Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR

Abstract

Objective:To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma.Summary Background Data:Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear.Methods:In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection.Results:Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7–57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery.Conclusions:This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.

Neoadjuvant immunotherapy of locoregionally advanced solid tumors

“…In addition to these two studies, the recently published results of the REDUCTOR trial demonstrated that short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib allowed radical resection of metastases in 81% of patients with prior unresectable locally advanced melanoma. 30 Optimization of neoadjuvant immunotherapy in melanoma: suggestions for future progress Altogether the above-mentioned studies show that neoadjuvant systemic therapy may play a significant role in locoregionally advanced melanoma that carries a high risk of relapse and death with surgery alone (table 1). Indeed, the results reported in these trials demonstrate that Open access neoadjuvant immunotherapy and TT are active and associated with high pCR rates and improved RFS.…”

“…In addition to these two studies, the recently published results of the REDUCTOR trial demonstrated that short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib allowed radical resection of metastases in 81% of patients with prior unresectable locally advanced melanoma. 30 …”

Efficacy of Neoadjuvant Targeted Therapy for Borderline Resectable III B-D or IV Stage BRAF V600 Mutation-Positive Melanoma

“…In the surgery group pCR was achieved in 35% (7/16), pPR in 35%, and no response in three, i.e., 15%. The 2-year OS was 84% [ 10 ]. As a consequence of the above-mentioned trials, in a recent pooled analysis from the International Neoadjuvant Melanoma Consortium covering 192 patients, only 51 received neoadjuvant targeted therapy.…”

“…About five to 15% of stage III melanoma patients are unable to undergo up-front resection due to the extent of their tumors, location of the tumor, and/or the anticipated morbidity of the surgery. In such cases, standard care with surgical resection followed by adjuvant treatment is impossible [ 10 , 11 ]. Moreover, up to 10% of melanoma patients develop locoregional recurrence [ 12 ].…”

“…The reported toxicity of neoadjuvant treatment with BRAFi/MEKi was acceptable and similar to that seen in patients treated for advanced disease. For dabrafenib and trametinib therapy, the major toxicities reported were fevers, chills, and headache; with grade 3–4 adverse events (AEs) in 29% of patients in the Neo Combi trial [ 30 ] and 15% of patients of grade 3 AEs in the REDUCTOR trial [ 10 ]. It is widely accepted that more research and reports of ongoing trials are needed to describe the efficacy of neoadjuvant melanoma treatment and to develop the new standard of care for patients with locally advanced melanoma [ 31 ].…”