PD‑1/PD‑L1 immune checkpoint inhibitors in neoadjuvant therapy for solid tumors (Review)

Abstract

A comprehensive search regarding programmed cell death protein 1 (PD‑1)/programmed death‑ligand 1 (PD‑L1) inhibitor monotherapy or combination therapy in neoadjuvant settings of 11 types of solid cancer was performed using the PubMed, Cochrane and Embase databases, and the abstracts of various conferences were screened. Data presented in 99 clinical trials indicated that preoperative treatment with PD‑1/PD‑L1 combined therapy, particularly immunotherapy plus chemotherapy, could achieve a higher objective response rate, a higher major pathologic response rate and a higher pathologic complete response rate, as well as a lower number of immune‑related adverse events compared with PD‑1/PD‑L1 monotherapy or dual immunotherapy. Although PD‑1/PD‑L1 inhibitor combination caused more treatment‑related adverse events (TRAEs) in patients, most of the TRAEs were acceptable and did not cause marked delays in operation. The data suggest that patients with pathological remission after neoadjuvant immunotherapy exhibit improved postoperative disease‑free survival compared with those without pathological remission. Further studies are still required to evaluate the long‑term survival benefit of neoadjuvant immunotherapy.

Keywords: MPR; ORR; clinical trials; neoadjuvant therapy; pCR; programmed cell death protein 1/programmed death‑ligand 1; solid tumor.

Figure 1

Flow chart of studies identified and selection criteria.

Figure 2

Efficacy and irAEs of neoadjuvant therapy for different types of cancer. (A) ORR. (B) MPR. (C) pCR. (D) Grade ≥3 irAEs. GEJ/GC, gastroesophageal junction and gastric cancer; irAE, immune-related adverse event; MPR, major pathologic response; ORR, objective response rate; pCR, pathologic complete response.

Figure 3

Efficacy and safety (including TRAEs and irAEs) of different neoadjuvant therapy regimens. (A) ORR. (B) MPR. (C) pCR. (D) Grade ≥3 TRAEs. (E) Grade ≥3 irAEs. IO, immune checkpoint inhibitor alone (PD-1 inhibitor or PD-L1 inhibitor alone); IO+IO, combination of PD-1/PD-L1 inhibitor and cytotoxic T-lymphocyte associated protein 4 inhibitor or lymphocyte activation gene-3 inhibitor; IO + chemotherapy, combination of PD-1/PD-L1 inhibitor and chemotherapy; IO + radiotherapy, combination of PD-1/PD-L1 inhibitor and radiotherapy; IO + chemoradiotherapy, combination of PD-1/PD-L1 inhibitor and chemotherapy plus radiotherapy; IO+VEGFR, combination of PD-1/PD-L1 inhibitor and angiogenesis inhibitor; IO + Others, combination of PD-1/PD-L1 inhibitor and special drugs; irAE, immune-related adverse event; MPR, major pathologic response; ORR, objective response rate; pCR, pathologic complete response; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TRAE, treatment-related adverse event.

Figure 4

ORR, MPR, pCR and AEs (including TRAEs and irAEs) of neoadjuvant immunotherapy. (A) ORR and MPR. (B) ORR and pCR. (C) pCR and grade ≥3 irAEs. (D) pCR and grade ≥3 TRAEs. IO, immune checkpoint inhibitor alone (PD-1 inhibitor or PD-L1 inhibitor alone); IO+IO, combination of PD-1/PD-L1 inhibitor and cytotoxic T-lymphocyte associated protein 4 inhibitor or lymphocyte activation gene-3 inhibitor; IO + chemotherapy, combination of PD-1/PD-L1 inhibitor and chemotherapy; IO + radiotherapy, combination of PD-1/PD-L1 inhibitor and radiotherapy; IO + chemoradiotherapy, combination of PD-1/PD-L1 inhibitor and chemotherapy plus radiotherapy; IO+VEGFR, combination of PD-1/PD-L1 inhibitor and angiogenesis inhibitor; IO + Others, combination of PD-1/PD-L1 inhibitor and special drugs; irAE, immune-related adverse event; MPR, major pathologic response; ORR, objective response rate; pCR, pathologic complete response; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TRAE, treatment-related adverse event.