Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma

A M Menzies; S N Lo; R P M Saw; M Gonzalez; S Ch'ng; O E Nieweg; K F Shannon; P M Ferguson; J Lee; L Emmett; R Kapoor; R V Rawson; J R Stretch; J F Thompson; A J Spillane; H Rizos; R A Scolyer; G V Long

doi:10.1016/j.annonc.2024.05.002

Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma

Ann Oncol. 2024 Aug;35(8):739-746. doi: 10.1016/j.annonc.2024.05.002. Epub 2024 May 14.

Authors

A M Menzies¹, S N Lo², R P M Saw³, M Gonzalez⁴, S Ch'ng³, O E Nieweg³, K F Shannon³, P M Ferguson⁵, J Lee⁶, L Emmett⁷, R Kapoor⁸, R V Rawson⁵, J R Stretch³, J F Thompson³, A J Spillane⁹, H Rizos¹⁰, R A Scolyer¹¹, G V Long¹²

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney; Faculty of Medicine and Health, The University of Sydney, Sydney; Royal North Shore Hospital, Sydney; Mater Hospital, Sydney. Electronic address: alexander.menzies@sydney.edu.au.
² Melanoma Institute Australia, The University of Sydney, Sydney; Faculty of Medicine and Health, The University of Sydney, Sydney.
³ Melanoma Institute Australia, The University of Sydney, Sydney; Faculty of Medicine and Health, The University of Sydney, Sydney; Mater Hospital, Sydney; Royal Prince Alfred Hospital, Sydney.
⁴ Melanoma Institute Australia, The University of Sydney, Sydney.
⁵ Melanoma Institute Australia, The University of Sydney, Sydney; Faculty of Medicine and Health, The University of Sydney, Sydney; Royal Prince Alfred Hospital, Sydney.
⁶ Royal Prince Alfred Hospital, Sydney; Macquarie University, Sydney.
⁷ St Vincent's Hospital, Sydney.
⁸ Mater Hospital, Sydney.
⁹ Melanoma Institute Australia, The University of Sydney, Sydney; Faculty of Medicine and Health, The University of Sydney, Sydney; Royal North Shore Hospital, Sydney; Mater Hospital, Sydney.
¹⁰ Melanoma Institute Australia, The University of Sydney, Sydney; Macquarie University, Sydney.
¹¹ Melanoma Institute Australia, The University of Sydney, Sydney; Faculty of Medicine and Health, The University of Sydney, Sydney; Royal Prince Alfred Hospital, Sydney; Charles Perkins Centre, The University of Sydney, Sydney; NSW Health Pathology, Sydney, Australia.
¹² Melanoma Institute Australia, The University of Sydney, Sydney; Faculty of Medicine and Health, The University of Sydney, Sydney; Royal North Shore Hospital, Sydney; Mater Hospital, Sydney; Charles Perkins Centre, The University of Sydney, Sydney.

PMID: 38754780
DOI: 10.1016/j.annonc.2024.05.002

Abstract

Background: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial.

Patients and methods: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12.

Results: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively.

Conclusions: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Keywords: 5-year survival update; dabrafenib plus trametinib; melanoma; neoadjuvant; targeted therapy.

Publication types

Clinical Trial, Phase II

MeSH terms

Adult
Aged
Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
Female
Follow-Up Studies
Humans
Imidazoles* / administration & dosage
Male
Melanoma* / drug therapy
Melanoma* / mortality
Melanoma* / pathology
Middle Aged
Neoadjuvant Therapy*
Neoplasm Staging*
Oximes* / administration & dosage
Pyridones* / administration & dosage
Pyrimidinones* / administration & dosage
Skin Neoplasms / drug therapy
Skin Neoplasms / mortality
Skin Neoplasms / pathology

Substances

dabrafenib
Oximes
trametinib
Pyrimidinones
Pyridones
Imidazoles