Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study

Xue Bai; Ahmed Shaheen; Charlotte Grieco; Paolo D d'Arienzo; Florentia Mina; Juliane A Czapla; Aleigha R Lawless; Eleonora Bongiovanni; Umberto Santaniello; Helena Zappi; Dominika Dulak; Andrew Williamson; Rebecca Lee; Avinash Gupta; Caili Li; Lu Si; Martina Ubaldi; Naoya Yamazaki; Dai Ogata; Rebecca Johnson; Benjamin C Park; Seungyeon Jung; Gabriele Madonna; Juliane Hochherz; Yoshiyasu Umeda; Yasuhiro Nakamura; Christoffer Gebhardt; Lucia Festino; Mariaelena Capone; Paolo Antonio Ascierto; Douglas B Johnson; Serigne N Lo; Georgina V Long; Alexander M Menzies; Kenjiro Namikawa; Mario Mandala; Jun Guo; Paul Lorigan; Yana G Najjar; Andrew Haydon; Pietro Quaglino; Genevieve M Boland; Ryan J Sullivan; Andrew J S Furness; Ruth Plummer; Keith T Flaherty

doi:10.1016/j.eclinm.2023.102290

Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study

EClinicalMedicine. 2023 Oct 31:65:102290. doi: 10.1016/j.eclinm.2023.102290. eCollection 2023 Nov.

Authors

Xue Bai^{1

2}, Ahmed Shaheen³, Charlotte Grieco⁴, Paolo D d'Arienzo⁴, Florentia Mina⁴, Juliane A Czapla², Aleigha R Lawless², Eleonora Bongiovanni⁵, Umberto Santaniello⁵, Helena Zappi⁶, Dominika Dulak⁷, Andrew Williamson⁸, Rebecca Lee⁹, Avinash Gupta⁸, Caili Li¹, Lu Si¹, Martina Ubaldi¹⁰, Naoya Yamazaki¹¹, Dai Ogata¹¹, Rebecca Johnson¹², Benjamin C Park¹³, Seungyeon Jung¹³, Gabriele Madonna¹⁴, Juliane Hochherz¹⁵, Yoshiyasu Umeda¹⁶, Yasuhiro Nakamura¹⁶, Christoffer Gebhardt¹⁵, Lucia Festino¹⁴, Mariaelena Capone¹⁴, Paolo Antonio Ascierto¹⁴, Douglas B Johnson¹³, Serigne N Lo¹⁷, Georgina V Long¹², Alexander M Menzies¹², Kenjiro Namikawa¹¹, Mario Mandala¹⁰, Jun Guo¹, Paul Lorigan⁹, Yana G Najjar¹⁸, Andrew Haydon⁶, Pietro Quaglino⁵, Genevieve M Boland², Ryan J Sullivan², Andrew J S Furness⁴, Ruth Plummer³, Keith T Flaherty²

Affiliations

¹ Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
² Massachusetts General Hospital, USA.
³ Newcastle University Centre for Cancer, UK.
⁴ Skin Unit, The Royal Marsden NHS Foundation Trust, London, UK.
⁵ Dermatologic Clinic, Department of Medical Sciences, University of Turin Medical School, Italy.
⁶ Alfred Health, Australia.
⁷ Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁸ The Christie NHS Foundation Trust, Manchester, UK.
⁹ Division of Cancer Sciences, University of Manchester and Christie NHS Foundation Trust, Manchester, UK.
¹⁰ University of Perugia, Italy.
¹¹ Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹² Melanoma Institute Australia, The University of Sydney; Faculty of Medicine and Health, The University of Sydney; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia.
¹³ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁴ Department of Melanoma, Cancer Immunotherapy and Development Therapeutics - Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.
¹⁵ Department of Dermatology, University Skin Cancer Center, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
¹⁶ Department of Skin Oncology/Dermatology, Comprehensive Cancer Center, Saitama Medical University International Medical Center, Saitama, Japan.
¹⁷ Melanoma Institute Australia, The University of Sydney, North Sydney, NSW, Australia.
¹⁸ UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Abstract

Background: Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers.

Methods: This multicenter, retrospective cohort study was conducted in 15 melanoma centers in Australia, China, Germany, Italy, Japan, UK, and US. We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1 between Jul 2015 and Oct 2022. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), recurrence pattern and toxicity.

Findings: We included 598 patients with stage III BRAF V600-mutant melanoma who received either adjuvant D/T (n = 393 [66%]) or PD-1 (n = 205 [34%]) post definitive surgery between Jul 2015 and Oct 2022. At a median follow-up of 33 months (IQR 21-43), the median RFS was 51.0 months (95% CI 41.0-not reached [NR]) in the D/T group, significantly longer than PD-1 (44.8 months [95% CI 28.5-NR]) (univariate: HR 0.66, 95% CI 0.50-0.87, P = 0.003; multivariate: HR 0.58, 95% CI 0.39-0.86, P = 0.007), with comparable OS with PD-1 (multivariate, HR 0.90, 95% CI 0.48-1.70, P = 0.75). Similar findings were observed using a restricted-mean-survival-time model. Among those who experienced recurrence, the proportion of distant metastases was higher in the D/T cohort. D/T had a higher incidence of treatment modification due to adverse events (AEs) than PD-1, but fewer persistent AEs.

Interpretation: In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS. D/T seems to provide a better outcome compared with PD-1, but a longer follow-up and ideally a large prospective trial are needed.

Funding: Dr. Xue Bai was supported by the Beijing Hospitals Authority Youth Programme (QMS20211101) for her efforts devoted to this study. Dr. Keith T. Flaherty was funded by Adelson Medical Research Foundation for the efforts devoted to this study.

Keywords: Adjuvant therapy; BRAF V600 mutation; Dabrafenib/trametinib; Melanoma; PD-1.