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

Alexander M Menzies; Serigne N Lo; Robyn P M Saw; Maria Gonzalez; Sydney Ch'ng; Omgo E Nieweg; Kerwin F Shannon; Peter M Ferguson; Jenny Lee; Louise Emmett; Rony Kapoor; Robert V Rawson; Jonathan R Stretch; John F Thompson; Andrew J Spillane; Helen Rizos; Richard A Scolyer; Georgina 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 May 14:S0923-7534(24)00141-8. doi: 10.1016/j.annonc.2024.05.002. Online ahead of print.

Authors

Alexander M Menzies¹, Serigne N Lo², Robyn P M Saw³, Maria Gonzalez⁴, Sydney Ch'ng³, Omgo E Nieweg³, Kerwin F Shannon³, Peter M Ferguson⁵, Jenny Lee⁶, Louise Emmett⁷, Rony Kapoor⁸, Robert V Rawson⁵, Jonathan R Stretch³, John F Thompson³, Andrew J Spillane⁹, Helen Rizos¹⁰, Richard A Scolyer¹¹, Georgina V Long¹²

Affiliations

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

Methods: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18) with histologically-confirmed, resectable, RECIST-measurable AJCC 7^th ed. clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Co-operative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with 150 mg dabrafenib (orally twice per day) plus 2 mg trametinib (orally once per day), with complete resection of the pre-therapy tumour bed at Week 12.

Results: Between August 20, 2014, and April 19, 2017, 35 patients were enrolled. At data cut-off (August 17, 2021), the median follow-up was 60 months (95% CI 56-72). Overall, 21 of 35 (60%) patients recurred, including twelve (57%) with first recurrence in locoregional sites (followed by later distant recurrence in six) and nine (43%) with first recurrence in distant sites, including three in the brain. Most recurrences occurred within two years, with no recurrences beyond three years. At five years, recurrence-free survival was 40% (95% CI 27-60), distant metastasis-free survival was 57% [95% CI 42-76%], and overall survival was 80% (95% CI 67-94). Five-year survival outcomes were stratified by pathological response: recurrence-free survival was 53% with pCR versus 28% with non-pCR (p=0.087), distant metastasis-free survival 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 recurrence-free survival, 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: Neoadjuvant; dabrafenib plus trametinib; five-year survival update; melanoma; targeted therapy.