ONCOLOGY LETTERS 21: 279, 2021 Clinical outcomes and influencing factors of PD‑1/PD‑L1 in hepatocellular carcinoma (Review) JITING WANG1, JUN LI2, GUIJU TANG1, YUAN TIAN1, SONG SU3 and YALING LI4 1Department of Clinical Pharmacy, Southwest Medical University, Luzhou; Departments of 2Traditional Chinese Medicine, 3Liver and Gallbladder, and 4Pharmacy, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China Received September 29, 2020; Accepted January 18, 2021 DOI: 10.3892/ol.2021.12540 Abstract. Hepatocellular carcinoma (HCC) has an increasing pembrolizumab and ipilimumab plus nivolumab are used incidence worldwide, and the global 5‑year survival rate ranges following sorafenib (but not lenvatinib) treatment in advanced from 5‑30%. In China, HCC seriously threatens the nation's HCC. Thus, tumor immunotherapy using PD‑1/PD‑L1 blockers health; the incidence of HCC ranks fourth among all theriomas, exhibits promising outcomes for the treatment of HCC, and and the mortality rate is the third highest worldwide. The more novel PD‑1/PD‑L1 inhibitors are being developed to fight main therapies for HCC are surgical treatment or liver trans‑ against this disease. The present review discusses the clinical plantation; however, most patients with HCC will experience results and influencing factors of PD‑1/PD‑L1 inhibitors in postoperative recurrence or metastasis, eventually resulting in HCC to provide insight into the development and optimization mortality. As for advanced or unresectable HCC, the current of PD‑1/PD‑L1 inhibitors in the treatment of HCC. appropriate treatment strategy is transarterial chemoembo‑ lization; however, limited therapeutic effect and natural or acquired drug resistance affect the efficacy of this approach. Contents Previous studies have demonstrated that PD‑L1 expression on host cells and myeloid cells plays an important role in PD‑L1 1. Introduction blocked‑mediated tumor regression. Thus, further research 2. Listed drugs on programmed cell death protein 1 (PD‑1) and programmed 3. Listed drugs in China death‑ligand 1 (PD‑L1) is required. Countries including the 4. Influencing factors United States, France, Britain and China have developed 5. Discussion PD‑1/PD‑L1 blockers, including nivolumab, pembrolizumab, 6. Conclusions cemiplimab, atezolizumab, avelumab, durvalumab, tori‑ palimab, sintilimab and camrelizumab. Notably, all of these blockers have therapeutic effect and influencing factors in 1. Introduction HCC. Factors that influence the clinical outcome of PD‑1 have also been discovered, such as inflammatory genes, specific Hepatocellular carcinoma (HCC) is a fatal malignancy origi‑ receptors and signaling pathways. The discovery of these nating in hepatocytes (1). HCC accounts for 90% of primary factors will help to identify novel methods, such as combi‑ liver cancers (2), whereby 850,000 new cases of HCC and nation treatment, to decrease the influence of other factors 745,500 mortalities are annually reported worldwide (3). on the efficacy of PD‑1/PD‑L1. Sorafenib and lenvatinib In China, there are nearly 466,000 new cases of HCC and have been approved for first‑line treatment for patients with 422,000 mortalities per year (4), and only 10‑15% of patients advanced HCC. When first‑line treatment frequently fails, meet conditions for surgical excision due to the severity of HCC (5). In advanced HCC, surgical treatment becomes infeasible due to the spread of the tumor beyond the liver. The current recommended treatment strategy in advanced disease is transarterial chemoembolization (TACE); however, most Correspondence to: Professor Yaling Li, Department of Pharmacy, Affiliated Hospital of Southwest Medical University, 25 Taiping patients with HCC have primary or acquired drug resistance, Street, Jiangyang, Luzhou, Sichuan 646000, P.R. China which affects the efficacy of TACE (6). Thus, it is important E‑mail: [email protected] to identify chemotherapeutic drugs aimed at novel targets to ameliorate chemotherapeutic resistance. Key words: advanced hepatocellular carcinoma, PD‑1, PD‑L1, Immune blockade inhibitors, also known as immune check‑ nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, point inhibitors (ICIs), are a novel type of monoclonal antibody durvalumab, toripalimab, sintilimab, camrelizumab, tislelizumab drug that can inhibit the function of inhibitory immune receptors to evoke an immune antineoplastic response (7). In principle, this interaction can be used to treat different types 2 WANG et al: CLINICAL OUTCOMES AND INFLUENCING FACTORS OF PD‑1/PD‑L1 of cancer, including lung cancer, melanoma, urothelial and reported that following sorafenib failure, nivolumab treatment renal carcinomas, Hodgkin's lymphoma and gastrointestinal is associated with improved OS (overall survival) and ORR cancers (8). Several clinical trials have investigated the poten‑ compared with regorafenib treatment (21). Nivolumab plus tial of similar treatments for HCC (9). The efficacy of single ipilimumab was evaluated in patients with advanced HCC drugs is limited, and various clinical trials are investigating pretreated with sorafenib. The ORR was 31%, disease control the potential combination of different ICIs or the combination rate (DCR) was 49% and a median duration of response was of ICIs and target agents (7). 17 months (22). NCCN recommends nivolumab as a subse‑ Amongst the numerous checkpoint molecules, the most quent therapy following disease progression in patients with widely studied, and those with the greatest clinical implica‑ CPA (Child‑Pugh class A) or CPB (Child‑Pugh class B) disease tions in human cancer, are cytotoxicity T lymphocyte protein 4 (a category 2A recommendation) (23). There are several other (CTLA‑4), programmed cell death protein 1 (PD‑1) and ongoing trials of combinations with nivolumab (Table I). programmed death‑ligand 1 (PD‑L1) (9). PD‑L1 is expressed on immune cells and tumor cells, and tumor cells use PD‑L1 Pembrolizaumab. Pembrolizaumab (Keytruda), produced by to bind to PD‑1 of T cells to ‘cheat’ the T cells and escape Merck & Co, is a strong and selective humanized monoclonal recognition, enabling them to continue to spread in the body. antibody of IgG 4/κ isotype (24). Nivolumab and pembroli‑ PD‑L1/PD‑1 antibodies can help T cells to evade this strategy zumab were enhanced by the Food and Drug Administration and retain their ability to identify and kill tumor cells (10). (FDA) on September 22 2017 and November 10 2018, The present review discusses recent progress in clinical respectively, as second‑line options for HCC therapy, based outcomes and influencing factors of PD‑1/PD‑L1 inhibitors, on the results of the CheckMate 040 phase I/II trial and the providing references and inspirations for the treatment of KEYNOTE‑224 phase II trial (24). In the KEYNOTE‑224 HCC. trial, when patients with advanced HCC exhibited progression or intolerance to sorafenib, they received 200 mg pembrolimab 2. Listed drugs every 3 weeks. The results demonstrated that pembrolizumab was tolerated and had an ORR of 17% and stable disease rate The National Comprehensive Cancer Network (NCCN) guide‑ of 44%, which initiated phase III (25). The phase III trial lines (2019) on HCC recommend sorafinib [Child‑Pugh A (KEYNOTE‑240, identifier: NCT02702401) was performed (Class 1 evidence) or B7] and lenvatinib (Child‑Pugh A only) to assess the safety and efficacy of pembrolizumab (26). for first‑line systematic therapy. Another targeted drug that However, the KEYNOTE‑240 trial did not reach its speci‑ can be used for first‑line treatment is linifanib. The objective fied endpoints of improvement in overall response (OR) and response rate (ORR) of linifanib is higher than that of solafinib; progression‑free survival (PFS) with pembrolizumab. The ORR however, no significant difference between the survival rates of the pembrolizumab group was markedly higher compared achieved by these drugs has been observed, thus, the guide does with the placebo group (16.9% vs. 2.2%) (25,26). Regardless not recommend the use of linifanib (11). A total of two drugs of the implications for the credibility of pembrolizumab as were recommended in the guidelines (2019) as second‑line second‑line monotherapy for advanced HCC compared with treatments, namely nivolumab and pembrolizaumab (11). placebo, the OS and PFS have exhibited clinically significant improvements, including the data from the KEYNOTE‑224 PD‑1 receptor blockers trial (24). Pembrolizumab plus lenvatinib was evaluated in a Nivolumab. Nivolumab (Opdivo) was developed by phase 1b trial, whereby patients with CPA disease did not have Bristol‑Myers Squibb and exhibits high affinity and specific prior systemic therapy, and the ORR was 50% and the control targeting of an epitope of PD‑1 (12,13). In September 2017, rate was 93.3%, lenvatinib plus pembrolizumab is being nivolumab received an accelerated approval for patients evaluated in a phase III study (NCT: 03713593) (27,28). NCCN with HCC pretreated with sorafenib, based on the results of recommends pembrolizumab as subsequent therapy following the phase I/II dose escalation and expansion cohort of the disease progression in patients with CPA liver function only Checkmate‑040 trial (14). The incidence of severe adverse (a category 2B recommendation) (23). There are several other events associated with grade 3/4 treatment was 4% (15). The ongoing trials of combinations involving pembrolizumab latest results were reported in January 2018 at the American (Table II). Society