1083MO - Brain metastases and survival evaluation in the SECOMBIT trial

Background

Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develop brain metastases. In the SECOMBIT study patients received the combination of encorafenib/binimetinib (E+B) as targeted therapy (T-T) or the combination of ipilimumab/nivolumab (I+N) as immunotherapy (I-O). In the present analysis, we updated survival outcomes and investigated if the incidence of and timing to brain metastasis onset were significantly different in patients receiving 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 reports, 4-year survival outcomes confirmed long-term benefit in ARM B and C pts. We also described preliminary biomarkers analyses where the loss-of-function affecting JAK or low baseline levels of serum interferon gamma (IFNy) are correlated to PFS and OS.

Methods

From Nov 2016 to May 2019, of 251 pts enrolled, 69 were randomized in ARM A, 71 pts in ARM B and 69 pts in ARM C. BMFS (Brain Metastasis Free Survival) was defined as time from start of first systemic therapy until new brain metastasis detection or last pts contact (censored BMFS). The Kaplan-Meier method was used to estimate OS and PFS. The median follow up was 43 months (IQR: 37-51).

Results

Pts treated in arm B and C had a lower risk to develop brain metastasis compared to pts in arm A. Brain metastasis occurred during first line treatment, in 17, 6, and 8 patients, respectively, treated in ARM A, B and C. During the study, an intracranial progression was detected in a total of 23, 11 and 9 patients in ARM A, B and C. The exploratory HR for BMFS was of 0.51 (0.25-1.04) for ARM B vs ARM A, and 0.37 (0.17-0.81) for ARM C vs ARM A. In the biomarker analysis, pts with high tumor mutational burden (TMB, ≥10 mut/mb) had an improved BMFS compared with pts with low TMB [HR 0.20 (0.05-0.95)]. JAK mutated pts had a better BMFS compared to wild type pts [HR 0.26 (0.06-1.12)].

Conclusions

Patients in ARM B and C had a longer BMFS compared with pts who started treatment with T-T. BMFS rate at 4 years was better in TMB high and in JAK mutated pts. At the time of the meeting it will also be reported the 5-years OS data.

Clinical trial identification

NCT02631447.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione Melanoma.

Funding

This study was supported by unconditioned grants from Bristol Myers Squibb (Princeton, NJ) and Array Biopharma Inc./Pfizer (Boulder, CO).

Disclosure

P.A. Ascierto: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna. All other authors have declared no conflicts of interest.