LBA40 - SECOMBIT: The best sequential approach with combo immunotherapy [ipilimumab (I) /nivolumab (N)] and combo target therapy [encorafenib (E)/binimetinib (B)] in patients with BRAF mutated metastatic melanoma: A phase II randomized study

Background

Treatment with targeted therapy (BRAF and MEK inhibitors) and immune-checkpoint inhibitors (anti-CTLA4, anti-PD-1) have improved the outcome of BRAF-V600 metastatic melanoma patients in first line. Targeted therapy demonstrated higher response rates, which may be limited over time; while the combination I+N is associated with lower but durable response rate. The best sequencing remains an open question. In addition, a short course of targeted therapy switched to I+N at best response is supported by models and may be clinically advantageous. To investigate the best sequential strategy, we started the SECOMBIT study: a randomized three-arm phase 2 study with no formal comparative test (NCT02631447).

Methods

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

Results

The study primary endpoint was met in each arm with at least 30 patients alive at 24 months. The median follow-up estimated with the reverse Kaplan-Meier method was 32.2 months (IQR= 27.9-41.6). The median OS was not reached in any of the treatment arms. The survival rate at 2 and 3 years was 65% and 54% in arm A, 73% and 62% in arm B and 69% and 60% in arm C respectively. Total PFS rate at 2 and 3 years was 46% and 41% in arm A, 65% and 53% in arm B, 57% and 54% in arm C.

Conclusions

The OS and TPFS rates at 2 and 3 years showed a better trend in arm B and C. Data continue to be collected to provide additional information on the long-term benefit of the three treatment combinations. The biomarkers analysis is ongoing.

Clinical trial identification

NCT02631447.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione Melanoma Onlus.

Funding

BMS and Array Biopharma/Pfizer.

Disclosure

P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS; Financial Interests, Personal, Other, Consultant and Advisory Role: Roche Genentech; Financial Interests, Personal, Other, Consultant and Advisory Role: MSD; Financial Interests, Personal, Other, Consultant and Advisory Role: Novartis; Financial Interests, Personal, Other, Consultant and Advisory Role: Array; Financial Interests, Personal, Other, Consultant and Advisory Role: Merck Serono; Financial Interests, Personal, Other, Consultant and Advisory Role: Pierre Fabre; Financial Interests, Personal, Other, Consultant and Advisory Role: Incyte; Financial Interests, Personal, Other, Consultant and Advisory Role: Genmab; Financial Interests, Personal, Other, Consultant and Advisory Role: Medimmune; Financial Interests, Personal, Other, Consultant and Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Consultant and Advisory Role: Sindax; Financial Interests, Personal, Other, Consultant and Advisory Role: Sun Pharma; Financial Interests, Personal, Other, Consultant and Advisory Role: Sanofi; Financial Interests, Personal, Other, Consultant and Advisory Role: Idera; Financial Interests, Personal, Other, Consultant and Advisory Role: Ultimovacs; Financial Interests, Personal, Other, Consultant and Advisory Role: Sandoz; Financial Interests, Personal, Other, Consultant and Advisory Role: Immunocore; Financial Interests, Personal, Other, Consultant and Advisory Role: 4SC; Financial Interests, Personal, Other, Consultant and Advisory Role: Alkermes; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Consultant and Advisory Role: Nektar; Financial Interests, Personal, Other, Consultant and Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Other, Advisory Role: Eisai; Financial Interests, Personal, Other, Consultant and Advisory Role: Regeneron; Financial Interests, Personal, Other, Consultant Role: Daiichi Sankyo; Financial Interests, Personal, Other, Consultant Role: Pfizer; Financial Interests, Personal, Other, Consultant Role: Oncosec; Financial Interests, Personal, Other, Consultant Role: Nouscom; Financial Interests, Personal, Other, Consultant Role: Takis; Financial Interests, Personal, Other, Consultant Role: Lunaphore; Financial Interests, Personal, Other, Advisory Role: Seagen; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Financial Interests, Institutional, Funding, Clinical Trial: Roche-Genentech; Financial Interests, Institutional, Funding, Clinical Trial: Array; Financial Interests, Institutional, Funding, Clinical Trial: Sanofi; Non-Financial Interests, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Invited Speaker, November 2017 - December 2020: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: SITC; Non-Financial Interests, Member: EORTC Melanoma Cooperative Group; Non-Financial Interests, Member: AIOM; Non-Financial Interests, Member: SMR; Other, Travel Support: MSD. M. Mandala: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis. P.F. Ferrucci: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Pierre Fabre. P. Rutkowski: Financial Interests, Personal, Advisory Role: Blueprint Medicines; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Invited Speaker: Merck Serono; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Research Grant: Pfizer; Non-Financial Interests, Officer: ASCO; Non-Financial Interests, Member: Polish Society of Surgical Oncology. M. Guidoboni: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Institutional, Research Grant: MSD. A.M. Arance Fernandez: Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Other, Travel expenses: Pierre Fabre; Financial Interests, Institutional, Research Grant: Pierre Fabre; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Other, Travel expenses: Novartis; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Other, Travel expenses: BMS; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Other, Travel expenses: MSD; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Personal, Advisory Role: Merck-Serono; Financial Interests, Personal, Invited Speaker: Merck-Serono; Financial Interests, Personal, Other, Travel expenses: Merck-Serono; Financial Interests, Institutional, Research Grant: Merck-Serono; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Other, Travel expenses: Sanofi; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Amgen. V. Ferraresi: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Other, Travel accomodation: BMS; Financial Interests, Personal, Other, Travel accomodation: Pierre Fabre; Financial Interests, Personal, Other, Travel accomodation: MSD. E. Maiello: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Travel expenses: AstraZeneca; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Other, Travel expenses: Sanofi; Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Other, Travel expenses: Servier; Financial Interests, Personal, Invited Speaker: Merck-Serono; Financial Interests, Personal, Advisory Board: Merck- Serono; Financial Interests, Personal, Other, Travel expenses: Merck-Serono; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Other, Travel expenses: Lilly; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Other, Travel expenses: Eisai; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: MSD. M. Guida: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pierre Fabre. M. Del Vecchio: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Sanofi. M.T. Fierro: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: AbbVie; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Other, Travel expenses: Novartis; Financial Interests, Personal, Other, Travel expenses: BMS; Financial Interests, Personal, Other, Travel expenses: MSD; Financial Interests, Personal, Other, Travel expenses: Pierre Fabre; Financial Interests, Personal, Other, Travel expenses: AbbVie; Financial Interests, Personal, Other, Travel expenses: Lilly. P. Queirolo: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Merck-Serono; Financial Interests, Personal, Advisory Role: Sun Pharma; Financial Interests, Personal, Advisory Role: Sanofi. C. Lebbe: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: BMS; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: Amgen; Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Other, Honoraria: Pierre Fabre; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Incyte; Financial Interests, Personal, Other, Travel expenses: BMS; Financial Interests, Personal, Other, Travel expenses: MSD; Financial Interests, Personal, Other, Travel expenses: Novartis; Financial Interests, Personal, Other, Travel expenses: Sanofi; Financial Interests, Personal, Other, Travel expenses: Pierre Fabre; Financial Interests, Personal, Other: Avantis Medical System. I. Melero: Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Alligator; Financial Interests, Institutional, Research Grant: Pharmamar; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Genmab; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Alligator; Financial Interests, Personal, Advisory Role: Pharmamar; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Genmab; Financial Interests, Personal, Advisory Role: Merck-Serono; Financial Interests, Personal, Advisory Role: Numab; Financial Interests, Personal, Advisory Role: Gossamer; Financial Interests, Personal, Advisory Role: Bioncotech. G. Palmieri: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Roche-Genentech. A.M. Grimaldi: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Roche-Genentech; Financial Interests, Personal, Invited Speaker: Merck-Serono; Financial Interests, Personal, Other, Travel grant: BMS; Financial Interests, Personal, Other, Travel grant: MSD; Financial Interests, Personal, Other, Travel grant: Merck- Serono. R. Dummer: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Catalaym; Financial Interests, Personal, Invited Speaker: MaxiVAX SA; Financial Interests, Personal, Invited Speaker: Amgend Takeda; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Sun Pharma; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Second Genome; Financial Interests, Personal, Invited Speaker: Regeneron; Financial Interests, Personal, Invited Speaker: Alligator; Financial Interests, Personal, Invited Speaker: T3Pharma. V. Chiarion Sileni: Financial Interests, Personal, Advisory Role: Merck-Serono; Financial Interests, Personal, Invited Speaker: Merck-Serono; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Other, Travel expenses: Pierre Fabre; Financial Interests, Personal, Other, Travel expenses: BMS; Financial Interests, Personal, Advisory Role: Pierre Fabre. All other authors have declared no conflicts of interest.