LBA45 - First report of efficacy and safety from the phase II study SECOMBIT (SEquential COMBo Immuno and Targeted therapy study)

Background

Treatment of BRAF-mutated melanoma has dramatically changed with the introduction of targeted therapy (TT) and immune-checkpoint blockade (I-O). TT (encorafenib + binimetinib- E+B) has higher response rates, but these may be limited in duration. Conversely, I-O (ipilimumab + nivolumab – I+N) may have lower response rates, but more durable responses. Both treatments increase OS in metastatic melanoma patients. The question about which should be the first option is open. One strategy could be a short course of TT, switched to combo IO prior to progression of disease. In order to answer to this question, we conducted the SECOMBIT study, a randomized three-arms phase II study (NCT02631447).

Methods

From Nov 2016 to May 2019, n.251 patients with untreated, metastatic BRAFV600 mutated melanoma, were enrolled at 37 centers in 9 countries. They were randomized 1:1:1 to Arm A [E+B until PD, followed by I+N], or Arm B (I+N until PD, followed by E+B) or Arm C (E+B for 8 weeks, followed by I+N until PD, followed by E+B). Patients received the treatments with the following schedules: TT, E 450mg p.o. daily + B 45mg p.o. bid; I-O, I 3mg/kg + N 1mg/kg Q3w x 4 cycles, followed by N 3mg/kg Q2w. Overall survival is the primary endpoint of the study. Secondary endpoints include total PFS, 2- and 3-years survival rate, best overall response rate, duration of response, biomarkers evaluation.

Results

69 patients were treated in arm A, 71 in arm B and 69 in arm C. At a median follow-up of 17.5 months (IQR 10.2-23.4– d.b.lock July 2020), we report preliminary data of PFS, ORR and safety. mPFS was 15.8 months in Arm A, 7.2 months in Arm B, and 11.4 months in Arm C. In the 3 Arms 1-year PFS was 60%, 43% and 46% and 2-year PFS was 35%, 38% and 39% respectively. ORR was 82.6% (CR 21.7%) in Arm A, 45.1% (CR 15.5%) in Arm B and 78.3% (CR 29.0%) in Arm C. G3/4 toxicity was 49% in Arm A, 73% in Arm B and 51% in Arm C, while G.3/4 treatment-related adverse events were 28%, 54% and 32%. 18 pts were discontinued due to adverse events, 7 in Arm A, 8 in Arm B and 3 in Arm C.

Conclusions

At a minimum follow up of 1 year, our data confirm what reported in the pivotal studies. Despite the difference in term of mPFS, the 2-yrs PFS rate is similar among the different arms. The study is still ongoing for the completion of the main endpoint (OS).

Clinical trial identification

NCT02631447.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione Melanoma Onlus.

Funding

Bristol Myers Squibb and Array Biopharma.

Disclosure

P.A. Ascierto: Advisory/Consultancy, Research grant/Funding (institution): Bristol Myers-Squibb; Advisory/Consultancy, Research grant/Funding (institution): Roche-Genentech; Advisory/Consultancy, Research grant/Funding (institution): Array; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Incyte; Advisory/Consultancy: Newlink Genetics; Advisory/Consultancy: Genmab; Advisory/Consultancy: MedImmune; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Syndax; Advisory/Consultancy: SunPharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Idera; Advisory/Consultancy: Ultimovacs; Advisory/Consultancy: Sandoz; Advisory/Consultancy: Immunocore; Advisory/Consultancy: 4SC; Advisory/Consultancy: Alkermes; Advisory/Consultancy: Italfarmaco; Advisory/Consultancy: Nektar; Advisory/Consultancy: Boehringer-Ingelheim. M. Mandala: Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Merck Serono. P.F. Ferrucci: Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche-Genentech; Advisory/Consultancy: Pierre Fabre. P. Rutkowski: Honoraria (self), Advisory/Consultancy: Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Blueprint Medicines; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: Amgen. M. Guidoboni: Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Novartis; Research grant/Funding (institution): Merck Sharp & Dohme. A.M. Arance Fernandez: Advisory/Consultancy, Speaker Bureau/Expert testimony: Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Serono; Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen. V. Ferraresi: Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre. E. Maiello: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Servier; Advisory/Consultancy: Sanofi Genzyme; Advisory/Consultancy: Roche; Advisory/Consultancy: Merck; Advisory/Consultancy: Eisai; Advisory/Consultancy: Pfizer. M. Guida: Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre. M. Del Vecchio: Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Sanofi. M.T. Fierro: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pierre Fabre. P. Queirolo: Advisory/Consultancy: Roche; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Merck; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Sun Pharma; Advisory/Consultancy: Sanofi. C. Lebbé: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self): Pierre Fabre; Honoraria (self), Advisory/Consultancy: Merck Serono; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self): Pfizer; Honoraria (self): Incyte. I. Melero: Honoraria (self), Advisory/Consultancy, Part of AstraZeneca partners of choice: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Part of BMS I-ON consortium: Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Bioncotech; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Alligator; Honoraria (self): Numab; Honoraria (self), Advisory/Consultancy: F-Star; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Part of Roche imCORE: Roche; Honoraria (self): Bayer; Honoraria (self), Research grant/Funding (self): Merck Serono; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme; Honoraria (self): Boston Pharmaceuticals; Honoraria (self): Servier; Research grant/Funding (self): Palo Biopharma. G. Palmieri: Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Incyte; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Roche Genentech. A.M. Grimaldi: Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self): Roche; Travel/Accommodation/Expenses: Sun Pharma; Travel/Accommodation/Expenses: Pierre Fabre; Honoraria (self), Travel/Accommodation/Expenses: Merck Serono. R. Dummer: Advisory/Consultancy, Project focused consulting: Novartis; Advisory/Consultancy, Project focused consulting: Merck Sharp & Dohme; Honoraria (institution), Project focused consulting: Bristol Myers Squibb; Advisory/Consultancy, Project focused consulting: Roche; Advisory/Consultancy, Project focused consulting: Amgen; Advisory/Consultancy, Project focused consulting: Takeda; Advisory/Consultancy, Project focused consulting: Pierre Fabre; Advisory/Consultancy, Project focused consulting: Sun Pharma; Advisory/Consultancy, Project focused consulting: Sanofi; Advisory/Consultancy, Project focused consulting: Catalym; Advisory/Consultancy, Project focused consulting: Second Genome; Advisory/Consultancy, Project focused consulting: Regeneron; Advisory/Consultancy, Project focused consulting: Alligator. V. Chiarion Sileni: Speaker Bureau/Expert testimony: Novartis; Travel/Accommodation/Expenses: Bristol Myers Squibb; Advisory/Consultancy, Travel/Accommodation/Expenses: Pierre Fabre; Speaker Bureau/Expert testimony: Merck Sharp & Dohme. All other authors have declared no conflicts of interest.