LBA41 - Phase II study SECOMBIT (sequential combo immuno and target therapy study): 4-years OS data and preliminary biomarkers evaluation

Background

To investigate the best sequential strategy in BRAFV600-mutated melanoma, the SECOMBIT study was carried out, a three parallel arms phase 2 randomized trial (NCT02631447). We used the combination of encorafenib/binimetinib (E+B) as targeted therapy (T-T) and the combination of ipilimumab/nivolumab (I+N) as immunotherapy (I-O). We explored T-T (Arm A) or I-O (Arm B) as first line with switch at progression, as well as the “sandwich” strategy with T-T first preplanned switched to combo I-O after 8 weeks, returning back to T-T after progression (Arm C). In our previous report overall survival (OS) and total progression free survival (tPFS) rates at 2 and 3 years showed a better trend in Arm B and C.

Methods

From Nov 2016 to May 2019, 251 patients (pts) from 37 centers in 9 countries with untreated, metastatic BRAFV600 melanoma were enrolled. Pts were randomized to Arm A, Arm B or C. OS is the primary endpoint of the study. Secondary endpoints include tPFS, 4-year survival rate and a preliminary biomarkers evaluation. NGS analysis and 21 inflammatory cytokines through Luminex assay or HS-ELISA were evaluated at baseline from 83 pts (29,24,30 for Arm A,B,C) and 93 pts (28,29, 36 for Arm A,B,C) respectively.

Results

The OS at 4 years, with median follow up of 43 months (IQR: 37-51), was calculated in the three arms for all pts, and in the subgroups normal or elevate LDH level and < 3 or ≥ 3 metastatic sites. OS and tPFS rates at 4 years with subgroup analysis are shown in table 1. In the biomarkers analysis we observed a correlation of JAK mutation with survival, IFN-gamma and CXCL5 cytokines with ORR and PFS. Table: 000LBA41

Conclusions

The OS and tPFS rates at 4 years revealed positive trend in pts on Arm B and Arm C indicating planned switch could be beneficial treatment strategy. In Arm B, IFN Gamma low seems to be related to ICI response. JAK mutations are associated with long term OS. Further biomarkers evaluations are 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, Roche Genentech, MSD, Novartis, Pfizer/Array, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Boehringer Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Advisory Role: Eisai, Seagen; Financial Interests, Personal, Other, Consultant Role: Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role: Medicenna, Bio-AI Health; Financial Interests, Personal, Advisory Board, Consultant and Advisory Role: Dohme, iTeos; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Financial Interests, Institutional, Funding, Clinical Trial: Roche Genentech, Pfizer/Array, 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 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, AIOM, SMR; Other, Travel Support: MSD. M. Mandala: Financial Interests, Personal, Advisory Board: MSD, Novartis, Sanofi, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: Sun Pharma. P.F. Ferrucci: Financial Interests, Personal, Advisory Board, Advisory board and Consultancy: Bristol myers squibb, MSD, Novartis, Pierre Fabre. M. Guidoboni: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: MSD, Pierre-Fabre; Financial Interests, Institutional, Research Grant: MSD. P. Rutkowski: Financial Interests, Personal, Invited Speaker, honoraria for lectures: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, Philogen; Financial Interests, Personal, Invited Speaker: Merck, Sanofi, Novartis; Financial Interests, Institutional, Research Grant, research grant for ISS: Pfzer; Financial Interests, Institutional, Funding, research grant for institution: BMS; Non-Financial Interests, Invited Speaker: Polish Society of Surgical Oncology; Non-Financial Interests, Officer: ASCO; Non-Financial Interests, Invited Speaker, President Elect: Polish Oncological Society. V. Ferraresi: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, MSD; Financial Interests, Personal, Invited Speaker: Bristol myers squibb, Novartis, Pierre-Fabre. A.M. Arance Fernandez: Financial Interests, Personal, Advisory Board, Consultant /Advisory/ Speaker / Travel, Accomodations, Expenses/: Pierre Fabre, Novartis, Roche, BMS, MSD, Merck, Sanofi; Financial Interests, Institutional, Other, Research Funding: Pierre Fabre, Novartis, MSD, BMS, Merck, Roche, Sanofi, Amgem. M. Guida: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre. H.J. Gogas: Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: MSD, BMS, Novartis, Pierre Fabre, Sanofi; Financial Interests, Invited Speaker: Amgen, Replimmune; Financial Interests, Institutional, Invited Speaker: Amgen, MSD, BMS, Replimmune, Iovance; Financial Interests, Institutional, Research Grant: BMS, Pfizer. E. Richtig: Financial Interests, Personal, Invited Speaker: Amgen, BMS, MSD, Novartis, Pierre Fabre, Novartis, Pierre Fabre; Financial Interests, Personal, Advisory Board: BMS, MSD, Merck, Novartis, Pierre Fabre, Sanofi, Roche; Financial Interests, Institutional, Invited Speaker: Amgen, BMS, Curevac, Incyte, MSD, Novartis, Pierre Fabre, Delcath, Roche; Financial Interests, Institutional, Other, Subinvestigator: Merck; Financial Interests, Institutional, Other, named patient program: Sanofi; Non-Financial Interests, Leadership Role, Member of the committee of the Austrian Cancer Aid/Styria, an non profit organisation: Austrian Cancer Aid/Styria; Non-Financial Interests, Leadership Role, Deputy secretary: Austrian Cancer Aid. M.T. Fierro: Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Bristol Myers Squibb, Novartis, AbbVie, Lilly. C. Lebbe: Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb, MSD, Novartis, Amgen, Roche, Merck Serono, Sanofi, Pierre Fabre; Financial Interests, Personal, Funding: Roche, Bristol Myers Squibb; Non-Financial Interests, Advisory Role: Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, Merck Serono, Sanofi, Pierre Fabre; Other, Honoraria, Speaker's Bureau: Roche; Other, Honoraira, Speaker's bureau, Travel, Accomodations, Expenses: Bristol Myers Squibb; Other, Honoraria, Speaker's bureau, Travel, Accommodations, Expenses: Novartis, MSD; Other, Honoraria, Speaker's bureau: Amgen; Other, Honoraria, Travel, Accommodations, Expenses: Pierre Fabre; Other, Honoraria: Pfizer; Other, Honoraria: Incyte; Other, Travel, accommodations, Expenses: Sanofi. H. Helgadottir: Financial Interests, Personal, Other, honoraria: Bristol Myers Squibb, MSD, Pierre Fabre. I. Melero: Financial Interests, Personal, Advisory Board: Gossamer Bio, Highlight Therapeutics, MSD, Alligator Bioscience, Genmab, Numab, NOXXON Pharma AG, BMS, CRISPR Therapeutics, Genentech, AstraZeneca, Boehringer Ingelheim, EMD Serono, Roche; Financial Interests, Personal, Other, Consultant: Pharma Mar; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, BMS, Genmab, Alligator. G. Palmieri: Financial Interests, Personal, Advisory Board: Novartis, Pierre-Fabre; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Pierre-Fabre. A.M. Grimaldi: Financial Interests, Personal, Advisory Board, advisory board and consultancy: Bristol Myers Squibb, Novartis, MSD; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Pierre Fabre, Novartis, Bristol Myers Squibb. R. Dummer: Financial Interests, Personal, Other, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaviVAX SA, touchIME, T3 Pharma, Pfizer. V. Chiarion Sileni: Financial Interests, Personal, Advisory Board, analysis of treatment modality ( diagnosis, stanging, surgery, radiotherapy, systemic therapy for Merkel cell carcinoma in Italy: Merck-serono; Financial Interests, Institutional, Invited Speaker, treatment option for BRAF mutated melanoma: novartis; Financial Interests, Institutional, Invited Speaker, Treatment choices for BRAF mutated melanoma, evidence-based, and biologically supported: Pierre -Fabre; Financial Interests, Institutional, Invited Speaker, Immunotherapy for melanoma treatment present and future: Bristol-Meyers-Squibb; Financial Interests, Personal, Other, Travel, registration, and accommodation to attend ASCO annual meetings: Pierre-Fabre; Financial Interests, Personal, Advisory Board, Travel expenses, registration, and accommodation to attend ASCO annual meeting and ESNO annual meeting: Bristol Myers Squibb. All other authors have declared no conflicts of interest.