SECOMBIT (sequential combo immuno and target therapy study): A three arms prospective, randomized phase II study to evaluate the best sequential approach with combo immunotherapy [ipilimumab (I) /nivolumab (N)] and combo target therapy [encorafenib (E)/binimetinib (B)] in patients with metastatic melanoma and BRAF mutation.

TPS9598 Background: Treatment of BRAF-mutated metastatic melanoma has dramatically changed with the introduction of targeted therapy (BRAF and MEK inhibitors) and immune-checkpoint blockade (anti-CTLA4, anti-PD-1, and anti-PD-L1). Target therapy has been associated with high response rates, but short-term responses. Conversely, treatment with immune checkpoint inhibitors was found to present with lower response rates, but long-term responses. Synergism has been demonstrated when targeted therapy is combined with immunotherapy. The risk of a high rate of toxicity limits the simultaneous combination of all the four compounds (target agents and immunomodulating monoclonal antibodies). Sequencing of these different combinations seems to be more feasible; finding the right treatment sequence represents an important issue to be addressed. Methods: Approximately, 230 patients with untreated, histologically-confirmed advanced melanoma (measurable disease by RECIST v1.1) and carrying the BRAFV600 mutation will be randomized to Arm A [E+B until disease progression (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 until PD). Patients will receive the combo treatments with the following schedules: target therapy, E 450mg p.o. od + B 45mg p.o. bid; immunotherapy, I 3mg/kg + N 1mg/kg Q3w x 4 cycles, followed by N 3mg/kg Q2w. The OS (time from the date of randomization until death from any cause) is primary efficacy endpoint of the study. Secondary endpoints include total PFS (time from randomization until the second progression), survival at 2 and 3 years, best overall response rate, duration of response. About 90 patients will take part in the ancillary study for the evaluation of biomarkers on the biological samples available (biopsies + blood samples). 30 Sites in Europe will concur to enroll the patients in the trial. This study is open and currently enrolling patients. Clinical trial information: NCT02631447.