Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment of BRAF-Mutant Melanoma: Part 2 of the Randomized, Open-Label, Phase III COLUMBUS Trial

Author:

Ascierto Paolo A.1ORCID,Dummer Reinhard2ORCID,Gogas Helen J.3ORCID,Arance Ana4,Mandala Mario5ORCID,Liszkay Gabriella6,Garbe Claus7ORCID,Schadendorf Dirk89ORCID,Krajsova Ivana10,Gutzmer Ralf11ORCID,Chiarion-Sileni Vanna12ORCID,Dutriaux Caroline13,de Groot Jan Willem B.14,Yamazaki Naoya15ORCID,Loquai Carmen16,Robert Caroline17ORCID,Flaherty Keith T.18ORCID

Affiliation:

1. Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy

2. Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland

3. Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece

4. Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain

5. Santa Maria Misericordia Hospital, University of Perugia, Perugia, Italy

6. Department of Dermatology, National Institute of Oncology, Budapest, Hungary

7. Department of Dermatology, University Hospital Tübingen, Tübingen, Germany

8. Department of Dermatology, University Hospital Essen, Essen, Germany

9. German Cancer Consortium, Partner Site Essen, Essen, Germany

10. Department of Dermatology and Venereology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic

11. 1Department of Dermatology, Skin Cancer Center Minden, Mühlenkreiskliniken, Ruhr University Bochum, Minden, Germany

12. 2Melanoma Cancer Unit, Istituto Oncologico Veneto IRCCS, Padua, Italy

13. 3Department of Oncologic Dermatology, Bordeaux University Hospital Center, Bordeaux Cédex, France

14. 4Isala Oncology Center, Isala, Zwolle, the Netherlands

15. 5Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan

16. 6Department of Dermatology, Klinikum Bremen-Ost, Gesundheitnord gGmbH, Bremen, Germany

17. 7Department of Medicine, Service of Dermatology, Paris-Saclay University, Cedex, France

18. 8Cancer Center, Massachusetts General Hospital, Boston, MA

Abstract

PURPOSE In COLUMBUS part 1, patients with advanced BRAFV600-mutant melanoma were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice a day (COMBO450), vemurafenib 960 mg twice a day, or encorafenib 300 mg once daily (ENCO300). As previously reported, COMBO450 improved progression-free survival (PFS) versus vemurafenib (part 1 primary end point) and ENCO300 (part 1 key secondary end point; not statistically significant). Part 2, requested by the US Food and Drug Administration, evaluated the contribution of binimetinib by maintaining the same encorafenib dosage in the combination (encorafenib 300 mg once daily plus binimetinib 45 mg twice daily [COMBO300]) and ENCO300 arms. METHODS In part 2, patients were randomly assigned 3:1 to COMBO300 or ENCO300. ENCO300 (parts 1 and 2) data were combined, per protocol, for PFS analysis (key secondary end point) by a blinded independent review committee (BIRC). Other analyses included overall response rate (ORR), overall survival, and safety. RESULTS Two hundred fifty-eight patients received COMBO300, and 86 received ENCO300. Per protocol, ENCO300 arms (parts 1 and 2 combined) were also evaluated (n = 280). The median follow-up for ENCO300 was 40.8 months (part 1) and 57.1 months (part 2). The median PFS (95% CI) was 12.9 months (10.9 to 14.9) for COMBO300 versus 9.2  months (7.4 to 11.1) for ENCO300 (parts 1  and  2) and 7.4  months (5.6 to 9.2) for ENCO300 (part 2). The hazard ratio (95% CI) for COMBO300 was 0.74 (0.60 to 0.92; two-sided P = .003) versus ENCO300 (parts 1  and  2). The ORR by BIRC (95% CI) was 68% (62 to 74) and 51% (45 to 57) for COMBO300 and ENCO300 (parts 1  and  2), respectively. COMBO300 had greater relative dose intensity and fewer grade 3/4 adverse events than ENCO300. CONCLUSION COMBO300 improved PFS, ORR, and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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