Robin Kate Kelley, MD of the University of California, San Francisco discusses the most effective way to combined a CTL4 inhibitor with a PDL1 inhibitor.
Bottom line:
In the initial cohort of this study (NCT02519348), the combination of double immune control point inhibitors (ICI) T (anti "“ CTLA-4) and D (anti "“ PD-L1) showed tolerability with positive objective response rate (ORR). Subsequent assessment of pts with solid tumors treated with can doses of T indicated priming with a higher dose of T can induce a stronger immune response and improve anti-tumor activity. The randomized expansion cohorts thus included 4 arms testing T and D as monotherapies and 2 T+D schemes, including a novel T+D scheme with a single priming dose of T.
Approaches:
T300+D (T 300 mg + D 1500 mg 1 dose followed by D Q4 weekly [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 dose] followed by D Q4W) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 dose] followed by D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W). Primary endpoint was safety. The ORR was evaluated by blinded, unbiased central review using RECIST v1.1, response length (DoR), circulating lymphocytes, and overall survival ( OS).
Analyses:
332 pts were inscribed at the data cut-off (09/02/2019). Median follow-ups for T300+D were 11.7 months (mo); 14.6 (T75+D), 8.9 (D), and 15.8 (T). Incidences of the treatment-related adverse event (trAE) are shown (Table); no deaths for T300+D or T were due to trAEs. The T300+D arm had the highest reported ORR (DoR did not hit [NR]) and the longest operating system (Table). The T300+D arm established a distinct proliferative T cell profile for pts, indicating additive biological activity for the combination, and showed high cytotoxic (CD8) counts of pts with an OR.
Conclusions Therein:
The supporting clinical activity and the tolerable safety profile suggest that T300+D offers the better benefit-risk balance versus T75+D or monotherapy. The T300+D regimen ‘s unusual pharmacodynamic behavior further supports its usage in aHCC. In the ongoing step III HIMALAYA analysis (NCT03298451) for first-line HCC vs sorafenib, T300+D and D are being evaluated. Credit: AstraZeneca. Details on clinical trials: NCT02519348.