Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma
Long, G. V.
Tawbi, H. A.
Flaherty, K. T.
Ascierto, P. A.
Nathan, P. D.
Ferrucci, P. F.
Grob, J. J.
Brase, J. C.
AffiliationUniversity Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. Gustave Roussy, Villejuif, and Paris-Saclay University, Orsay, France. The University of Texas MD Anderson Cancer Center, Houston, TX. Dana-Farber Cancer Institute/Harvard Medical School and Massachusetts General Hospital, Boston, MA. Istituto Nazionale Tumori, IRCCS, Fondazione 'G. Pascale,' Naples, Italy. Mount Vernon Cancer Centre, Northwood, United Kingdom. Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland. Clinical Oncological Dispensary, Omsk, Russia. Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux, France. Unit of Medical Oncology, University of Perugia, Perugia, Italy. Unit of Medical Oncology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom. Department of Experimental Oncology, European Institute of Oncology, IRCCS, Milan, Italy. Timone Hospital AP-HM and Aix-Marseille University, Marseille, France. Université Toulouse III-Paul Sabatier, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1037-CRCT, Toulouse, France. Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. Moscow City Oncology Hospital, Moscow, Russia. Hospital Clinic of Barcelona, Barcelona, Spain. Novartis Pharma AG, Basel, Switzerland. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA. University Hospital Essen, Essen, and German Cancer Consortium, Heidelberg, Germany.
MetadataShow full item record
AbstractPURPOSE Preclinical data suggest the combination of an anti–programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600–mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti–programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600–mutant unresectable or metastatic melanoma. METHODS Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age $ 18 years with unresectable or metastatic BRAF V600–mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692). RESULTS At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placeboDabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P 5 .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade $ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm. CONCLUSION The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.
CitationDummer R, Long GV, Robert C, Tawbi HA, Flaherty KT, Ascierto PA, et al. Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600–Mutant Unresectable or Metastatic Melanoma. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2022.
JournalJournal of Clinical Oncology
- Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with <i>BRAF</i> V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i).
- Authors: Tawbi HA, Robert C, Brase JC, Gusenleitner D, Gasal E, Garrett J, Savchenko A, Görgün G, Flaherty KT, Ribas A, Dummer R, Schadendorf D, Long GV, Nathan PD, Ascierto PA
- Issue date: 2022 Jun
- Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i.
- Authors: Dummer R, Lebbé C, Atkinson V, Mandalà M, Nathan PD, Arance A, Richtig E, Yamazaki N, Robert C, Schadendorf D, Tawbi HA, Ascierto PA, Ribas A, Flaherty KT, Pakhle N, Campbell CD, Gusenleitner D, Masood A, Brase JC, Gasal E, Long GV
- Issue date: 2020 Oct
- Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAF<sup>V600</sup>-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial.
- Authors: Dummer R, Brase JC, Garrett J, Campbell CD, Gasal E, Squires M, Gusenleitner D, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Flaherty K, Larkin J, Robert C, Kefford R, Kirkwood JM, Hauschild A, Schadendorf D, Long GV
- Issue date: 2020 Mar
- Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected <i>BRAF</i> V600-Mutant Stage III Melanoma.
- Authors: Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Lesimple T, Plummer R, Dasgupta K, Haas T, Shilkrut M, Gasal E, Kefford R, Kirkwood JM, Long GV
- Issue date: 2018 Dec 10
- Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.
- Authors: Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JBAG, Hansson J, Utikal J, Ferraresi V, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, Davies MA, Lane SR, Legos JJ, Mookerjee B, Grob JJ
- Issue date: 2017 Jul 1