapy.
Median event-free survival was significantly longer in the former group than in the latter at 19.7 vs 2.9 months, meaning the risk for disease progression or death was a significant 98.4% lower with neoadjuvant plus adjuvant dabrafenib and trametinib compared with standard care.
All patients were aged 18 years and older and had histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAF V600E or BRAF V600K-mutated melanoma.
The neoadjuvant plus adjuvant dabrafenib and trametinib regimen comprised 8 weeks of neoadjuvant oral dabrafenib 150 mg twice daily and oral trametinib 2 mg daily followed by surgery, then up to 44 weeks of adjuvant dabrafenib plus trametinib. Adjuvant therapy available to the standard of care group included ipilimumab, interferon or peg-interferon alfa2b, or a five-drug chemotherapy regimen.
As reported in The Lancet Oncology, Wargo and team also found that 58% of 12 patients who underwent surgery and received neoadjuvant dabrafenib and trametinib achieved a pathologic complete response. At the time of analysis, none of these patients had developed distant metastases, compared with three of five patients without a pathological complete response.
This suggests that “neoadjuvant therapy might confer clinical benefit by providing an early surrogate marker for long-term outcomes that could be used to optimise and personalise adjuvant therapy for this patient population,” they write.
The investigators note that only one patient in the standard care group received adjuvant therapy, and therefore acknowledge that the outcomes in this group might have been better if more patients had received this additional treatment.
Despite the early termination of the trial, Wargo et al say their data “provide a strong rationale for continued exploration of neoadjuvant plus adjuvant therapy in high-risk, BRAF-mutant, resectable melanoma.”
They conclude: “Understanding predictors of a pathological complete response to neoadjuvant therapy and its association with long-term outcomes will help to develop new strategies to further improve outcomes and overcome treatment resistance.”
Commenting on the findings, Paolo Ascierto (Istituto Nazionale Tumori Fondazione “G Pascale”, Naples, Italy) and Alexander Eggermont (University Paris-Sud, France) say that although the trial “suggested that neoadjuvant therapy offers promise in the treatment of patients with stage III–IV oligometastatic melanoma, its potential role in clinical practice is unclear for now.”
They add: “Adjuvant dabrafenib plus trametinib as well as nivolumab monotherapy have also achieved good results in this setting, raising the question of whether a neoadjuvant approach is really needed (especially given a possible reduction of the role of surgery in the future) or whether adjuvant therapy with more effective agents than previously available is a better way forward.”
By Laura Cowen
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