Efficacy and safety of finotonlimab plus docetaxel vs. docetaxel in previously treated advanced squamous cell non-small-cell lung cancer: a randomized, double-blinded, phase III trial

Introduction

Lung cancer is the second most commonly diagnosed cancer worldwide and remains the leading cause of cancer death, with non-small cell lung cancer (NSCLC) being the primary histological type, accounting for approximately 85% of all lung cancer cases (1). Squamous cell NSCLC (sqNSCLC) accounts for up to 30% (2) and the majority have poor survival because only a few mutations are targetable with current treatments (3).

Programmed cell death-1 (PD-1) is a key immune checkpoint expressed on T cells. Its function is to inhibit T cell activity to prevent autoimmunity. Blocking the PD-1 pathway can restore T cell function and destroy cancer cells, which has been shown to be effective in several tumors. Anti-PD-1 monoclonal antibodies have become a key component of the therapeutic regimen for sqNSCLC, not only extending median overall survival (mOS) as monotherapy (4-7) but also showing promise in combination with other agents (8,9).

Docetaxel is the most commonly used cytotoxic drug for its anti-tumor activity, which is achieved by enhancing and stabilizing microtubule assembly and preventing their depolymerization in the absence of guanosine triphosphate (GTP). The mOS for patients with sqNSCLC treated with docetaxel is 6–8 months (4,6). Additionally, docetaxel is widely utilized in sqNSCLC and offers better benefits than checkpoint inhibitors in patients positive for epidermal growth factor receptor (EGFR) mutations (10). A phase 2 trial (PROLUNG) demonstrated that combining anti-PD-1 antibodies with chemotherapy is more effective in treating NSCLC than chemotherapy alone, indicating a potential synergistic effect of these treatments (11).

Finotonlimab (SCT-I10A), developed by Sinocelltech Ltd. in Beijing, China, is a humanized anti-PD-1 immunoglobulin G (IgG) monoclonal antibody that has demonstrated effective inhibition of tumor growth in both mouse models and human patients (12,13). Finotonlimab has shown high efficacy and a favorable safety profile across several cancer types (14,15). This phase III trial aims to evaluate the efficacy and safety of finotonlimab plus docetaxel compared to docetaxel alone in patients with previously treated sqNSCLC. We present this article in accordance with the CONSORT reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-1042/rc).

Methods

Trial design

In this randomized, double-blind, placebo-controlled phase III study (ClinicalTrials.gov identifier, NCT04171284), eligible patients (age ≥18 years and ≤75 years) from 56 hospitals in China were randomly assigned with a ratio of 2:1 to finotonlimab plus docetaxel group (finotonlimab plus docetaxel) and docetaxel group (placebo plus docetaxel). The stratification factors included Eastern Cooperative Oncology Group (ECOG) performance status (PS) score (0 vs. 1), sex (male vs. female), and brain metastasis (yes vs. no).

Patients

Eligible patients included those with histologically or cytologically confirmed locally advanced or recurrent stage IIIB–IV sqNSCLC who had progressed or relapsed after, or were intolerant to, first-line platinum-based chemotherapy. Other inclusion criteria were: patients should have at least a measurable tumor according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; an ECOG PS of 0 or 1; expected life expectancy ≥12 weeks; adequate organ and hematopoietic function.

Key exclusion criteria included any exposure to anti-PD-1 antibodies or other target of T cells or docetaxel, presence of factors (diseases or treatments) leading to immune deficiency, other pathophysiologic types of NSCLC, strong cytochrome P450 3A4 inhibitors in use, bisphosphonate therapy within 28 days, symptomatic central nervous system metastases, toxicity from prior treatment not recovering to grade 0 or 1 [defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0].

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study protocol was reviewed and approved by the Ethics Committee of Shanghai Chest Hospital (No. LS1955) prior to the commencement of the study. Written informed consent was obtained from all participants before their inclusion in the study.

Interventions

The study consisted of two periods: the combination therapy period, in which patients received either finotonlimab plus docetaxel or placebo plus docetaxel for two to six cycles (with each cycle lasting 3 weeks), and the maintenance therapy period, during which patients received finotonlimab/placebo monotherapy for a maximum of 2 years. During the combination therapy period, docetaxel (70–75 mg/m², intravenously) was administered every 3 weeks (Q3W), after finotonlimab/placebo injection (200 mg, intravenously). In the maintenance therapy period, patients achieving controlled disease [complete response (CR)/partial response (PR)/stable disease (SD)] by RECIST v1.1 received monotherapy of finotonlimab or placebo respectively. The treatments were continued until disease progression, loss to follow-up, death, initiation of new antitumor therapy, or unacceptable toxicity, with a maximum dosing time of 2 years. Crossover from the docetaxel group to the finotonlimab plus docetaxel group was not permitted in the study after six cycles of treatment.

Outcomes

The primary endpoint was overall survival (OS) of patients in the full analysis set. OS was defined as the time from first dose to death. Secondary endpoints were safety, immunogenicity and other efficacy endpoints. Secondary efficacy endpoints included (I) progression-free survival (PFS), defined as time from first dose to first confirmed PD or death; (II) OS rate; (III) objective response rate (ORR), defined as proportion of patients achieving CR or PR; (IV) duration of response (DoR), defined as time from first recorded CR/PR to first confirmed PD or death; and (V) disease control rate (DCR), defined as proportion of patients achieving CR, PR, or SD. The PFS and objective response were assessed by investigators according to RECIST 1.1.

Irrespective of treatment delays, tumor assessments were performed at fixed intervals every 6 weeks by contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI) according to RECIST version 1.1 until disease progression, initiation of new anti-tumor drug therapy, withdrawal from the study, death, loss to follow-up as assessed by the investigator. Safety evaluations were carried until the 28 days after last dose according to the NCI-CTCAE version 5.0. Immune-related adverse events (irAEs) were defined as adverse events of any grade that have been determined to have a causal relationship with immune mechanisms.

Statistical analysis

Randomization was done via Interactive Voice Response System/Interactive Web Response System. The statistical analysis was performed using SAS version 9.4. The full analysis set included patients who received at least one dose on an intention-to-treat basis. The safety set included patients who received at least one dose. Analyses of PFS and OS were based on the full analysis set. The DoR analysis was focused on the population with a confirmed CR or PR. OS, PFS, DoR, and their 95% confidence intervals (CIs) were analyzed with the Kaplan-Meier method and Brookmeyer and Crowley method. In this study, the stratified log-rank test was applied to compare survival differences between the two groups, with stratification variables of ECOG PS score, sex, and brain metastasis. Stratified Cox proportional hazards models was conducted to estimate hazard ratios (HRs). ORR and DCR were calculated using the Clopper-Pearson method to derive 95% CIs. For comparisons between groups for ORR/DCR, stratified Cochran-Mantel-Haenszel tests were used to determine rate differences, their 95% CIs, and P values. All P values were two-sided and calculated using stratified methods, with strata based on ECOG PS score, sex, and brain metastasis.

Results

Patient characteristics

Between April 7, 2020 and September 1, 2021, 188 patients were enrolled (finotonlimab plus docetaxel group, n=126; docetaxel group, n=62, Figure 1). The data cutoff was July 24, 2023. The demographic and baseline disease characteristics were presented in Table 1. In the finotonlimab plus docetaxel group, there were 92.9% (117/126) male patients, compared to 95.2% (59/62) in the docetaxel group. There were 88.1% (111/126) former/current smokers in the finotonlimab plus docetaxel group and 83.9% (52/62) in the docetaxel group. The majority of patients enrolled had stage IV disease, 81.7% (103/126) in the finotonlimab plus docetaxel group and 79.0% (49/62) in the docetaxel group. Programmed cell death-ligand 1 (PD-L1) positive patients with tumor proportion score (TPS) ≥1% were 55.6% (70/126) in the finotonlimab plus docetaxel group and 56.5% (35/62) in the docetaxel group. There were 97.6% (123/126) patients in the finotonlimab plus docetaxel group and 95.2% (59/62) in the docetaxel group received this treatment as second-line therapy.

Figure 1 Trial profile.

Efficacy

The median follow-up in two groups was 24.2 months (95% CI: 23.1, 25.4) in the finotonlimab plus docetaxel group and 23.2 months (95% CI: 19.6, 24.6) in the docetaxel group. There were 61.9% (78/126) deaths in the finotonlimab plus docetaxel group and 71.0% (44/62) deaths in the docetaxel group. As shown in Figure 2, the mOS was 17.1 months (95% CI: 11.2, 20.0) in the finotonlimab plus docetaxel group and 10.4 months (95% CI: 5.9, 14.0) in the docetaxel group. HR was 0.66 (95% CI: 0.45, 0.96; P=0.03). The 1-year survival rates were 54.7% (95% CI: 45.4%, 63.1%) and 47.0% (95% CI: 33.8%, 59.1%), respectively in the finotonlimab plus docetaxel group and docetaxel group.

Figure 2 Kaplan-Meier curves of OS in the full analysis set. Kaplan-Meier estimates of OS according to treatment group in the total population (A) and forest plot of the OS findings in subgroups (B). OS analysis included two patients who completed the OS assessments 4 days after the cutoff date. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; OS, overall survival; PD-L1, programmed cell death-ligand 1; PS, performance status; TPS, tumor proportion score.

Median PFS (mPFS) was 4.2 months (95% CI: 3.3, 6.9) and 2.9 months (95% CI: 1.5, 3.8), respectively in the finotonlimab plus docetaxel group and docetaxel group (Figure S1). HR was 0.45 (95% CI: 0.31, 0.66, P<0.001). The subgroup analysis demonstrated that patients received finotonlimab plus docetaxel had significantly longer PFS than those received docetaxel in both TPS ≥1% and TPS <1% (Figure 3).

Figure 3 Kaplan-Meier curves of OS and PFS in patients with TPS ≥1% and TPS <1%. The OS curves for patients with TPS ≥1% (A) and TPS <1% (B) and the PFS curves for patients with TPS ≥1% (C) and TPS <1% (D) were estimated to comparing the efficacy of finotonlimab plus docetaxel group and docetaxel group. CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; TPS, tumor proportion score.

As shown in Table 2, there were 34 PRs and two PRs in the finotonlimab plus docetaxel and docetaxel groups, respectively, with ORRs of 27.0% (95% CI: 19.5%, 35.6%) and 3.2% (95% CI: 0.4%, 11.2%), and a rate difference of 24.84% (95% CI: 15.73%, 33.95%, P<0.001). The DCR was 68.3% (86/126) in the finotonlimab plus docetaxel group and 56.5% (35/62) in the docetaxel group.

Safety

There were 96.8% (122/126) patients in the finotonlimab plus docetaxel group and 93.5% (58/62) patients in the docetaxel group (Table 3) reported treatment-emergent adverse events (TEAEs). Treatment-related adverse events (TRAEs) occurred in 91.3% (115/126) of patients in the finotonlimab plus docetaxel group and 87.1% (54/62) of patients in the docetaxel group, with the most common TRAEs being anemia (38.9% vs. 38.7%), leukopenia (29.4% vs. 24.2%), neutropenia (28.6% vs. 19.4%), alopecia (27.0% vs. 21.0%), and decreased appetite (21.4% vs. 16.1%) for the two groups, respectively. The occurrence rate of grade 3 TEAEs or higher was 43.7% (55/126) in the finotonlimab plus docetaxel group and 41.9% (26/62) in the docetaxel group, with 33.3% (42/126) and 37.1% (23/62) being treatment-related, respectively. The grade 3 TRAEs or higher with incidences greater than 10% were neutropenia [13.5% (17/126) vs. 14.5% (9/62)] and leukopenia [9.5% (12/126) vs. 11.3% (7/62)] in the two groups.

Serious adverse events (SAEs) occurred in 40.5% (51/126) of patients in the finotonlimab plus docetaxel group and 35.5% (22/62) of patients in the docetaxel group. Treatment-related SAEs were observed in 26.2% (33/126) and 25.8% (16/62) of patients in the finotonlimab plus docetaxel and docetaxel groups, respectively. IrAEs occurred in 40.5% (51/126) of patients in the finotonlimab plus docetaxel group with 5.6% (7/126) experiencing grade 3 or higher events. The most common irAEs were hypothyroidism (13.5%) and hyperthyroidism (12.7%).

Death caused by TRAEs were in 2.4% (three patients, two unknown causes and one septic shock) in the finotonlimab plus docetaxel group and 4.8% (three patients, two respiratory tract hemorrhages and one pneumonitis) in the docetaxel group.

Discussion

This study showed that patients with previously treated sqNSCLC who received finotonlimab plus docetaxel had a significantly longer OS and a reduced risk of death compared to those who received docetaxel. The combination of finotonlimab plus docetaxel also significantly prolonged mPFS, increased ORR and DCR and was well tolerated.

Currently, the recommended immune checkpoint inhibitors for second-line and subsequent treatments are atezolizumab, pembrolizumab, and nivolumab, administered as monotherapies. In the phase III OAK trial, patients with sqNSCLC receiving atezolizumab monotherapy achieved a mOS of 8.9 months, compared to 7.7 months for those treated with docetaxel monotherapy (5). The CheckMate-017 trial reported an mOS of 9.2 months in the nivolumab group vs. 6.0 months in the docetaxel group (4). Given potential racial differences in treatment response, the ORIENT-3 phase III study focused on an Asian population with sqNSCLC. Patients treated with sintilimab had a mOS of 11.79 months, compared to 8.25 months for the docetaxel control group (6). Similarly, the RATIONALE-303 study, which included approximately 80% Asian patients with NSCLC, found a mOS of 16.9 months for the treatment group, compared to 11.9 months for the docetaxel group (7). Approximately 24.2% (15/62) of patients in the docetaxel group received immunotherapy post-treatment, including those who exited the trial earlier due to disease progression. This may have influenced the observed OS, potentially contributing to the narrowing of the OS difference between the two groups in the later stages of the trial. In this study, patients treated with finotonlimab plus docetaxel achieved a mOS of 17.1 months, compared to docetaxel or other reported immune checkpoint inhibitors used as monotherapy. Chemotherapy remains a widely accepted first-line treatment option for sqNSCLC, especially in resource-limited regions. This study provides insights into the potential synergistic benefits of combining chemotherapy with PD-1 inhibitors, particularly for patients who have received first-line platinum-based chemotherapy. While the study did not include patients previously treated with PD-1 inhibitors, evidence suggests that chemotherapy agents like docetaxel can induce the release of tumor antigens, potentially re-sensitizing the tumor microenvironment to subsequent PD-1 blockade (16). This mechanism supports further research into the combination of docetaxel and PD-1 inhibitors as a second or later-line therapy for patients who have failed first-line pembrolizumab or nivolumab treatments.

The mPFS in finotonlimab plus docetaxel group was 4.2 months, similar to the 5.5 months reported in the phase II PROLUNG study of pembrolizumab plus docetaxel in second-line NSCLC treatment (11). In this study, the ORR was 27% in the finotonlimab plus docetaxel group, compared to 3.2% in the docetaxel group, which is comparable to previously published data reporting an ORR of 2.2% to 15.8% in patients treated with docetaxel (4,6,7,11). This phase III trial was based on a large-scale phase Ib study of SCT-I10A involving 250 patients with advanced solid tumors. Among these, SCT-I10A monotherapy demonstrated promising efficacy in 23 late-stage sqNSCLC patients. The DCR was 60.9%, and the mPFS was 4.2 months. Considering the established effectiveness of PD-1 inhibitors in sqNSCLC and the poor tolerability of chemotherapy, the use of docetaxel was restricted to six cycles in this study. This treatment regimen was consistent with the PROLUNG trial, which compared pembrolizumab plus docetaxel to docetaxel alone (11). Evidence indicates that the Chinese population may have a lower response to docetaxel. In trials predominantly involving Chinese patients, such as ORIENT-3, RATIONALE-303, and CheckMate078, the ORR for squamous NSCLC treated with docetaxel ranged from 1.5% to 7.1% (6,7,17). In our study, the docetaxel group showed an ORR of 3.2%, which falls within this range but is notably lower than the 9% or higher ORRs reported in studies with predominantly Caucasian populations, such as CheckMate017 and PROLUNG.

Compared to the phase II PROLUNG study, our study showed a relatively lower incidence of neutropenia, hypothyroidism, and pneumonitis with finotonlimab plus docetaxel (28.6%, 13.5%, and 10.3%) vs. pembrolizumab plus docetaxel (40%, 28%, and 23%) in the PROLUNG study (11). Leukopenia and hepatic enzyme increased were observed in our study, and they are common AEs caused by docetaxel (18) and anti-PD-1 antibodies (19). Most irAEs in this study were grade 1–2, with hypothyroidism being the most common, and it is comparable to other PD-1 inhibitors such as nivolumab and pembrolizumab.

A limitation of the study is that it did not compare finotonlimab with other reported immune checkpoint inhibitors. At the time of the study, platinum-based chemotherapy regimens were the first-line treatment for sqNSCLC, and docetaxel was the standard second-line treatment in China. However, with the approval of several immune checkpoint inhibitors, these therapies have rapidly become the first- and second-line treatment options for sqNSCLC. In summary, this phase III study demonstrates that finotonlimab plus docetaxel is significantly more effective than docetaxel alone, without increasing the safety risk (16). The second limitation is that this study did not include genetic testing, which plays an important role in identifying potential therapeutic targets.

Conclusions

SCT-I10A, in combination with docetaxel, significantly extended mOS and enhanced clinical outcomes in patients with previously treated advanced sqNSCLC compared to docetaxel alone, without raising safety concerns.

Acknowledgments

We thank the participants of the study. We also thank Dongfang Liu and Yuanxin Chen of Sinocelltech Ltd. for data analysis and medical writing.

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-1042/rc

Trial Protocol: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-1042/tp

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-1042/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-1042/prf

Funding: This work was provided by Sinocelltech Ltd. including coverage of publication costs for this manuscript, and by the National Science and Technology Major Projects of China (No. 2019ZX09732-001).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-1042/coif). Z.H., C.L., L.Y., Jinling Wang, and L.X. are currently employees of Sinocelltech Ltd. L.X. holds stock in Sinocelltech Ltd., the sponsor of this study. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study protocol was reviewed and approved by the Ethics Committee of Shanghai Chest Hospital (No. LS1955) prior to the commencement of the study. Written informed consent was obtained from all participants before their inclusion in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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