Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial

Long, Georgina V.; Saw, Robyn P.M.; Lo, Serigne; Nieweg, Omgo E.; Shannon, Kerwin F.; Gonzalez, Maria; Guminski, Alexander; Lee, Jenny; Lee, Hansol; Ferguson, Peter M.; Rawson, Robert V.; Wilmott, James S.; Thompson, John F.; Kefford, Richard; Ch’ng, Sydney; Stretch, Jonathan R.; Emmett, Louise; Kapoor, Rony; Rizos, Helen; Spillane, Andrew J.; Scolyer, Richard A.; Menzies, Alexander M.

doi:10.1016/s1470-2045(19)30331-6

Cited by 143 publications

(98 citation statements)

References 22 publications

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“…Similar results were obtained in the II phase trial, NeoCombi [7], in which patients in the IIB-C stage with confirmed BRAF mutation, received dabrafenib with trametinib for 12 weeks before the resection of metastases and 40 weeks after the surgery. The study comprised 35 patients and in 30 of them (86%), the response to the preoperative treatment, according to the RECIST criteria, was observed, whilst in 17patients (49%) a pathological complete response (pCR) was found.…”

Section: Neoadjuvant Treatmentsupporting

confidence: 75%

New developments in the perioperative treatment of melanomas with locoregional advancement

Rutkowski

Wysocki

Świtaj

et al. 2019

Nowotwory. Journal of Oncology

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Surgical intervention is the treatment of choice for patients with melanomas. However, the prognoses of the patients with melanomas at the IIC-IV stage, even after a complete resection of the lesions, is very diverse and, to a great degree, connected with a high risk of disease recurrence. The positive results of the studies in this area have resulted in systemic adjuvant therapy becoming the standard for patients in this group. New methods of systemic treatment-both the molecularly targeted treatment with BRAF and MEK inhibitors (dabrafenib with trametinib) and anti-PD-1 immunotherapy (nivolumab or pembrolizumab)-are already registered in the United States and the European Union. Also the results of the studies concerning the use of preoperative systemic treatment in patients with loco-regionally advanced melanomas seem to be very promising.

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Section: Neoadjuvant Treatmentsupporting

confidence: 75%

New developments in the perioperative treatment of melanomas with locoregional advancement

Rutkowski

Wysocki

Świtaj

et al. 2019

Nowotwory. Journal of Oncology

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“…A similar phase 2 trial evaluated neoadjuvant and adjuvant DT therapy in 35 patients with resectable stage IIIB/C BRAFV600E/K mutant melanoma. 12 Among the 17 (49%) pCR patients, the 12-and 24-month RFS were 82.4% and 63.3%, respectively, compared with 72.2% and 24.4%, respectively, for <pCR patients. Together these trials underscored the potential clinical relationship between pCR and improved patient survival following neoadjuvant DT for BRAFV600E/K mutant melanoma and are consistent with neoadjuvant trials in breast cancer where pCR predicts better RFS and overall survival (OS).…”

Section: Introductionmentioning

confidence: 86%

“…Two recent phase 2 clinical trials demonstrated feasibility and efficacy of neoadjuvant targeted therapy with dabrafenib and trametinib (DT) in patients with clinically detected, 7 th edition American Joint Committee on Cancer (AJCC) stage IIIB/IIIC 10 surgically resectable BRAFV600E/K mutant melanoma. 11,12 In the first randomized phase 2 clinical trial, neoadjuvant and adjuvant DT was compared with standard of care (SOC) upfront surgery. 11 Patients receiving neoadjuvant therapy experienced a >60-fold reduced risk of relapse compared with those who underwent SOC surgery and RFS was prolonged among patients with pCR compared with those with non-pCR.…”

Section: Introductionmentioning

confidence: 99%

Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma

Tetzlaff

Adhikari

et al. 2020

Annals of Oncology

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Background: Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. Methods: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. Results: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P ¼ 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P ¼ 0.014), whereas necrosis (P ¼ 0.012) and/or immature/ proliferative fibrosis (P ¼ 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P ¼ 0.035). Conclusions: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.

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“…Neoadjuvant systemic therapy in melanoma is not yet an established treatment pathway; however, a number of studies using various agents have been reported [35][36][37][38][39]. Neoadjuvant therapy may have numerous advantages, including reducing tumor burden to facilitate resection and providing information regarding pathological response (which has been used as a surrogate endpoint of improved survival in the treatment of other cancers).…”

Section: Future Directionsmentioning

confidence: 99%

Applying adjuvant therapy for melanoma into clinical practice

Krishnan

Menzies

Roberts‐Thomson

2020

Expert Review of Anticancer Therapy

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Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial

Cited by 143 publications

References 22 publications

New developments in the perioperative treatment of melanomas with locoregional advancement

New developments in the perioperative treatment of melanomas with locoregional advancement

Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma

Applying adjuvant therapy for melanoma into clinical practice

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