Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials

Abstract

Background: Inhibitors targeting programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have unprecedented effects in cancer treatment. However, the objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS) of PD-1/PD-L1 blockade monotherapy have not been systematically evaluated.

Methods: We searched Embase, PubMed, and Cochrane database from inception to July 2019 for prospective clinical trials on single-agent PD-1/PD-L1 antibodies (avelumab, atezolizumab, durvalumab, cemiplimab, pembrolizumab, and nivolumab) with information regarding ORR, PFS, and OS.

Results: Totally, 28,304 patients from 160 perspective trials were included. Overall, 4747 responses occurred in 22,165 patients treated with PD-1/PD-L1 monotherapy [ORR, 20.21%; 95% confidence interval (CI), 18.34-22.15%]. Compared with conventional therapy, PD-1/PD-L1 blockade immunotherapy was associated with more tumor responses (odds ratio, 1.98; 95% CI, 1.52-2.57) and better OS [hazard ratio (HR), 0.75; 95% CI, 0.67-0.83]. The ORRs varied significantly across cancer types and PD-L1 expression status. Line of treatment, clinical phase and drug target also impacted the response rates in some tumors. A total of 2313 of 9494 PD-L1 positive patients (ORR, 24.39%; 95% CI, 22.29-26.54%) and 456 of 4215 PD-L1 negative patients (ORR, 10.34%; 95% CI, 8.67-12.14%) achieved responses. For PD-L1 negative patients, the ORR (odds ratio, 0.92; 95% CI, 0.70-1.20) and PFS (HR, 1.15; 95% CI, 0.87-1.51) associated with immunotherapy and conventional treatment were similar. However, PD-1/PD-L1 blockade monotherapy decreased the risk of death in both PD-L1 positive (HR, 0.66; 95% CI, 0.60-0.72) and PD-L1 negative (HR, 0.86; 95% CI, 0.74-0.99) patients compared with conventional therapy.

Conclusion: The efficacies associated with PD-1/PD-L1 monotherapy vary significantly across cancer types and PD-L1 expression. This comprehensive summary of clinical benefit from immunotherapy in cancer patients provides an important guide for clinicians.

Keywords: PD-1; PD-L1; cancer; immunotherapy; tumor response.

Figure 1.

Flow-chart diagram of selected trials included in this study.

Figure 2.

The pooled ORRs in 26 different types of cancers. Vertical line indicates the overall mean incidence of tumor responses calculated from all 22,165 patients in 160 eligible trials. CI, confidence interval; GC/GEJC, gastric or gastro-esophageal junction cancer; ORR, objective response rate.

Figure 3.

Comparison of the ORRs between patients that were PD-L1 positive (blue) and patients that were PD-L1 negative (red) in PD-1 or PD-L1 blockade monotherapy. CI, confidence interval; GC/GEJC, gastric or gastro-esophageal junction cancer; ORR, objective response rate; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1.

Figure 4.

The association between tumor responses and several major clinicopathological characteristics in lung cancer (A), melanoma (B), urothelial cancer (C), GC/GEJC (D), head and neck cancer (E), and renal cancer (F). CI, confidence interval; GC/GEJC, gastric or gastro-esophageal junction cancer; ORR, objective response rate; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1.

Figure 5.

Comparison of the ORRs between PD-1 or PD-L1 blockade monotherapy and conventional therapy in (A) all recruited patients, (B) patients who were PD-L1 positive, and (C) patients who were PD-L1 negative. CI, confidence interval; GC/GEJC, gastric or gastro-esophageal junction cancer; ORR, objective response rate; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1.

Figure 6.

Comparison of PFS (A) and OS (B) between PD-1 or PD-L1 blockade monotherapy and conventional therapy. Blue, patients that were PD-L1 positive; red, patients that were PD-L1 negative; black, all recruited patients. CI, confidence interval; GC/GEJC, gastric or gastro-esophageal junction cancer; PFS, progression-free survival; ORR, objective response rate; OS, overall survival; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1.