Clinical outcomes and influencing factors of PD‑1/PD‑L1 in hepatocellular carcinoma (Review)
- Authors:
- Published online on: February 10, 2021 https://doi.org/10.3892/ol.2021.12540
- Article Number: 279
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Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Hepatocellular carcinoma (HCC) is a fatal malignancy originating in hepatocytes (1). HCC accounts for 90% of primary liver cancers (2), whereby 850,000 new cases of HCC and 745,500 mortalities are annually reported worldwide (3). In China, there are nearly 466,000 new cases of HCC and 422,000 mortalities per year (4), and only 10–15% of patients 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 patients with HCC have primary or acquired drug resistance, which affects the efficacy of TACE (6). Thus, it is important to identify chemotherapeutic drugs aimed at novel targets to ameliorate chemotherapeutic resistance.
Immune blockade inhibitors, also known as immune checkpoint inhibitors (ICIs), are a novel type of monoclonal antibody 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 of cancer, including lung cancer, melanoma, urothelial and renal carcinomas, Hodgkin's lymphoma and gastrointestinal cancers (8). Several clinical trials have investigated the potential of similar treatments for HCC (9). The efficacy of single drugs is limited, and various clinical trials are investigating the potential combination of different ICIs or the combination of ICIs and target agents (7).
Amongst the numerous checkpoint molecules, the most widely studied, and those with the greatest clinical implications in human cancer, are cytotoxicity T lymphocyte protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) (9). PD-L1 is expressed on immune cells and tumor cells, and tumor cells use PD-L1 to bind to PD-1 of T cells to ‘cheat’ the T cells and escape recognition, enabling them to continue to spread in the body. PD-L1/PD-1 antibodies can help T cells to evade this strategy and retain their ability to identify and kill tumor cells (10).
The present review discusses recent progress in clinical outcomes and influencing factors of PD-1/PD-L1 inhibitors, providing references and inspirations for the treatment of HCC.
Listed drugs
The National Comprehensive Cancer Network (NCCN) guidelines (2019) on HCC recommend sorafinib [Child-Pugh A (Class 1 evidence) or B7] and lenvatinib (Child-Pugh A only) for first-line systematic therapy. Another targeted drug that can be used for first-line treatment is linifanib. The objective response rate (ORR) of linifanib is higher than that of solafinib; however, no significant difference between the survival rates achieved by these drugs has been observed, thus, the guide does not recommend the use of linifanib (11). A total of two drugs were recommended in the guidelines (2019) as second-line treatments, namely nivolumab and pembrolizaumab (11).
PD-1 receptor blockers
Nivolumab
Nivolumab (Opdivo) was developed by Bristol-Myers Squibb and exhibits high affinity and specific targeting of an epitope of PD-1 (12,13). In September 2017, nivolumab received an accelerated approval for patients with HCC pretreated with sorafenib, based on the results of the phase I/II dose escalation and expansion cohort of the Checkmate-040 trial (14). The incidence of severe adverse events associated with grade 3/4 treatment was 4% (15). The latest results were reported in January 2018 at the American Society of Clinical Oncology GI annual meeting, based on 154 sorafenib-treated patients, with the conclusion that nivolumab has a significant effect in patients with HCC, with sorafenib pretreatment (16). The randomized phase III CheckMate 459 trial was performed to assess nivolumab vs. sorafenib as a first-line treatment in unresectable HCC; however, the result did not reach the specified end point (17). Although the results failed to meet the predefined threshold of statistical significance, the overall survival rate with nivolumab was significantly higher compared with sorafenib (18). Regorafenib vs. nivolumab following sorafenib failure in patients with HCC suggests that survival outcomes do not differ significantly (19). However, nivolumab may be more effective than regorafenib in nonprogressors (20). Research reported that following sorafenib failure, nivolumab treatment is associated with improved OS (overall survival) and ORR compared with regorafenib treatment (21). Nivolumab plus ipilimumab was evaluated in patients with advanced HCC pretreated with sorafenib. The ORR was 31%, disease control rate (DCR) was 49% and a median duration of response was 17 months (22). NCCN recommends nivolumab as a subsequent therapy following disease progression in patients with CPA (Child-Pugh class A) or CPB (Child-Pugh class B) disease (a category 2A recommendation) (23). There are several other ongoing trials of combinations with nivolumab (Table I).
 | Table I.Ongoing clinical trails combined with nivolumab as second-line treatment for hepatocellular carcinoma. |
Pembrolizaumab
Pembrolizaumab (Keytruda), produced by Merck & Co, is a strong and selective humanized monoclonal antibody of IgG 4/κ isotype (24). Nivolumab and pembrolizumab were enhanced by the Food and Drug Administration (FDA) on September 22 2017 and November 10 2018, respectively, as second-line options for HCC therapy, based on the results of the CheckMate 040 phase I/II trial and the KEYNOTE-224 phase II trial (24). In the KEYNOTE-224 trial, when patients with advanced HCC exhibited progression or intolerance to sorafenib, they received 200 mg pembrolimab every 3 weeks. The results demonstrated that pembrolizumab was tolerated and had an ORR of 17% and stable disease rate of 44%, which initiated phase III (25). The phase III trial (KEYNOTE-240, identifier: NCT02702401) was performed to assess the safety and efficacy of pembrolizumab (26). However, the KEYNOTE-240 trial did not reach its specified endpoints of improvement in overall response (OR) and progression-free survival (PFS) with pembrolizumab. The ORR of the pembrolizumab group was markedly higher compared with the placebo group (16.9% vs. 2.2%) (25,26). Regardless of the implications for the credibility of pembrolizumab as second-line monotherapy for advanced HCC compared with placebo, the OS and PFS have exhibited clinically significant improvements, including the data from the KEYNOTE-224 trial (24). Pembrolizumab plus lenvatinib was evaluated in a phase 1b trial, whereby patients with CPA disease did not have prior systemic therapy, and the ORR was 50% and the control rate was 93.3%, lenvatinib plus pembrolizumab is being evaluated in a phase III study (NCT: 03713593) (27,28). NCCN recommends pembrolizumab as subsequent therapy following disease progression in patients with CPA liver function only (a category 2B recommendation) (23). There are several other ongoing trials of combinations involving pembrolizumab (Table II).
| Table II.Ongoing trails combined with pembrolizumab as second-line treatment for hepatocellular carcinoma. |
PD-L1 receptor blockers
Atezolizumab
Atezolizumab (Tecentriq), created by Genentech, is a monoclonal antibody against PD-L1 (29). PD-L1 acts in immune system inhibition induced by disease by inducing the proliferation of antigen-specific CD8+ T cells and controlling the accumulation of exogenous antigen-specific T cells (29). Although atezolizumab has been approved in the United States as a second-line therapy for urothelial carcinoma (30), trials focusing on its effect on HCC are still ongoing. The breakthrough IMbrave150 study demonstrated that at the time of the primary analysis, the hazard ratio for death with atezolizumab (atezo) + bevacizumab (bev) was 0.58 compared with sorafenib. Furthermore, OS time at 12 months was 67.2 and 54.6%, median PFS time was 6.8 and 4.3 months in the atezo+bev and sorafenib groups. Grade 3 or 4 adverse events occurred in 56.5% of 329 patients in the atezo+bev group and in 55.1% of 156 patients in the sorafenib group (31). Other high-grade toxic effects were rare, suggesting that atezo+bev lead to better OR and PFS outcomes compared with sorafenib in patients with unresectable HCC (31). Atezo+bev is likely to become the first-line drug for HCC, such as sorafenib. The primary endpoint of the study was improving PFS for atezo+bev. Arm F (in which patients were randomized 1:1 to atezo+bev or atezo) demonstrated that atezo and bev made separate contributions to the overall treatment effect. With longer follow-up, Arm A (in which patients received atezo+bev) demonstrated a sustained response to atezo+bev monotherapy, which together with tolerable safety demonstrates that atezo+bev has potential as a first-line treatment for unresectable HCC (32). There are ongoing trials (Table III).
| Table III.Ongoing trials of the listed PD-L1 receptor blockers not included in second-line treatment for hepatocellular carcinoma. |
Avelumab
Avelumab (Bavencio), a product of Merck KGaA and Pfizer, is also a PD-L1 receptor blocker. Data from a phase 1b trial of first-line avelumab+axitinib in patients with advanced HCC (NCT03289533) demonstrated that 15 (68.2%) and 16 (72.7%) patients met RECIST and mRECIST criteria, respectively, with ORRs of 13.6 and 31.8%, respectively. The preliminary safety of avelumab+axitinib in HCC has been established, and both avelumab and axitinib are known to be safe when administered as monotherapy (33). These results suggest antineoplastic activity in HCC (Table III).
Durvalumab
Durvalumab (Imfinzi) is a humanized monoclonal antibody against PD-L1 protein developed by AstraZeneca (34). Durvalumab 10 mg/kg Q2W has been demonstrated to exert antineoplastic activity and OS, with a tolerable safety profile in a liver cancer population; the ORR was 10.0%, with a median OS time of 13.2 months (35). A phase I/II study of durvalumab and tremelimumab in patients with unresectable HCC (NCT02519348) demonstrated no unexpected safety outcomes. The combination resulted in a durable ORR of 18% and clinical activity was mainly observed in patients without concomitant HBV or HCV infection, although interpretation of the results was limited by the small subset of 40 patients (36). Combined ICI therapy with tremelimumab and durvalumab in patients with HCC (NCT02821754) was well tolerated and exhibited productive activity (37). A randomized, multicenter phase III study of durvalumab and tremelimumab as first-line treatment in patients with unresectable HCC (NCT03298451) is still ongoing. In a study of ramucirumab and durvalumab treatment of metastatic NSCLC, gastric/gastroesophageal junction (G/GEJ) adenocarcinoma and HCC (NCT02572687) exhibited no unexpected toxicity, and the combination exerted antitumor activity, with a durable ORR of 11% (38). Results in patients with high-PD-L1 HCC warrant further assessment (Table III).
Cemiplimab
Cemiplimab (Libtayo), produced by Sanofi and Regeneron, is an intravenous immunotherapy targeting the PD-1 pathway that helps the immune system fight cancer cells (39). In the phase I trial (NCT02383212), patients with advanced or metastatic HCC using cemiplimab 3 mg/kg Q2W produced an ORR of 19.2%, the durable disease control rate was 42.3% and the median observation time to response was 1.9 months (40). The results indicate a meaningful therapeutic effect in advanced or metastatic HCC, and he safety is similar to other PD-1/PD-L1 blockers (Table III).
Listed drugs in China
Recently, several countries, including China, have focused research on PD-1/PD-L1 inhibitors to develop novel drugs (41–45). Chinese companies, such as Junshi Bioscience, Xinda Bioscience and Hengrui Medicine aim to compete with Bristol-Myers Squibb, Merck & Co., Inc. and other famous pharmaceutical enterprises. Although there is a long process from research to improvement in clinical outcomes, Chinese pharmaceutical companies hope to see patients benefit from their efforts.
On June 15, 2018, the China CFDA approved the listing of the nivolumab injection, which was the first PD-1 receptor blocker to be approved for marketing in China. Pembrolizaumab entered the Chinese market shortly afterwards as a second-line option for HCC therapy, along with nivolumab. To advance the development of tumor immunotherapy, Chinese pharmaceutical companies have also independently developed new PD-1/PD-L1 inhibitors, including toripalimab, sintilimab, camrelizumab and tislelizumab (41). All the listed drugs in China have their own limited indications, and their effectiveness and safety in HCC is still under investigation in clinical trials (Table IV).
Toripalimab
Toripalimab is a domestic novel recombinant human anti-PD-1 monoclonal antibody, which is the first self-developed PD-1 inhibitor in China. Toripalimab was approved by the National Medical Products Administration in December 2018 to treat unresectable or metastatic malignant melanoma that failed to respond to prior systemic treatment (42). There are other clinical trials of toripalimab in HCC (42,43), including a multicenter phase III clinical study of postoperative high-risk HCC resection, with toripalimab as adjunctive therapy, the main purpose of this study was to determine the clinical efficacy of JS001 as postoperative adjuvant therapy in patients with advanced HCC compared with placebo, and to evaluate the safety and tolerance of JS001 (43).
Camrelizumab
At the end of 2018, the FDA and CFDA approved camrelizumab in combination with apatinib for first-line treatment of advanced liver cancer based on the results of a multicenter phase III study (NCT03764293) (43). At the ASCO meeting in 2019, Shukui Qin reported the results of a multicenter phase II study of camrelizumab combined with FOLFOX-4 or GEMOX as first-line treatment for advanced HCC or cholangiocarcinoma (BTC). The ORR of the 34 patients in the HCC group was 26.5% and the DCR was 79.4%, not up to median overall survival. The incidence of level 3 and above treatment-related adverse events was 85.3% in the HCC group, and grade 3 and above immune-related adverse events accounted for only 5.9%, suggesting that the combination of the camrelizumab monoclonal antibody with FOLFOX4 or GEMOX chemotherapy is well tolerated. This combination is expected to be effective for advanced HCC (44). A randomized, controlled, multicenter phase III study of camrelizumab combined with FOLFOX4 systemic chemotherapy for advanced HCC is being carried out (NCT 03605706) (44).
Tislelizumab
Tislelizumab has attracted great attention due to its high ORR in classical Hodgkin's lymphoma therapy (45). Experimental data from an international multicenter phase IA/IB clinical study of tislelizumab treatment for advanced solid tumor demonstrated that the ORR among 50 patients with liver cancer was 12.2% and the DCR was 51% (46). An international multicenter phase II clinical trial, RATIONALE 301, comparing tislelizumab with sorafenib as the first-line treatment of advanced liver cancer is ongoing.
Influencing factors
PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory genes, including CD274, CD8A, LAG3 and STAT1, have been developed with improved survival and response (47). Biomarkers have been reported to be associated with clinical outcomes (48). High PD-1 expression may indicate that T cells have been depleted in the tumor microenvironment (TME), which can help identify which type of patient will benefit from ICI therapy by inhibiting the PD-1/PD-L1 signal axis (39). Markers of systemic inflammation, such as elevated neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and α-fetoprotein are associated with poor prognosis in HCC (40).
Recent evidence suggest that when cells gradually evolve into malignant tumors, PD-L1 expression increases and the interaction between PD-1 and PD-L1 inhibits the self-reactive T cells, resulting in the over balance of PD-L1, PD-L2 and PD-1 (49). It has been demonstrated that androgen (AR) receptor can inhibit PD-L1 expression in HCC cells, and AR transcriptionally represses PD-L1 by binding to its promoter. In human clinical HCC samples, AR is negatively associated with PD-L1 expression (50). Thus, overexpression of AR weakens the effect of PD-L1 inhibitors in vivo.
Previous studies have demonstrated that EGFR signaling also regulates host antitumor immunity, including driving PD-L1 expression (51–53). In non-small cell lung cancer (NSCLC), the role of EGFR signaling on PD-L1 has made a breakthrough. Compared with NSCLC cell lines with wild-type EGFR, PD-L1 expression is significantly higher in cell lines with mutant EGFR (54). Using EGFR-TKIs (gefitinib or erlotinib) to inhibit EGFR can decrease PD-L1 expression in NSCLC cell lines with mutant EGFR (55). Increasing evidence suggest that inhibiting EGFR can modulate the TME, which will optimize the antitumor activity of immunotherapy and increase the number of patients who benefit from PD-1/PD-L1 inhibitors (51–55).
Discussion
Nivolumab and pembrolizaumab have been brought into guidelines due to their exact efficacy (11). PD-1 and PD-L1 expression, biomarkers of inflammation, inflammatory genes, AR and EGFR signaling have clear evidence of the impact on PD-1/PD-L1 clinical outcomes (47–55). The reason why cemiplimab, atezolizumab, avelumab, durvalumab have not been included in the guidelines for the treatment of HCC is that their efficacy and safety is not completely certain, and several trials are still ongoing (29–40). Nivolumab as a first-line treatment option compared with sorafenib is still under research, and nivolumab may become first-line treatment if the result is positive (12–23); atezo+bev has potential as a first-line treatment for unresectable HCC; both avelumab and axitinib are known to be safe when administered as monotherapy; cemiplimab and durvalumab have also demonstrated effectiveness in ORR (30,33,35,37,40). With an increase in the number of clinical trails, cemiplimab, atezolizumab, avelumab and durvalumab may be added to the guidelines. The breakthrough of the IMbrave150 trial offers the best pick-me-up to the development and application of PD-1/PD-L1 inhibitors (31).
Recent Chinese effort on PD-1 and PD-L1 blockers has proved useful, including toripalimab, sintilimab, camrelizumab and tislelizumab (42–45). They are listed in China with their specific indications, and their efficacy and safety in patients with HCC is under research. The results have demonstrated that the combination of camrelizumab with FOLFOX4 or GEMOX chemotherapy is well tolerated, and this combination is expected to be effective for advanced HCC (43,44). In addition, tislelizumab has exhibited effectiveness in ORR (45). In each willingness to pay (WTP) threshold among different countries, United States has a high WTP, which is 10,000~150,000/quality- adjusted life year, while the PD-1/PD-L1 inhibitors produced by China are more cost-effective (56).
Conclusions
The present review introduces eight drugs targeting PD-1 and PD-L1 developed in the United States, France, England and China, two of which (nivolumab and pembrolizaumab) have been recommended as second-line options for patients with HCC by the NCCN clinical practice guidelines. ICIs targeting PD-1/PD-L1 have notably improved the symptoms of several patients with different malignant tumors. However, treatment is associated with typically transient immune-related adverse events (irAEs), which are severe or even deadly (57–59). Rapidly detecting these side effects and efficiently activating systemic immunosuppression can improve outcomes, without affecting the efficacy of ICIs (57). A common and early irAE associated with ICIs is dermatologic toxicity, which can lead to dermatologic/mucosal toxicity, and oral mucositis and/or dry mouth symptoms have been observed following treatment with PD-1/PD-L1 (58). Other common irAEs include diarrhea and effects on the adrenal, pituitary and thyroid glands, which are difficult to identify due to the atypical symptoms, including fatigue, headache and nausea. Less frequent irAEs are observed in the lung, eye, kidney and pancreas (59). Meta-analyses of treatment-related adverse events in 2018 and 2019 (60,61) demonstrated that the most common all-grade adverse events were fatigue, diarrhea and pruritus. The most common grade 3 or higher adverse events were anemia, fatigue and increased aspartate aminotransferase. Hypothyroidism (6.07%) and hyperthyroidism (2.82%) were the most frequent all-grade endocrine irAEs. In addition, the rates of hypothyroidism pneumonitis, colitis and hypophysitis were higher in the presence of anti-PD-1 drugs compared with standard treatment. Among the general adverse events associated with immune activation, only the incidence of rash increased, whereas the incidence of diarrhea and fatigue were similar to the control group (60,61).
With the rapid development of molecular immunology and molecular biology, immunotherapy has emerged as a novel strategy with some promising results. However, it is not without limitations. The influencing factors, such as AR, require further investigation to improve the clinical outcomes, along with the suitable combination therapy for elevating response rate. In addition, more biomarkers are required to accurately predict efficacy, and it is essential to overcome immunotherapy resistance.
Pharmacists can easily collect PD-1/PD-L1-related data to provide a reference for clinicians, and the available data indicates that the development of PD-1/PD-L1 inhibitors to treat HCC will provide more options for combination therapy, and improve outcomes in patients who do not respond to first-line treatment. Publication of the results of ongoing clinical trials of PD-1/PD-L1 inhibitors is believed to provide more data and insight for the effective treatment of HCC.
Acknowledgements
Not applicable.
Funding
The present review was supported by the National Natural Science Foundation of China (grant no. 81803019).
Availability of data and materials
Not applicable.
Authors' contributions
JL and YL confirmed the authenticity of all the raw data. GT, YT and JW performed the literature review. JW drafted the initial manuscript. JL, YL and SS revised the manuscript for important intellectual content. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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