Abstract
Background
Immune checkpoints inhibitors (ICIs) have emerged as a treatment option for several malignancies. Nivolumab, pembrolizumab, nivolumab plus ipilimumab, and atezolizumab plus bevacizumab have been approved for the management of advanced‐stage hepatocellular carcinoma (HCC). We aimed to systematically review the literature and summarize the characteristics and outcomes of patients with HCC treated with ICIs.
Methods
A systematic literature search of PubMed, the Cochrane Library, and ClinicalTrials.gov was performed according to the PRISMA statement (end of search date: November 7, 2020). Quality of evidence assessment was also performed.
Results
Sixty‐three articles including 2,402 patients were analyzed, 2,376 of whom received ICIs for unresectable HCC. Response to ICIs could be evaluated in 2,116 patients; the overall objective response rate (ORR) and disease control rate (DCR) were 22.7% and 60.7%, respectively, and the mean overall survival (OS) was 15.8 months. The ORR, DCR, and OS for nivolumab (n = 846) were 19.7%, 51.1%, and 18.7 months, respectively; for pembrolizumab (n = 435) they were 20.7%, 64.6% and 13.3 months, respectively. The combination of atezolizumab/bevacizumab (n = 460) demonstrated an ORR and DCR of 30% and 77%, respectively. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre‐LT for bridging, 14 for post‐LT recurrence); fatal graft rejection was reported in 40.0% (n = 6/15) and mortality in 80.0% (n = 12/15).
Conclusion
ICIs are safe and effective against unresectable HCC, but caution is warranted regarding their use in the LT setting because of the high graft rejection rate.
Implications for Practice
This systematic review pooled the outcomes from studies reporting on the use of immune checkpoint inhibitors (ICIs) for the management of 2,402 patients with advanced‐stage hepatocellular carcinoma (HCC), 2,376 of whom had unresectable HCC. The objective response rate and disease control rate were 22.7% and 60.7%, respectively, and the mean overall survival was 15.8 months. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre‐LT for bridging, 14 for post‐LT recurrence). Six of these patients experienced graft rejection (40.0%).
Keywords: Immune checkpoint inhibitors, Immunotherapy, Hepatocellular carcinoma, PD‐1 inhibitors, CTLA‐4 inhibitors
Short abstract
Favorable initial survival outcomes of immune checkpoint inhibitor (ICI) treatment have led to broader use as first‐ or second‐line options in patients with unresectable hepatocellular carcinoma (HCC). This article summarizes the available data on characteristics and outcomes of patients with HCC treated with ICIs.
Introduction
Hepatocellular carcinoma (HCC) constitutes the most frequent primary liver malignancy (85%–90%) and the fourth most common cause of cancer‐related mortality in the world [1]. Resection, liver transplantation (LT), and ablation remain the mainstay of cure in the early stages, but recurrence rates are high, and most patients present with advanced‐stage disease not amenable to these modalities [2]. Sorafenib, an antiangiogenic tyrosine kinase inhibitor, gained Food and Drug Administration (FDA) approval in 2007 and stood as the only FDA‐approved therapy in HCC for a decade [3]. Starting in 2017, several other systemic agents have gained full approval for advanced HCC based on randomized phase III data, including lenvatinib and atezolizumab/bevacizumab in the first line [4] and regorafenib [5], cabozantinib [6], and ramucirumab [7] in refractory disease.
The emergence of immune checkpoints inhibitors (ICIs) in the management of multiple advanced malignancies [8, 9] led to the initiation of several trials aiming to evaluate the role of these agents in the treatment of HCC. The presence of tumor‐infiltrating lymphocytes with increased programmed cell death protein‐1 (PD‐1) expression in HCC and their correlation with outcome provided evidence for a novel therapeutic target in HCC [10, 11, 12]. Nivolumab and pembrolizumab are humanized monoclonal antibodies that inhibit the interaction between PD‐1 and programmed death‐ligand 1 (PD‐L1), thus inhibiting T‐cell apoptosis and enhancing the cellular immune antitumor effects. These anti–PD‐1 agents have recently gained accelerated approval as second‐line treatments after sorafenib for patients with advanced HCC [13, 14]. Ipilimumab is a human monoclonal antibody exhibiting antitumor activity through an upregulation in T‐cell activation; this is achieved via blockade of the inhibitory receptor cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4), which is otherwise bound to the B7 molecule on the surface of antigen presenting cells [15]. Ipilimumab combined with nivolumab has also recently gained accelerated FDA approval for patients previously treated with sorafenib [16, 17]. The most recent ICI to show promise in advanced HCC is the PD‐L1 inhibitor atezolizumab. In a randomized, phase III trial, the combination of atezolizumab and the antivascular endothelial growth factor antibody bevacizumab demonstrated a survival benefit over sorafenib, the first regimen to ever do so in advanced HCC, and thus gained full FDA approval in HCC [18].
The favorable initial survival outcomes of ICIs have led to their broader use on and off label as either first‐ or second‐line options in patients with unresectable HCC [19]. Therefore, we aimed to summarize the available data on the demographic, clinical characteristics, and outcomes of patients with HCC treated with ICIs.
Materials and Methods
Study Design and Search Strategy
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement (supplemental online Table 1) [20] and in line with the protocol agreed by all authors. Eligible studies were restricted to clinical trials, cohort studies, case series, or case reports providing data on the safety and efficacy of PD‐1, PD‐L1, or CTLA‐4 antibodies in patients with unresectable or metastatic HCC. Non‐English studies and abstracts without full text were excluded, and no sample size restriction was applied. Studies were identified through search of the PubMed bibliographical database, Cochrane Library, and ClinicalTrials.gov (end of search date: November 7, 2020). The reference lists of studies included in the systematic review were also hand‐searched for missed studies using the systematic “snowballing” procedure guidelines [21]. The literature search was conducted by four independent investigators (I.A.Z., A.P.E., D.G., M.H.H.), using the search strategy provided in supplemental online Table 2. All disagreements were resolved by consensus with the senior author (G.T.).
Data Extraction and Tabulation
Standardized, prepiloted forms were used for data extraction and tabulation as well as for quality assessment of eligible studies. Data extraction was performed independently by four investigators (I.A.Z., A.P.E., D.G., M.H.H.). The following data were extracted from the included studies: study characteristics (first author, year of publication, study design, study period if applicable, ICI used and setting of use, number of patients), age, sex, presence of risk factors (hepatitis B virus [HBV] and hepatitis C virus [HCV] infection, alcoholic liver disease, nonalcoholic steatohepatitis, cirrhosis), Eastern Cooperative Oncology Group (ECOG) performance status, Barcelona Clinic Liver Cancer (BCLC) stage, Child‐Pugh (CP) classification, HCC disease extent, prior therapies implemented, adverse events, treatment response (complete response, partial response, stable disease, progressive disease, objective response rate [ORR], disease control rate [DCR]), and survival (progression‐free survival [PFS], overall survival [OS], 6‐month and 1‐year survival rates). ORR was defined as the sum of all patients demonstrating complete or partial response divided by the total of evaluable patients, and DCR was defined as the sum of all patients demonstrating complete or partial response or stable disease divided by the total of evaluable patients.
Statistical Analysis
Continuous variables were summarized as means ± SD or median (interquartile range [IQR]), and categorical variables as frequencies and percentages accompanied by 95% confidence intervals (95% CIs). When continuous data were presented as medians and range, we applied the Hozo et al. [22] method to estimate the respective means and SDs. If the medians and IQR were reported within the included articles, we converted them to means and SDs according to Wan et al. [23]. All relative rates were estimated based on available data for each variable of interest, and available data were handled according to the principles stated in the Cochrane Handbook [24]. Data on outcomes of interest were tabulated and analyzed cumulatively. Data analyses were performed with IBM SPSS Statistics 25 software (IBM Corp., Armonk, NY).
Quality of Evidence Assessment
For randomized controlled trials (RCTs), quality of evidence assessment was conducted with the modified Jadad scale, which includes randomization, blinding, withdrawals/dropouts, inclusion/exclusion criteria, adverse effects, and statistical analysis [25]. The score spans from 0 to 8, with a score of 4 to 8 indicating high quality and 0 to 3 indicating low quality.
For nonrandomized studies, quality of evidence assessment was performed using the Newcastle‐Ottawa scale (NOS) [26], and studies were deemed of high (3 or 4 in selection domain AND 1 or 2 in comparability domain AND 2 or 3 in outcome domain), fair (2 in selection domain AND 1 or 2 in comparability domain AND 2 or 3 in outcome domain), and low quality (0 or 1 in selection domain OR 0 in comparability domain OR 0 or 1 in outcome domain), respectively.
The quality of the case series included in the present systematic review was assessed with a tool developed by the National Heart, Lung, and Blood Institute (NHLBI) [27]. The NHLBI scale ranges from 0 to 9, with a score 0 to 3 denoting low quality, 4 to 6 fair quality, and 7 to 9 high quality of studies.
The risk of bias of the eligible case reports was assessed with the Joanna Briggs Institute (JBI) scale [28]. This scale includes demographic characteristics, patient history, clinical condition, diagnostic tests, interventions, postintervention condition, adverse events/harms, and takeaway lessons. The range of the JBI scale is between 0 and 8, with a score of 0 to 3 denoting low quality and 4 to 8 denoting high quality.
Two reviewers (A.P.E., D.G.) rated the studies working independently, and final decision was reached by consensus with another author (I.A.Z.). A quality cutoff for exclusion of low‐quality studies was set a priori according the scoring system of each individual scale as described above.
Results
Eligible Studies
Our systematic search of the literature yielded a total of 373 records, 63 of which were deemed eligible and were ultimately included in the present study [13, 14, 18, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88]. This included 11 clinical trials (4 randomized and 7 nonrandomized) and 8 cohort studies (Table 1), 12 case series, and 32 case reports (supplemental online Table 3). Fifty of the articles described the use of immunotherapy agents in the setting of unresectable HCC [13, 14, 18, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75], 3 in the neoadjuvant setting [76, 77, 78], and 10 in the setting of LT [79, 80, 81, 82, 83, 84, 85, 86, 87, 88], and they reported on 2,402 patients in total (Fig. 1).
Table 1.
Demographics of the clinical trials and cohort studies included in the systematic review
| Year | First author | Country | Phase | Drug | Total patients, n | Patients with evaluable outcomes, n | ORR % (n/n) | Time to response, mean ± SD, months | DCR % (n/n) | PFS, mean ± SD, months | OS, mean ± SD, months |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Clinical trials | |||||||||||
| 2020 | Qin | China | II | Camrelizumab | 217 | 195 | 16.4 (32/195) | 2.4 ± 1.1 | 49.2 (96/195) | NA | 13.8 ± 18.2 |
| 2020 | Lee | International | Ib | Atezolizumab plus bevacizumab (non‐randomized) | 104 | 99 | 37.4 (37/99) | NA | 74.7 (74/99) | 7.3 ± 11.7 | Median 17.1 a |
| Atezolizumab plus bevacizumab (randomized) | 60 | 57 | 21.1 (12/57) | NA | 70.2 (40/57) | 5.6 ± 7.5 | Not estimable | ||||
| Atezolizumab (randomized) | 59 | 54 | 18.5 (10/54) | NA | 53.7 (29/54) | 3.4 ± 6.4 | Not estimable | ||||
| 2020 | Finn | International | III | Atezolizumab plus bevacizumab | 336 | 304 | 27.3 (89/326) | NA | 73.6 (240/326) | 6.8 ± 12.2 | Not estimable |
| 2020 | Bang | International | Ia/b | Ramucirumab plus durvalumab | 28 | 26 | 10.7 (3/28) | 7.9 ± 12.3 | 60.7 (17/28) | 4.4 ± 5.1 | 10.7 ± 16.5 |
| 2020 | Finn | International | III | Pembrolizumab vs. placebo | 278 | 263 | 19.4 (51/263) | 5.9 ± 2.6 | 65.8 (173/263) | 3 ± 5.5 | 13.9 ± 4.7 |
| 2019 | Agdashian | U.S. | I/II | Tremelimumab | 39 | 34 | 23.5 (8/34) | NA | 67.6 (23/34) | NA | 10.9 ± 8.2 |
| 2019 | Doi | Japan | I | Nivolumab plus mogamulizumab | 15 | 15 | 26.7 (4/15) | NA | 66.7 (10/15) | 3.8 ± 5.8 | 11.3 a |
| 2019 | Feun | U.S. | II | Pembrolizumab | 29 | 28 | 32.1 (9/28) | NA | 46.4 (13/28) | 4.5 ± 6.6 | 13 a |
| 2018 | Zhu | International | II | Pembrolizumab | 104 | 98 | 18.4 (18/98) | 2.8 ± 1.5 | 65.3 (64/98) | 4.9 ± 9.9 | 12.9 ± 15.1 |
| 2017 | El‐Khoueiry | International | I/II | Nivolumab | 262 | 250 | 19.6 (49/250) | 4.0 ± 7.1 | 66.4 (166/250) | 4.0 ± 9.3 | 15.0 ± 17.4 |
| 2013 | Sangro | Spain | II | Tremelimumab | 21 | 17 | 17.6 (3/17) | NA | 76.5 (13/17) | 6.5 ± 5.7 | 8.2 ± 18.3 |
| Cohort studies | |||||||||||
| 2020 | Sung | Korea | NA | Nivolumab | 33 | 29 | 20.7 (6/29) | NA | 34.5 (10/29) | NA | 13.7 ± 9.7 |
| 2020 | Choi | Korea | NA | Nivolumab | 203 | 181 | 12.7 (23/181) | 7.6 ± 11.9 | 39.8 (72/181) | 6.9 ± 10.1 | 31.9 ± 48.8 |
| 2020 | Fessas | International | NA | Nivolumab | 233 | 218 | 22.4 (49/218) | NA | 52.3 (114/218) | 10.1 ± 30.6 | 12.2 ± 28.7 |
| 2020 | Mahn | Germany | NA | Nivolumab (n = 10) or pembrolizumab (n = 4) | 14 | 13 | 30.8 (4/13) | NA | 76.9 (10/13) | 6.2 ± 4.5 | 7.0 ± 4.9 |
| 2020 | Kawaoka | Japan | NA | Pembrolizumab | 82 | 2 | NA | NA | NA | NA | NA |
| 2019 | Zhan | U.S. | NA | Nivolumab plus ipilimumab | 23 | 22 | 77.3 (17/22) | NA | 95.5 (21/22) | NA | NA |
| 2019 | Scheiner | Austria & Germany | NA | Nivolumab or pembrolizumab | 65 | 54 | 14.8 (8/54) | 5.4 a | 59.3 (32/54) | 4.9 ± 8.5 | 9.9 ± 6.9 |
| 2019 | Yu | Korea | NA | Nivolumab | 76 a | 70 | 12.9 (9/70) | NA | 22.9 (16/70) | NA | NA |
Not included in cumulative data because of the lack of data distribution measure.
Abbreviations: DCR, disease control rate; NA, not available; ORR, objective response rate; OS, overall survival; PFS, progression‐free survival.
Figure 1.
Preferred Reporting Items for Systematic Reviews and Meta‐Analyses flowchart of the search strategy.Abbreviation: HCC, hepatocellular carcinoma.
Quality of Evidence Assessment
The score of the modified Jadad scale for the RCTs [18, 54, 59, 63] was 6.5 ± 0.9 (supplemental online Table 4). The mean score of the NOS scale for the nonrandomized studies [13, 14, 30, 35, 36, 42, 45, 53, 56, 57, 58, 60, 66, 70, 73] was 7.4 ± 0.6 (supplemental online Table 5). The mean score of the NHBLI scale for the case series [31, 32, 37, 39, 40, 44, 51, 62, 67, 77, 80, 84] was 6.8 ± 0.9 (supplemental online Table 6). The mean score of the JBI scale for the case reports [29, 33, 34, 38, 41, 43, 46, 47, 48, 49, 50, 52, 55, 61, 64, 65, 68, 69, 71, 72, 74, 75, 76, 78, 79, 81, 82, 83, 85, 86, 87, 88] was 7.2 ± 1.1 (supplemental online Table 7). These results highlight that the included studies were of high quality on average.
Unresectable Setting
A total of 2,376 patients received immunotherapy for the management of unresectable HCC. The mean age was 61.9 ± 10.8 years, and 82.0% were male (n = 1,948/2,376). The vast majority of patients had an ECOG performance status of 0 or 1 (94.2%, n = 1,988/2,110), CP class A liver disease (83.6%, n = 1,905/2,279), and BCLC stage C HCC (84.6%, n = 1,701/2,011). Macrovascular invasion was reported in 27.1% (n = 530/1,953) and extrahepatic disease in 64.3% (n = 1,473/2,292) of the patients. Prior localized therapies before ICI included liver resection in 28.0% (n = 332/1,187) of patients, transarterial chemoembolization in 43.3% (n = 386/891), radiofrequency or microwave ablation in 14.9% (n = 205/1,372), and yttrium‐90 radioembolization in 48.4% (n = 44/91). Sorafenib preceded ICI therapy in 60.5% (n = 949/1,568) of patients. Details on patient demographics, disease extent, and prior treatments are presented in Table 2 and supplemental online Table 8.
Table 2.
Demographic characteristics of the patients receiving immune checkpoint inhibitors in the unresectable setting
| Year | First author | Age, years | Sex (M/F) | HBV | HCV | ECOG 0–1 | ECOG > 1 | BCLC A | BCLC B | BCLC C | BCLC D | CP A | CP B | CP C | Alcoholic | NASH | Cirrhosis |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2020 | Ando | 64.0 | 1/0 | 0 | 1 | NA | NA | NA | NA | NA | NA | 0 | 1 | 0 | NA | NA | NA |
| 2020 | Bang | 60.0 ± 14.9 | 24/4 | 4 | 10 | 28 | 0 | 0 | 6 | 22 | 0 | NA | NA | NA | 8 | NA | NA |
| 2020 | Choi | 56.6 ± 10.6 | 171/32 | 168 | 8 | 180 | 23 | 0 | 8 | 195 | 0 | 132 | 71 | 0 | NA | NA | NA |
| 2020 | Fessas | 63.0 ± 9.7 | 184/49 | 83 | 95 | 143 | 11 | 4 | 23 | 204 | 2 | 158 | 75 | 0 | 29 | 24 | NA |
| 2020 | Finn | 63.6 ± 11.1 | 277/59 | 164 | 72 | 336 | 0 | 8 | 52 | 276 | 0 | 333 | 1 | 0 | NA | NA | NA |
| 2020 | Lee a | 57.3 ± 9.8 | 84/20 | 51 | 31 | 104 | 0 | 0 | 10 | 94 | 0 | 77 | 21 | 6 | NA | NA | NA |
| 2020 | Lee b | 56.0 ± 12.8 | 54/6 | 34 | 11 | 60 | 0 | 0 | 6 | 54 | 0 | 43 | 17 | 0 | NA | NA | NA |
| 2020 | Lee c | 58.5 ± 13.4 | 49/10 | 32 | 10 | 59 | 0 | 2 | 4 | 53 | 0 | 42 | 17 | 0 | NA | NA | NA |
| 2020 | Mahn | 64.6 ± 8.7 | 10/4 | 2 | 4 | 10 | 4 | 0 | 3 | 11 | 0 | 9 | 4 | 0 | 3 | 3 | NA |
| 2020 | Meng | 66.0 ± 6.6 | 4/0 | 4 | 0 | NA | NA | 0 | 2 | 2 | 0 | 4 | 0 | 0 | NA | NA | 4 |
| 2020 | Nabrisky | 60.0 | 1/0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2020 | Oh | 56.4 ± 11.6 | 3/2 | 3 | 1 | NA | NA | NA | NA | NA | NA | 4 | 1 | 0 | 0 | 1 | NA |
| 2020 | Qin | 49.7 ± 13.4 | 196/21 | 181 | NA | 217 | 0 | 0 | 11 | 206 | 0 | 213 | 4 | 0 | NA | NA | NA |
| 2020 | Schulte | 62.0 | 0/1 | NA | NA | 1 | 0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2020 | De Somer | 83.0 | 1/0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2020 | Sung | 57.5 ± 10.1 | 25/8 | 29 | 1 | NA | NA | 0 | 4 | 29 | 0 | 26 | 7 | 0 | NA | NA | NA |
| 2020 | Tan | 62.0 | 1/0 | 0 | 1 | NA | NA | NA | NA | NA | NA | 0 | 1 | 0 | 0 | 0 | 0 |
| 2020 | Yang | 71.0 | 1/0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2020 | Zhao | 37.0 | 1/0 | 1 | 0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0 | 0 | NA |
| 2020 | Kawaoka | 67.8 ± 9.9 | 67/15 | 13 | 33 | NA | NA | 8 | 20 | 48 | 6 | 47 | 6 | 29 | NA | NA | NA |
| 2020 | Kidampi | 57.0 | 1/0 | 1 | 1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2020 | Finn | 60.7 ± 12.2 | 226/52 | 72 | 43 | 278 | 0 | 0 | 56 | 222 | 0 | 277 | 1 | 0 | 159 | NA | NA |
| 2019 | Adcock | NA | NA | 0 | 0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0 | 0 | 0 |
| 2019 | Agdashian | 59.9 ± 10.5 | 34/5 | 7 | 21 | 39 | 0 | 0 | 9 | 30 | 0 | 23 | 3 | 13 | NA | NA | 26 |
| 2019 | Ang | 66.4 ± 8.5 | 12/5 | 4 | 12 | NA | NA | NA | NA | NA | NA | NA | NA | NA | 6 | 1 | |
| 2019 | Chakrabarti | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2019 | Choi | 70.0 | 1/0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2019 | Dasanu | 69.0 | 1/0 | 0 | 1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | 1 | NA | 1 |
| 2019 | Doi | 67.3 ± 11.5 | 14/1 | NA | NA | 15 | 0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2019 | Feun | 62.6 ± 15.3 | 25/4 | 5 | 9 | 29 | 0 | NA | NA | NA | NA | 28 | 1 | 0 | NA | NA | NA |
| 2019 | Kambhampati | 61.0 ± 15.0 | 13/5 | 6 | 5 | 17 | 1 | 0 | 4 | 14 | 0 | 0 | 18 | 0 | 2 | 3 | 18 |
| 2019 | Liu | 63.0 | 1/0 | 1 | 0 | NA | NA | 0 | 0 | 1 | 0 | 0 | 1 | 0 | NA | NA | 1 |
| 2019 | Petrioli | 73.0 | 0/1 | NA | NA | 1 | 0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2019 | Qayyum | 68.2 ± 7.1 | 6/3 | 1 | 4 | NA | NA | NA | NA | NA | NA | 9 | 0 | 0 | 0 | 4 | 9 |
| 2019 | Roderburg | 77.0 | 0/1 | 0 | 1 | NA | NA | 0 | 0 | 1 | 0 | NA | NA | NA | 0 | 0 | 1 |
| 2019 | Scheiner | 65.2 ± 11.1 | 49/16 | 8 | 10 | NA | NA | 0 | 8 | 51 | 6 | 32 | 28 | 5 | 19 | 11 | NA |
| 2019 | Tighe | 66.0 | 1/0 | 0 | 1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0 | 1 | 1 |
| 2019 | Wong | 68.2 ± 5.6 | 6/0 | 4 | 0 | NA | NA | NA | NA | NA | NA | 4 | 0 | 0 | 0 | 2 | 6 |
| 2019 | Yu | 61.1 ± 10.8 | 65/11 | 56 | 6 | 73 | 3 | 0 | 4 | 69 | 3 | 59 | 14 | 3 | 6 | NA | NA |
| 2019 | Zhan | NA | 17/6 | 8 | 8 | NA | NA | 0 | 2 | 21 | 0 | 16 | 5 | 0 | 4 | NA | NA |
| 2018 | Harsh | 65.0 | 0/1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2018 | Brown | 61.0 | 1/0 | 0 | 1 | NA | NA | NA | NA | NA | NA | 0 | 1 | 0 | NA | NA | 1 |
| 2018 | Grierson | 82.0 | 1/0 | 0 | 0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0 | 0 | 0 |
| 2018 | Joerger | 68.0 | 1/0 | 0 | 0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0 |
| 2018 | Zhu | 67.6 ± 8.3 | 86/18 | 22 | 26 | 104 | 0 | 0 | 25 | 79 | 0 | 98 | 6 | 0 | 80 | NA | NA |
| 2017 | Saenz | 57.0 | 0/1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2017 | El‐Khoueiry | 63.1 ± 10.5 | 207/55 | 66 | 60 | 262 | 0 | NA | NA | NA | NA | 258 | 4 | 0 | NA | NA | NA |
| 2017 | Chen | 62.0 | 1/0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 0 | 1 |
| 2017 | Mamdani | 79.0 | 1/0 | 0 | 0 | NA | NA | NA | NA | NA | NA | 1 | 0 | 0 | NA | 1 | 1 |
| 2017 | Feng | 55.4 ± 8.1 | 8/3 | 11 | 0 | 11 | 0 | 0 | 4 | 7 | 0 | NA | NA | NA | NA | NA | NA |
| 2016 | Truong | 75.0 | 1/0 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 2013 | Sangro | 65.2 ± 7.8 | 15/6 | 0 | 21 | 21 | 0 | 3 | 6 | 12 | 0 | 12 | 9 | 0 | NA | NA | 21 |
| Total | 61.9 ± 10.8 | 1,948/425 | 44.3% (1,042/2,350) | 21.6% (508/2,350) | 93.8% (1,988/2,110) | 2.1% (43/2,110) | 1.2% (25/2,011) | 13.3% (267/2,011) | 84.6% (1,701/2,011) | 0.9% (18/2,011) | 83.6% (1,905/2,279) | 13.9% (317/2,279) | 2.5% (57/2,279) | 36.7% (314/856) | 13.9% (55/396) | 78.3% (267/341) |
Αtezolizumab plus bevacizumab (nonrandomized).
Αtezolizumab plus bevacizumab (randomized).
Atezolizumab alone (ramdomized).
Abbreviations: BCLC, Barcelona Clinic Liver Cancer; CP, Child‐Pugh class; ECOG, Eastern Cooperative Oncology Group performance status; F, female; HBV, hepatitis B virus; HCV, hepatitis C virus; M, male; NA, not available; NASH, nonalcoholic steatohepatitis.
Treatment response could be evaluated in 2,116 patients with HCC. The ORR and DCR were 22.7% (n = 481/2,116; 95% CI: 21.0%–24.6%) and 60.7% (n = 1,285/2,116; 95% CI: 58.6%–62.8%), respectively, in the overall population, and the mean time to treatment response was 4.8 months. The mean PFS was 6.0 months, and mean OS was 15.8 months. Six‐month and 1‐year overall survival rates were 71.6% (n = 1,434/2,002; 95% CI: 69.6%–73.6%) and 49.7% (n = 862/1,735; 95% CI: 47.3%–52.0%), respectively.
Efficacy data for nivolumab, pembrolizumab, atezolizumab/bevacizumab, and tremelimumab were individually analyzed. Treatment response to nivolumab could be evaluated in 846 patients with HCC. The ORR and DCR were 19.7% (n = 167/846; 95% CI: 17.2%–22.6%) and 51.1% (n = 432/846; 95% CI: 47.7%–54.4%), respectively, and the mean time to response was 5.4 months. The mean PFS was 7.3 months, and mean OS was 18.7 months. Six‐month and 1‐year overall survival rates were 63.1% (n = 539/854; 95% CI: 59.8%–66.3%) and 32.4% (n = 191/589; 95% CI: 28.8%–36.3%), respectively. Given that the published data on the outcomes after treatment with ipilimumab plus nivolumab in unresectable HCC were limited to 22 patients, these were excluded from the nivolumab‐only analyses and demonstrated that ORR and DCR were 77.3% (n = 17/22; 95% CI: 56.2%–90.3%) and 95.5% (n = 21/22; 95% CI: 76.5% to >99.9%), respectively.
Treatment response to pembrolizumab could be evaluated in 435 patients with HCC. The ORR and DCR were 20.7% (n = 90/435; 95% CI: 17.1%–24.8%) and 64.6% (n = 281/435; 95% CI: 60.0%–69.0%), respectively, and the mean time to treatment response was 5.1 months. The mean PFS was 3.9 months, and mean OS was 13.3 months. Six‐month and 1‐year overall survival rates were 75.2% (n = 318/423; 95% CI: 70.8%–79.1%) and 53.2% (n = 224/421; 95% CI: 48.4%–57.9%), respectively.
Treatment response to atezolizumab/bevacizumab could be evaluated in 460 patients with HCC. One subgroup of 54 evaluable patients receiving atezolizumab alone was excluded from these analyses to minimize heterogeneity. The ORR and DCR were 30.0% (n = 138/460; 95% CI: 26.0%–34.3%) and 77.0% (n = 354/460; 95% CI: 72.9%–80.6%), respectively, whereas the mean time to treatment response was not available. The mean PFS was 6.8 months, and OS was not estimable. Six‐month and 1‐year overall survival rates were 84.1% (n = 370/440; 95% CI: 80.4%–87.2%) and 66.4% (n = 292/440; 95% CI: 61.8%–70.6%), respectively.
Treatment response to tremelimumab could be evaluated in 53 patients with HCC. The ORR and DCR were 22.6% (n = 12/53; 95% CI: 13.3%–35.7%) and 69.8% (n = 37/53; 95% CI: 56.4%–80.6%), respectively. The mean PFS was 6.5 months, and mean OS was 9.8 months. Six‐month and 1‐year overall survival rates were 69.8% (n = 37/53; 95% CI; 56.4%–80.6%) and 47.2% (n = 25/53; 95% CI; 34.4%–60.3%), respectively.
Neoadjuvant Setting
An additional 11 patients with a mean age of 51.5 ± 24.7 years received immunotherapy in the neoadjuvant setting for unresectable or potentially resectable HCC and were successfully bridged to liver resection. The etiology of their liver disease included HBV (n = 1/3) and HCV (n = 2/3) infection. Seven of 11 patients were treated with nivolumab monotherapy, and 4 patients were treated with combination of nivolumab plus ipilimumab. Data on outcomes were available for five (two with nivolumab and three with nivolumab plus ipilimumab) of the patients. The mean time to response was 1.6 months (range 1.5–2.0); ORR and DCR were 80% (n = 4/5; 95% CI: 36.0–98.0) and 100% (n = 5/5; 95% CI: 51.1–100.0), respectively; and the mean PFS and OS from the time of ICI administration were 2.0 and 4.0 (range 2.0–6.0) months, respectively.
Liver Transplant Setting
One patient with HCC received nivolumab as a bridge to LT and was successfully downstaged to within Milan criteria and was able to undergo LT; however, the patient experienced fatal graft rejection soon after LT.
Fourteen patients received ICIs (ten nivolumab, two pembrolizumab, and two ipilimumab) for the management of recurrent disease after LT for HCC. The mean age of patients was 50.8 ± 17.2 years [median (IQR) 56.4 (41.0–62.0) years], 71.4% (n = 10/14) were male, and the etiology of their liver disease included HBV (n = 1/7) and HCV (n = 5/7) infection. Seven patients had cirrhosis prior to LT, whereas CP class was not available for any patient. The mean ± SD and median (IQR) time from LT to HCC recurrence for these 14 patients was 38.6 ± 26.6 months and 34.2 (IQR: 14.4–62.0) months, respectively. Twelve of the 14 patients (85.7%) had received sorafenib for the management of HCC recurrence prior to ICI treatment. The mean ± SD and median (IQR) PFS on ICI treatment (n = 14) was 1.4 ± 0.8 months and 1.3 (IQR: 0.7–2.2) months, respectively. The mean ± SD and median (IQR) OS after starting ICI treatment (n = 14) was 1.8 ± 1.9 and 1.1 (1.0–1.3) months, respectively. Eleven of the 14 patients (78.6%) eventually died after HCC recurrence. Graft rejection was the cause of death in 45.4% (n = 5/11), and the mean ± SD and median (IQR) OS from time of ICI administration for these patients was 1.0 ± 0.1 and 1.0 (0.98–1.1) months, respectively. Disease progression or multiorgan failure were the causes of death in 54.5% (n = 6/11), and the mean ± SD and median (IQR) OS from time of ICI administration for these patients was 2.4 ± 2.2 and 1.3 (1.1–3.0) months, respectively. Three of the 14 patients (21.4%) were still alive with functional graft at 29, 20, and 10 months of follow‐up after ICI initiation, respectively.
The characteristics of all 15 patients receiving ICIs in the setting of LT are summarized in Table 3.
Table 3.
Characteristics of the patients receiving ICIs in the liver transplant setting
| Year | Author | ICI | Age/sex | ECOG | Transplant to ICI administration, years | Response | OS, months a | PFS, months a | Graft rejection | Transplant to graft failure, years | Prior sorafenib therapy | Immunosuppression | Last status |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pretransplant | |||||||||||||
| 2019 | Nordness | Nivolumab | 65/M | NA | 2 b | Yes | 0.3 c | NA | Yes | NA | Yes | Tacrolimus, MMF | Death |
| Post‐transplant | |||||||||||||
| 2020 | Anugwom | Ipilimumab | 62/M | NA | 5 | No | NA | NA | Yes | NA | Yes | Tacrolimus | Death |
| 2020 | Pandey | Ipilimumab | 65/F | NA | 7.1 | Yes | 29 | NA | No | NA | Yes | Everolimus, Tacrolimus | Alive |
| 2019 | Amjad | Nivolumab | 62/F | NA | 1.3 | Yes | 20 | NA | No | NA | No | Tacrolimus, MMF | Alive |
| 2018 | DeLeon | Nivolumab | 56.8/M | NA | 2.7 | No | 1.2 | 2.2 | No | NA | Yes | Tacrolimus | Death |
| Nivolumab | 55.9/M | 1 | 7.8 | No | 1.1 | 0.7 | No | NA | Yes | Sirolimus, MMF | Death | ||
| Nivolumab | 34.9/M | 0 | 3.7 | No | 1.3 | 1.3 | No | NA | Yes | Tacrolimus | Death | ||
| Nivolumab | 63.6/F | 1 | 1.2 | NA | 0.3 | NA | No | NA | Yes | Tacrolimus | Death | ||
| Nivolumab | 68/M | 1 | 1.1 | NA | 0.9 | NA | Yes | 1.2 | Yes | Sirolimus | Death | ||
| 2018 | Gassmann | Nivolumab | 53/F | NA | 2 | No | 1 | NA | Yes | 2.1 | Yes | Everolimus, Tacrolimus | Death |
| 2018 | Rammohan | Pembrolizumab | 57/M | NA | 4.4 | Yes | 10 | NA | No | NA | Yes | Tacrolimus | Alive |
| 2017 | De Toni | Nivolumab | 41/M | NA | 1 | Yes | 7 | NA | No | NA | No | Tacrolimus | Death |
| 2017 | Friend | Nivolumab | 20/M | NA | 4 | NA | 1 | NA | Yes | 4.1 | Yes | Sirolimus | Death |
| Nivolumab | 14/M | NA | 3 | NA | 1 | NA | Yes | 3.1 | Yes | Tacrolimus | Death | ||
| 2017 | Varkaris | Pembrolizumab | 70/M | NA | 8 | No | 3 | NA | No | NA | Yes | Tacrolimus | Death |
From time of ICI administration.
Time from ICI therapy initiation to transplant procedure (pretransplant setting); treated with nivolumab until 8 days pretransplant.
Overall survival from liver transplantation.
Abbreviations: ECOG, Eastern Cooperative Oncology Group performance status; F, female; ICI, immune checkpoint inhibitor; M, male; MMF, mycophenolate mofetil; NA, not available; OS, overall survival; PFS, progression‐free survival.
Adverse Events
Adverse events leading to ICI discontinuation were documented in 14.9% of all the systematically reviewed patients (n = 327/2,201, 95% CI: 13.4%–16.4%). This included 7.0% of those who received nivolumab (n = 63/905, 95% CI: 5.5%–8.8%), 13.6% of those managed with pembrolizumab (n = 74/546, 95% CI: 10.9%–16.7%), 37.4% of those managed with atezolizumab/bevacizumab (n = 187/500, 95% CI: 33.3%–41.7%), and 3.2% of those managed with tremelimumab (n = 2/63, 95% CI: 0.2%–11.5). The overall rate of graft rejection in those that received ICIs in the setting of LT was 40.0% (n = 6/15, one patient receiving ICI pre‐LT and five post‐LT; 95% CI: 19.8–64.3). Fatigue was the most common adverse event in the total population (13.9%), followed by diarrhea (10.2%), rash (10.0%), pruritus (9.9%), and decreased appetite (8.5%). Additionally, the rate of hepatotoxicity in the total population, as defined by a significant increase in aspartate or alanine aminotransferase, bilirubin, or alkaline phosphatase levels, was 13.2% (n = 290/2,201, 95% CI: 11.8%–14.7%), 10.9% (n = 240/2,201, 95% CI: 9.7%–12.3%), 7.6% (n = 167/2,201; 95% CI: 6.6%–8.8%), and 2.6 (n = 57/2,201; 95% CI: 2.0%–3.4%), respectively. The clinical and laboratory treatment‐related adverse events are summarized in Table 4 and supplemental online Table 9.
Table 4.
Adverse events occurring in more than 5% of the patients
| Clinical manifestation | Total a | Nivolumab | Pembrolizumab | Atezolizumab/Bevacizumab | Tremelimumab | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Frequency, % (n/n) | 95% CI | Frequency, % (n/n) | 95% CI | Frequency, % (n/n) | 95% CI | Frequency, % (n/n) | 95% CI | Frequency, % (n/n) | 95% CI | |
| Adverse events leading to ICI discontinuation | 14.9 (327/2,201) | 13.4–16.4 | 7.0 (63/905) | 5.5–8.8 | 13.6 (74/546) | 10.9–16.7 | 37.4 (187/500) | 33.3–41.7 | 3.2 (2/63) | 0.2–11.5 |
| Grade 3 treatment‐related adverse events | 15.3 (336/2,201) | 13.8–16.8 | 10.9 (99/905) | 9.1–13.2 | 31.9 (174/546) | 28.1–35.9 | 10.2 (51/500) | 7.8–13.2 | 1.6 (1/63) | <0.01–9.3 |
| Clinical treatment‐related AEs | ||||||||||
| Fatigue | 13.9 (305/2,201) | 12.5–15.4 | 11.2 (101/905) | 9.3–13.4 | 15.9 (87/546) | 13.1–19.3 | 18.2 (91/500) | 15.1–21.8 | 11.1 (7/63) | 5.2–21.5 |
| Diarrhea | 10.2 (224/2,201) | 9.0–11.5 | 6.7 (61/905) | 5.3–8.6 | 12.5 (68/546) | 9.9–15.5 | 13.2 (66/500) | 10.5–16.5 | 9.5 (6/63) | 4.1–19.6 |
| Rash | 10.0 (220/2,201) | 8.8–11.3 | 7.6 (69/905) | 6.1–9.6 | 10.8 (59/546) | 8.5–13.7 | 13.0 (65/500) | 10.3–16.3 | 20.6 (13/63) | 12.3–32.3 |
| Pruritus | 9.9 (217/2,201) | 8.7–11.2 | 8.3 (75/905) | 6.7–10.3 | 12.1 (66/546) | 9.6–15.1 | 13.4 (67/500) | 10.7–16.7 | 0.0 (0/63) | 0.0–6.9 |
| Decreased appetite | 8.5 (187/2,201) | 7.4–9.7 | 3.1 (28/905) | 2.1–4.5 | 10.6 (58/546) | 8.3–13.5 | 15.4 (77/500) | 12.5–18.8 | 15.9 (10/63) | 8.7–27.0 |
| Proteinuria | 7.6 (168/2,201) | 6.6–8.8 | 0.0 (0/905) | 0.0–0.5 | 0.0 (0/546) | 0.0–0.8 | 22.8 (114/500) | 19.3–26.7 | 0.0 (0/63) | 0.0–6.9 |
| Fever | 6.1 (134/2,201) | 5.2–7.2 | 0.3 (3/905) | 0.1–1.0 | 5.7 (31/546) | 4.0–8.0 | 17.8 (89/500) | 14.7–21.4 | 0.0 (0/63) | 0.0–6.9 |
| Abdominal pain | 5.8 (128/2,201) | 4.9–6.9 | 0.2 (2/905) | <0.01–0.9 | 7.9 (43/546) | 5.9–10.5 | 14.0 (70/500) | 11.2–17.3 | 3.2 (2/63) | 0.2–11.5 |
| Nausea | 5.8 (127/2,201) | 4.9–6.8 | 3.9 (35/905) | 2.8–5.4 | 8.1 (44/546) | 6.0–10.7 | 7.8 (39/500) | 5.7–10.5 | 0.0 (0/63) | 0.0–6.9 |
| Hypothyroidism | 4.5 (100/2,201) | 3.8–5.5 | 0.6 (5/905) | 0.2–1.3 | 4.4 (24/546) | 2.9–6.5 | 9.6 (48/500) | 7.3–12.5 | 1.6 (1/63) | <0.01–9.3 |
| Hepatitis | 3.4 (76/2,201) | 7–4.2.3 | 0.0 (0/905) | 0.0–0.5 | 0.9 (5/546) | 0.3–2.2 | 8.6 (43/500) | 6.4–11.4 | 0.0 (0/63) | 0.0–6.9 |
| Dyspnea | 3.4 (75/2,201) | 7–4.2.3 | 0.1 (1/905) | <0.01–0.7 | 4.2 (23/546) | 2.8–6.3 | 9.4 (47/500) | 7.1–12.3 | 0.0 (0/63) | 0.0–6.9 |
| Anaphylactic reaction | 3.3 (72/2,201) | 2.6–4.1 | 0.6 (5/905) | 0.2–1.3 | 1.7 (9/546) | 0.8–3.2 | 7.2 (36/500) | 5.2–9.8 | 1.6 (1/63) | <0.01–9.3 |
| Weight loss | 2.6 (58/2,201) | 2.0–3.4 | 0.3 (3/905) | 0.1–1.0 | 0.6 (3/546) | 0.1–1.7 | 9.6 (48/500) | 7.3–12.5 | 0.0 (0/63) | 0.0–6.9 |
| Arthralgia | 2.6 (58/2,201) | 2.0–3.4 | 0.1 (1/905) | <0.01–0.7 | 5.1 (28/546) | 3.6–7.3 | 5.0 (25/500) | 3.4–7.3 | 1.6 (1/63) | <0.01–9.3 |
| Muscle weakness | 2.6 (57/2,201) | 2.0–3.4 | 0.0 (0/905) | 0.0–0.5 | 5.5 (30/546) | 3.9–7.8 | 5.0 (25/500) | 3.4–7.3 | 0.0 (0/63) | 0.0–6.9 |
| Ascites | 2.4 (53/2,201) | 1.8–3.1 | 0.0 (0/905) | 0.0–0.5 | 2.4 (13/546) | 1.4–4.1 | 6.8 (34/500) | 4.9–9.4 | 0.0 (0/63) | 0.0–6.9 |
| Myalgia | 2.3 (51/2,201) | 1.8–3.0 | 0.6 (5/905) | 0.2–1.3 | 5.3 (29/546) | 3.7–7.6 | 2.2 (11/500) | 1.2–3.9 | 0.0 (0/63) | 0.0–6.9 |
| Abdominal distention | 2.0 (44/2,201) | 1.5–2.7 | 0.0 (0/905) | 0.0–0.5 | 0.2 (1/546) | <0.01–1.1 | 7.2 (36/500) | 5.2–9.8 | 0.0 (0/63) | 0.0–6.9 |
| Laboratory treatment‐related AEs | ||||||||||
| Increased AST | 13.2 (290/2,201) | 11.8–14.7 | 5.8 (52/905) | 4.4–7.5 | 15.8 (86/546) | 12.9–19.1 | 13.0 (65/500) | 10.3–16.3 | 22.2 (14/63) | 13.6–34.0 |
| Increased ALT | 10.9 (240/2,201) | 9.7–12.3 | 5.2 (47/905) | 3.9–6.9 | 12.6 (69/546) | 10.1–15.7 | 9.8 (49/500) | 7.5–12.7 | 11.1 (7/63) | 5.2–21.5 |
| Increased bilirubin | 7.6 (167/2,201) | 6.6–8.8 | 1.7 (15/905) | 1.0–2.7 | 12.5 (68/546) | 9.9–15.5 | 9.0 (45/500) | 6.8–11.9 | 11.1 (7/63) | 5.2–21.5 |
| Anemia | 5.0 (110/2,201) | 4.2–6.0 | 1.1 (10/905) | 0.6–2.1 | 6.2 (34/546) | 4.5–8.6 | 9.2 (46/500) | 7.0–12.1 | 1.6 (1/63) | <0.01–9.3 |
| Thrombocytopenia | 4.9 (108/2,201) | 4.1–5.9 | 0.3 (3/905) | 0.1–1.0 | 1.5 (8/546) | 0.7–2.9 | 11.8 (59/500) | 9.2–14.9 | 0.0 (0/63) | 0.0–6.9 |
| Increased ALP levels | 2.6 (57/2,201) | 2.0–3.4 | 0.7 (6/905) | 0.3–1.5 | 1.5 (8/546) | 0.7–2.9 | 6.6 (33/500) | 4.7–9.2 | 0.0 (0/63) | 0.0–6.9 |
| Hyponatremia | 2.0 (45/2,201) | 1.5–2.7 | 0.3 (3/905) | 0.1–1.0 | 0.9 (5/546) | 0.3–2.2 | 4.8 (24/500) | 3.2–7.1 | 20.6 (13/63) | 12.3–32.3 |
| Neutropenia | 1.9 (41/2,201) | 1.4–2.5 | 0.0 (0/905) | 0.0–0.5 | 1.7 (9/546) | 0.8–3.2 | 4.0 (20/500) | 2.6–6.1 | 6.4 (4/63) | 2.1–15.7 |
The four drug columns do not add up to the total column because either the adverse events were attributed to ICIs other than those four or the drug that these events were attributed to was not specified.
Abbreviations: AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; ICI, immune checkpoint inhibitor.
Ongoing Studies
The ongoing studies on the use of ICIs for the management of HCC are summarized in supplemental online Table 10.
Discussion
In the present systematic review assessing the use of ICIs in patients with HCC, we identified 63 eligible studies reporting on a total of 2,402 patients. Our findings highlight that approximately 23% of the patients receiving ICIs for the management of unresectable HCC demonstrated an objective response, whereas more than 61% achieved disease control. The mean PFS and OS were 6.0 and 15.8 months, respectively. Overall, ICIs were found to have manageable toxicity with fewer than 15% of the patients discontinuing therapy because of adverse events. These results highlight the promising and emerging role of ICIs in the armamentarium for the management of HCC.
Before the emergence of ICIs, patients with advanced‐stage HCC relied mainly on sorafenib in the first line, which demonstrated a response rate of 2% and median OS of 10.7 months [3], and regorafenib in the second line, which exhibited a response rate of 11% and median OS of 10.6 months [5]. Our systematic review showed that the ORRs for nivolumab, pembrolizumab, and tremelimumab were 19.7%–22.6% and that the mean OS was 18.7, 13.3, and 9.8 months, respectively. The rate of patients that discontinued treatment is approximately 20% for sorafenib [89] and approximately 10% for regorafenib [5], whereas the rates for nivolumab, pembrolizumab, and tremelimumab were about 7%, 14%, and 3%, respectively. Because of the high heterogeneity among the studies included in our review, these results aim to synthesize all the available evidence and not perform head‐to‐head comparisons between ICIs and other systemic therapies.
The recent global, open‐label, phase III IMBRAVE150 trial demonstrated the superiority of anti–PD‐L1 inhibitor atezolizumab plus the antivascular endothelial growth factor receptor monoclonal antibody bevacizumab over sorafenib in both OS and PFS outcomes in patients with unresectable HCC and CP class A [18]. This study led to FDA approval of atezolizumab/bevacizumab for the frontline treatment of advanced HCC. Combining the results of this trial with the results of the GO30140 trial [59], we showed that the ORR for atezolizumab/bevacizumab was 30% and the PFS was 6.8 months, whereas about 37% of patients discontinued treatment because of adverse events. These findings may pave the way toward exploring the use of this combination in other settings. In addition, ongoing trials evaluating the role of ICIs combined with systemic therapies or locoregional modalities are ongoing and may affect the treatment algorithm for advanced HCC in the future.
Immune checkpoint inhibitor use for the management of recurrent disease after LT for HCC has been reported in 14 patients and as a bridge to LT in one patient. The high graft rejection rate of 40%, albeit in a limited number of cases, raises the question of the safety of ICIs in the management of HCC recurrence after LT. However, good tolerability and signs of significant anticancer efficacy were observed in some cases, so additional research into mechanisms of ICI‐related graft rejection may provide insight to allow ICIs to be a viable salvage option for select LT recipients.
A growing body of evidence from non‐HCC cancers suggests that certain biomarkers may predict response to checkpoint inhibitors and thus can assist in the selection of patients who may benefit the most from treatment [90, 91, 92, 93, 94]. Specifically, in patients with advanced solid tumors, DNA mismatch repair and microsatellite instability (MSI) status can be predictive of response to ICI [92]. A second predictive biomarker is PD‐L1 expression in tumor or immune cells, and ICIs have gained FDA approvals linked to PD‐L1 positivity in multiple solid tumors [95]. In HCC, MSI is rarely seen, whereas PD‐L1 expression is more common and seen in 17%–62% of the patients [13, 96, 97].
Two trials that notably evaluated the association of PD‐L1 positivity with response to ICI in advanced HCC included the KEYNOTE‐224 study [14] evaluating pembrolizumab and he CheckMate 040 study [13] evaluating nivolumab, after both progression on and intolerance to sorafenib. KEYNOTE‐224 showed in a prespecified exploratory analysis that PD‐L1 expression as assessed by the combined positive score was associated with response to therapy in a subset of patients with a combined positive score of at least 1, but the association with the tumor proportion score was not significant. CheckMate 040 showed that PD‐L1 expression as assessed by the tumor proportion score was not significantly associated with response to therapy. However, because most studies in the present systematic review did not assess tumor positivity for PD‐L1 and because of the high interstudy heterogeneity, results could not be cumulatively summarized for patients with PD‐L1–positive and PD‐L1–negative HCCs separately. Future research, in the form of RCTs investigating the outcomes of patients with HCC based on biomarker selection [98] could help identify subsets of patients with higher chances of benefit from ICI treatment in HCC; such studies may inform therapeutic decision‐making, hence incarnating the concept of personalized medicine.
The present study has certain limitations. Firstly, the included studies comprised heterogeneous patient groups with various stages of disease that received several additional treatments for HCC; although we planned to perform subgroup analyses by disease stage, in most studies the outcomes were reported together for all stages, and thus subgroup analyses could not be conducted. Secondly, many of the eligible studies were retrospectively analyzed cohort studies, cases series, or case reports and thus impart a degree of selection bias; however, the average study quality according to our quality assessment was high. Thirdly, as with any systematic review, certain included articles did not report on all outcomes of interest; consequently, although this study had a systematic and detailed extraction of data, relative rates were estimated based on available data. Finally, we are aware of the “survival tail” commonly seen in patients treated with ICIs, which renders the use of median survival more relevant than mean survival; however, as in all systematic reviews and pooled analyses, the only way to cumulatively pool the outcomes is by converting the continuous variables from median and range/IQR to mean and SD, and thus our results are reported in means ± SD.
Conclusion
Over the past years, efforts have led to the development of new systemic agents for patients with HCC not amenable to resection. ICIs have proven to be effective in achieving deep and durable responses and an improvement in patient survival. Despite the wide range of adverse events associated with the use of ICIs, our findings suggest that they can be adequately tolerated as a treatment option in patients with HCC with only about 15% of the patients experiencing adverse events that lead to treatment discontinuation. However, caution is warranted regarding the use of ICIs in the setting of LT because of the high rate of graft loss, possibly related to dysregulated immune activation. The full texts of published abstracts and ongoing prospective comparative trials are awaited to provide additional data for more rigorous quantitative synthesis of evidence.
Author Contributions
Conception/design: Ioannis A. Ziogas, Lipika Goyal, Georgios Tsoulfas
Provision of study material or patients: Ioannis A. Ziogas, Alexandros P. Evangeliou, Dimitrios Giannis, Muhammad H. Hayat, Konstantinos S. Mylonas, Samer Tohme, David A. Geller, Nahel Elias, Lipika Goyal, Georgios Tsoulfas
Collection and/or assembly of data: Ioannis A. Ziogas, Alexandros P. Evangeliou, Dimitrios Giannis, Muhammad H. Hayat
Data analysis and interpretation: Ioannis A. Ziogas, Alexandros P. Evangeliou, Dimitrios Giannis, Muhammad H. Hayat, Konstantinos S. Mylonas
Manuscript writing: Ioannis A. Ziogas, Alexandros P. Evangeliou, Lipika Goyal, Georgios Tsoulfas
Final approval of manuscript: Ioannis A. Ziogas, Alexandros P. Evangeliou, Dimitrios Giannis, Muhammad H. Hayat, Konstantinos S. Mylonas, Samer Tohme, David A. Geller, Nahel Elias, Lipika Goyal, Georgios Tsoulfas
Disclosures
Lipika Goyal: Debiopharm, H3 Biomedicine, Agios Pharmaceuticals, Taiho Pharmaceuticals, Klus Pharmaceuticals, QED, Pieris Pharmaceuticals, Alentis Therapeutics, Incyte Corporation, SIRTEX (SAB), Incyte, QED, H3Biomedicine, Alentis (C/A), Astra Zeneca (other—independent data monitoring committee). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Supplemental Table 1 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐analysis) checklist
Supplemental Table 2. Search strategy
Supplemental Table 3. Demographics of the case series and case reports included in the systematic review
Supplemental Table 4. Quality assessment of included randomized controlled trial using the modified Jadad scale.
Supplemental Table 5. Quality assessment of included non‐randomized studies using the Newcastle‐Ottawa scale (NOS)
Supplemental Table 6. The tool developed by National Heart Lung Blood Institute (NHLBI) for the quality assessment of case series
Supplemental Table 7. The Joanna Briggs Institute (JBI) critical appraisal checklist for case reports
Supplemental Table 8. Disease extent and prior therapies of the patients receiving ICI in the unresectable setting
Supplemental Table 9. Adverse events occurring in less than 5% of the patients
Supplemental Table 10. Ongoing clinical trials
Disclosures of potential conflicts of interest may be found at the end of this article.
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Contributor Information
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
See http://www.TheOncologist.com for supplemental material available online.
Supplemental Table 1 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐analysis) checklist
Supplemental Table 2. Search strategy
Supplemental Table 3. Demographics of the case series and case reports included in the systematic review
Supplemental Table 4. Quality assessment of included randomized controlled trial using the modified Jadad scale.
Supplemental Table 5. Quality assessment of included non‐randomized studies using the Newcastle‐Ottawa scale (NOS)
Supplemental Table 6. The tool developed by National Heart Lung Blood Institute (NHLBI) for the quality assessment of case series
Supplemental Table 7. The Joanna Briggs Institute (JBI) critical appraisal checklist for case reports
Supplemental Table 8. Disease extent and prior therapies of the patients receiving ICI in the unresectable setting
Supplemental Table 9. Adverse events occurring in less than 5% of the patients
Supplemental Table 10. Ongoing clinical trials