KEY TAKEAWAYS
- The phase 1b/2 study aimed to determine if the combination of Pepinemab and Pembrolizumab improves the efficacy of immunotherapy in R/M HNSCC.
- The primary endpoint was OR, and the secondary endpoints included PFS, DoR, OS, and exploratory biomarker analyses.
- KN-B84 interim analysis showed pepinemab + pembrolizumab, improved response in the PD-L1 low group, and identified TME biomarker changes.
Studies in preclinical and clinical settings have revealed that blocking semaphorin 4D (SEMA4D) with antibodies can counter this suppression. This blockade diminishes the recruitment and function of MDSCs while promoting the arrangement of immune cell clusters in tumors. These changes have shown promise in boosting the effectiveness of ICIs.
Pepinemab, a SEMA4D blocking antibody, when paired with avelumab, displayed good tolerance and provided clinical advantages in patients with NSCLC having low PD-L1 levels and resistance to ICIs.
The primary goal of this ongoing exploratory KEYNOTE-B84 (NCT04815720) study was to ascertain whether combining pepinemab with pembrolizumab can enhance the effectiveness of immunotherapy in R/M HNSCC. It targets patients new to immunotherapy with tumor PD-L1 combined positive scores (CPS) below 20 and 20 or higher.
An interim analysis was conducted after the initial tumor response assessment in 36 patients. The primary efficacy measure was ORR, and secondary outcomes included PFS, DoR, OS, and exploratory biomarker analyses.
The combination of pepinemab and pembrolizumab seemed well-tolerated, with no observed dose-limiting toxicities (DLTs) or safety concerns flagged by the SMC. In patients with low PD-L1 levels (CPS<20, totaling 19 individuals), the combination led to doubled Objective Response Rate (ORR), Disease Control Rate (DCR), and Progression-Free Survival (PFS) compared to pembrolizumab alone.
Among CPS<20 patients, the ORR reached 21.1% (including 2 complete responses and 2 partial responses), with a DCR of 73.7% and a median PFS of 5.79 months. Conversely, in the CPS≥20 subgroup (n=17), the ORR at 17.6% aligned with ICI monotherapy.
Spatial multiplex IHC analysis of pre-and post-treatment tumor biopsies revealed increased activated antigen-presenting cells (APC), reduced recruitment of myeloid-derived suppressor cells (MDSC), and well-structured immune clusters, correlating with disease control.
The interim analysis of the ongoing KN-B84 study indicated that combining pepinemab with pembrolizumab was well-tolerated. It hinted at early indications of enhanced anti-tumor responses compared to single-agent pembrolizumab, particularly in the challenging-to-treat PD-L1 low group.
The treatment induced biomarker changes in the TME of responsive tumors, notably the development of dense lymphoid aggregates.
Source: https://jitc.bmj.com/content/11/Suppl_1/A767
Clinical Trial: https://clinicaltrials.gov/study/NCT04815720
Fisher T, Evans E, Mallow C, et al676 Pepinemab, a semaphorin 4D inhibitor, in combination with pembrolizumab induced formation of organized lymphoid aggregates in phase 1b/2 study for first-line treatment of R/M HNSCC (KEYNOTE-B84)Journal for ImmunoTherapy of Cancer 2023;11:doi: 10.1136/jitc-2023-SITC2023.0676.
