According to a study conducted by JAMA Oncology, anti-PD-1 exhibited better survival outcomes than anti-PD-L1 in patients with solid tumors in either overall, monotherapy, or combination therapy settings with comparable safety profiles.
“There is a need to better understand the similarities and differences between anti-PD-1 and anti-PD-L1 for the ultimate benefit of patients with cancer,” the authors wrote.
In this cohort of 11,379 patients across 19 randomized clinical trials, anti-PD-1 exhibited superior overall survival (OS; HR, 0.75; 95% CI, 0.65-0.86; P < .001) and progression-free survival (PFS; HR, 0.73; 95% CI, 0.56-0.96; P = .02) compared with anti-PD-L1. PFS was conducted using the frequentist approach, and OS results were analyzed using mirror groups.
Researchers indicated that the improved efficacy could possibly be due to the inherent differences between anti-PD-1 and anti-PD-L1. “PD-1 antibodies can bind to PD-1 and further block the binding of PD-1 to its ligands (PD-L1 and PD-L2) at the same time,” the authors wrote. “However, although PD-L1 antibodies would also inhibit the binding of PD-1 to PD-L1, the interaction of PD-1 and PD-L2 remains intact, which may inhibit activation of T cells.”
When the Bayesian framework was used, the data indicated that anti-PD-1 exhibited significant or borderline significant OS and PFS superiority compared with anti-PD-L1 across different tumor types in either overall population (OS: HR, 0.79; 95% credible interval [CrI], 0.71-0.88; PFS: HR, 0.80; 95% CrI, 0.69-0.93), as monotherapy (OS: HR, 0.85; 95% CrI, 0.74-0.97; PFS: HR, 0.77; 95% CrI, 0.58-1.02), or combined with standard treatment (OS: HR, 0.67; 95% CrI, 0.55-0.82; PFS: HR, 0.82; 95% CrI, 0.69-0.97).
The overall safety profiles of anti-PD-1 and anti-PD-L1 were comparable for both any adverse event (AE; grades 3-5: risk ratio [RR], 1.04; 95% CI, 0.78-1.39; P = .78) and immune-related AEs (grades 3-5: RR, 0.88; 95% CI, 0.46-1.68; P = .69). The risk of AEs leading to death or discontinuation were also comparable between anti-PD-1 and anti-PD-L1 (any AE leading to death: RR, 1.01; 95% CI, 0.53-1.93; P = .98; any AE leading to discontinuation: RR, 1.20; 95% CI, 0.95-1.52; P = .13; immune-related AEs leading to death: RR, 1.38; 95% CI, 0.11-16.89; P = .80).
The survival superiority of anti-PD-1 was elevated when used in combination with standard therapies, which lowered the risk of death by 32% compared with anti-PD-L1 plus standard therapies. Previous studies have indicated that chemotherapy may enhance the expression of PD-L1, leading to the synergistic effect of immune checkpoint inhibitors with chemotherapy. Thus, T-cell activation could be inhibited by PD-L1 antibody overconsumption owing to extra PD-L1 expression, though the authors noted future studies are necessary to explore this idea.
The selected studies covered 10 trials with anti-PD-1 (including 3 with nivolumab [Opdivo] and 3 with pembrolizumab [Keytruda] in monotherapy settings, and 4 with pembrolizumab in combination with standard therapy) and 9 trials with anti-PD-L1 (including 2 with avelumab [Bavencio] and 3 with atezolizumab [Tecentriq] in monotherapy settings, and 1 with avelumab and 3 with atezolizumab in combination with standard therapy).
Thirteen trials were done in patients with non-squamous cell lung cancer (NSCLC), 2 in patients with gastroesophageal junction cancer (GC), 2 trials in patients with urothelial cancer (UC), and 2 in patients with renal cell carcinoma (RCC).
According to the researchers, future head-to-head studies are necessary for direct comparison across alternative interventions.
Duan J, Cui L, Zhao X, et al. Use of Immunotherapy With Programmed Cell Death 1 vs Programmed Cell Death Ligand 1 Inhibitors in Patients With Cancer. JAMA Oncology. doi:10.1001/jamaoncol.2019.5367.