Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma

被引：129

作者：

Dummer, Reinhard ^{[1
]}

Long, Georgina V. ^{[2
,3
,4
]}

Robert, Caroline ^{[5
,6
]}

Tawbi, Hussein A. ^{[7
]}

Flaherty, Keith T. ^{[8
,9
]}

Ascierto, Paolo A. ^{[10
]}

Nathan, Paul D. ^{[11
]}

Rutkowski, Piotr ^{[12
]}

Leonov, Oleg ^{[13
]}

Dutriaux, Caroline ^{[14
]}

Mandala, Mario ^{[15
,16
]}

Lorigan, Paul ^{[17
,18
]}

Ferrucci, Pier Francesco ^{[19
]}

Grob, Jean Jacques ^{[20
,21
]}

Meyer, Nicolas ^{[22
]}

Gogas, Helen ^{[23
]}

Stroyakovskiy, Daniil ^{[24
]}

Arance, Ana ^{[25
]}

Brase, Jan C. ^{[26
]}

Green, Steven ^{[26
]}

Haas, Tomas ^{[26
]}

Masood, Aisha ^{[27
]}

Gasal, Eduard ^{[27
]}

Ribas, Antoni ^{[28
]}

Schadendorf, Dirk ^{[29
,30
]}

机构：

[1] Univ Hosp Zurich, Skin Canc Ctr, Zurich, Switzerland

[2] Univ Sydney, Melanoma Inst Australia, Sydney, NSW, Australia

[3] Royal North Shore Hosp, Sydney, NSW, Australia

[4] Mater Hosp, Sydney, NSW, Australia

[5] Gustave Roussy, Villejuif, France

[6] Paris Saclay Univ, Orsay, France

[7] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[8] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA

[9] Massachusetts Gen Hosp, Boston, MA 02114 USA

[10] Fdn G Pascale, Ist Nazl Tumori, IRCCS, Naples, Italy

[11] Mt Vernon Canc Ctr, Northwood, Middx, England

[12] Maria Sklodowska Curie Natl Res Inst Oncol, Warsaw, Poland

[13] Clin Oncol Dispensary, Omsk, Russia

[14] Hop St Andre, Ctr Hosp Univ Bordeaux, Bordeaux, France

[15] Univ Perugia, Unit Med Oncol, Perugia, Italy

[16] Papa Giovanni XXIII Canc Ctr Hosp, Unit Med Oncol, Bergamo, Italy

[17] Univ Manchester, Manchester, Lancs, England

[18] Christie NHS Fdn Trust, Manchester, Lancs, England

[19] IRCCS, European Inst Oncol, Dept Expt Oncol, Milan, Italy

[20] Timone Hosp, AP HM, Marseille, France

[21] Aix Marseille Univ, Marseille, France

[22] Univ Toulouse III Paul Sabatier, Inst Natl Sante & Rech Med Unite Mixte Rech 1037, Toulouse, France

[23] Natl & Kapodistrian Univ Athens, Laiko Gen Hosp, Sch Med, Athens, Greece

[24] Moscow City Oncol Hosp, Moscow, Russia

[25] Hosp Clin Barcelona, Barcelona, Spain

[26] Novartis Pharma AG, Basel, Switzerland

[27] Novartis Pharmaceut, E Hanover, NJ USA

[28] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA

[29] Univ Hosp Essen, Essen, Germany

[30] German Canc Consortium, Heidelberg, Germany

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2022年 / 40卷 / 13期

关键词：

CLINICAL-PRACTICE GUIDELINES; SURVIVAL; VEMURAFENIB; DIAGNOSIS; PLACEBO;

D O I：

10.1200/JCO.21.01601

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PURPOSE 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 placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .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. (C) 2022 by American Society of Clinical Oncology

引用

页码：1428 / +

页数：13

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