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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 3  |  Page : 676-687

Prognostic role of programmed cell death ligand-1 expression in head and neck cancer treated with programmed cell death protein-1/programmed cell death ligand-1 inhibitors: A meta-analysis based on clinical trials


1 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China; Sun Yat-Sen University Cancer Center, Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
2 Biotherapy Center, Sun Yat-Sen University Cancer Center, Guangzhou, China

Date of Submission31-Oct-2020
Date of Decision20-Jan-2021
Date of Acceptance08-Mar-2021
Date of Web Publication9-Jul-2021

Correspondence Address:
Yunfei Xia
Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1606_20

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 > Abstract 


Purpose: The purpose of our meta-analysis is to clarify whether the biomarker of programmed cell death ligand-1 (PD-L1) could predict the treatment efficacy and prognosis of programmed cell death protein-1 (PD-1)/PD-L1 immune-checkpoint inhibitors (ICIs) in head and neck cancer (HNC) patients.
Materials and Methods: We performed the article search in four main online databases. The search deadline was September 8, 2020. To elucidate whether a positive or negative PD-L1 expression correlates with different efficacy and prognosis of PD-1/PD-L1–related therapy in HNC, the relative risk (RR) and 95% confidence interval (95% CI) were pooled. Our meta-analysis assigned the overall survival (OS) at 6 and 12 months and the objective response rate (ORR) for the primary end points.
Results: The present meta-analysis included 11 relevant studies, which have 1663 HNC cases who received the treatment of PD-1/PD-L1 ICIs. The pooled results revealed that the high or positive expression of PD-L1 predicted better 6- and 12-month OS in head and neck squamous cell carcinoma (HNSCC) (RR 1.30, 95% CI: 1.02–1.65, P = 0.03; and RR 1.31, 95% CI: 1.05–1.62, P = 0.01). PD-L1 expressors were also relevant with higher ORR in HNC patients who had treatment of PD-1/PD-L1 inhibitors compared to PD-L1 nonexpressors (RR 1.84, 95% CI: 1.41–2.41, P < 0.00001).
Conclusions: In summary, PD-L1–positive HNSCC patients portend favorable OS at 6 and 12 months from PD-1/PD-L1 ICIs. Increased ORR also favored to appear in PD-L1 expressors of HNC or recurrent/metastatic HNSCC who received PD-1/PD-L1 ICIs. Therefore, PD-L1 proved to be an appropriate biomarker to predict the clinical efficacy and prognosis of PD-1/PD-L1 ICIs in HNC.

Keywords: Expression, head and neck cancer, immune-checkpoint inhibitors, programmed cell death ligand-1, programmed cell death ligand-1, prognosis


How to cite this article:
Huang Z, Zheng S, Ding S, Wei Y, Chen C, Liu X, Li H, Xia Y. Prognostic role of programmed cell death ligand-1 expression in head and neck cancer treated with programmed cell death protein-1/programmed cell death ligand-1 inhibitors: A meta-analysis based on clinical trials. J Can Res Ther 2021;17:676-87

How to cite this URL:
Huang Z, Zheng S, Ding S, Wei Y, Chen C, Liu X, Li H, Xia Y. Prognostic role of programmed cell death ligand-1 expression in head and neck cancer treated with programmed cell death protein-1/programmed cell death ligand-1 inhibitors: A meta-analysis based on clinical trials. J Can Res Ther [serial online] 2021 [cited 2021 Aug 5];17:676-87. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/676/321013




 > Introduction Top


It is acknowledged that head and neck cancer (HNC) contains a series of malignant cancer located in the paranasal sinuses, nasal cavity, oral cavity, pharynx, and larynx.[1] According to the Global Burden of Disease Study data, 1 million HNC patients existed worldwide up to 2015. It revealed that approximately 400,000 HNC patients died in 2015.[2] Local recurrence and metastasis are the most common reasons for treatment failure in HNC, especially for local advanced or metastatic HNC in the initial diagnosis. Therefore, surgery is combined with other therapeutics, such as chemotherapy, immunotherapy, and radiotherapy, and the synthesis therapies considerably reduced the rate of local recurrence and metastasis.[3] Recently, encouraging clinical benefits were revealed in targeting the axis of programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) in HNC. Therefore, more PD-1/PD-L1 immune-checkpoint inhibitors (ICIs) were authorized by the Food and Drug Administrator (FDA) and applied to clinical practice in succession.

On account of the unusual biological behavior of nasopharyngeal carcinoma (NPC), the clinical characteristics of NPC are different from other kinds of HNC. It also leads to the therapeutical difference between NPC and non-NPC HNC. For instance, the first-line chemotherapy for recurrent or metastatic NPC (R/M NPC) and R/M non-NPC HNC is different based on the recommended National Comprehensive Cancer Network (NCCN) guidelines. The NCCN suggested that platinum, fluorouracil, and cetuximab are preferred in first-line chemotherapy for R/M non-NPC HNC.[4] In contrast, the first-line chemotherapy for R/M NPC is the combination of gemcitabine and cisplatin (GP regimen), which showed encouraging antitumor clinical efficacy in phase 3 randomized controlled clinical trials (RCTs).[5] Chemotherapy regimens are diverse in R/M NPC, non-NPC HNC, and immunotherapy regimens. NCCN guidelines suggested Keytruda (pembrolizumab, a kind of PD-1 inhibitor) as the first choice of immunotherapy for R/M non-NPC HNC since a phase 3 RCT proved that pembrolizumab significantly prolonged overall survival (OS).[4],[6] For previously untreated R/M NPC, Fang et al. revealed that camrelizumab (a kind of PD-1 ICIs) combined with GP regimen might improve clinical tumor remission benefits and the toxicity of the combination of the three drugs is manageable.[7] If R/M NPC patients had been previously treated, camrelizumab monotherapy is recommended by the NCCN guidelines, and a phase 1 study showed promising clinical efficacy.[5],[7] In general, PD-1/PD-L1 ICIs displayed excellent clinical antitumor outcomes in HNC. Considering NPCs are different from non-NPC HNC in various aspects, such as clinical characteristics, biological behavior, standard treatment, and prognosis, our meta-analysis excluded the NPC-related studies to ensure the homogeneity of the included studies and data.

Our previous meta-analysis included 18 studies, which demonstrated that PD-1/PD-L1 negative or positive had no statistical correlation with the prognosis of NPC.[8] Li et al. pooled data from 17 articles, and it proved that PD-L1 expression levels could not predict OS for HNC cases.[9] However, NPC or HNC cases in the two meta-analyses mostly received conventional therapy, including radiotherapy, chemotherapy, and surgery. Rarely of the included cases were treated with PD-1/PD-L1 ICIs.

In another meta-analysis of nonsmall cell lung cancer (NSCLC) cases, all received PD-1/PD-L1 ICIs, and the high level of PD-L1 expression indicated better objective response rate (ORR).[10] A pooled study showed that patients with PD-L1–positive melanoma could gain better tumor remission benefits from PD-1/PD-L1 ICIs, regardless of the set definitions of PD-L1 positivity.[11] However, a similar meta-analysis has not been done in HNC to explore the relationship between PD-L1 expression level and its clinical efficacy or prognosis.

Although some of PD-1/PD-L1 ICIs have been approved by the FDA and NCCN as one of the standard therapeutics for HNC, whether PD-L1 could be an appropriate biomarker to screen out the more clinical efficacy and beneficial survival population of HNC remains unclear. Accordingly, this meta-analysis aims to clarify whether the biomarker of PD-L1 in HNC could predict the treatment efficacy and prognosis from PD-1/PD-L1 ICIs. The present meta-analysis only included clinical trials on HNC that received PD-1/PD-L1 ICIs relevant immunotherapy. It effectively prevents the interference of non-PD-1/PD-L–related therapy, which is the highlight of our meta-analysis and makes it unique. Besides, it is the first study to solve the problem mentioned above, based on high-grade evidence-based medicine methods.


 > Materials and Methods Top


Protocol and registration

The meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines[12] and the Cochrane Handbook.[13] In addition, we have registered the information on the international prospective register of systematic reviews ahead of writing, with a registration number of CRD42020152650.

Literature research

We performed the article search in four main online databases, PubMed, EMBASE, Web of Science, and the Cochrane Library. The search deadline was September 8, 2020. We accomplished the search by utilizing the following keywords: “PD-1 inhibitor or PD-L1 inhibitor or nivolumab or pembrolizumab or atezolizumab or durvalumab or avelumab,” “oral cavity or nasal cavity or paranasal sinuses or oropharynx or larynx or hypopharynx or lip or head neck,” and “cancer or carcinoma or tumor.” To avoid losing important studies, we did manual retrieval from the references to enlarge the retrieval field. The subgroup analysis that originated from the same clinical trial study was not included in our meta-analysis. Unless the original clinical trial did not provide available data for us to pool the relevant data, we would consider including its subgroup study in our analysis. Furthermore, the same cohorts of patients can only be included once.

Inclusion and exclusion criteria

The included studies should satisfy all of the following four key criteria:

  1. Studies that enrolled HNC patients
  2. Studies containing PD-1 or PD-L1 ICIs relevant treatment
  3. Available data for ORR or OS based on PD-L1 expression that can be obtained
  4. Trials that were registered in ClinicalTrials.gov, with a valid registration number.


Those who met the following criteria will be excluded from the analysis:

  1. Any other types that are not prospective clinical trials, such as reviews, letters, case reports, news, basic research, and retrospective or prospective observational cohort studies
  2. Studies that enrolled NPC patients
  3. Duplicates studies
  4. Studies not written in English.


Data extraction

Two investigators (Zilu Huang and Shuohan Zheng) separately completed articles selection. We also extracted the necessary information from the included studies. Disagreements were settled by consulting a professional researcher (Yunfei Xia). The extraction details mainly include the author, publication year, registration number, phases of clinical trials, patients' region, recruitment period, tumor category, the regimen of PD-1 or PD-L1 ICIs, ORR (95% confidence interval [CI]), median OS (95% CI), total number of patients, number of patients in the immunotherapy group number, PD-L1 immunohistochemistry assays, PD-L1 evaluation criteria, definitions for PD-L1–positive, number of PD-L1–positive patients, prognostic end points, and the standard of tumor response assessment. The extracted data above are all summarized in [Table 1]. Besides, we extracted the necessary data about clinical efficacy and prognosis for the relevant end point meta-analysis.
Table 1: Main characteristics of included studies in this meta-analysis

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End points and statistical analysis

To elucidate whether a positive or negative PD-L1 expression correlates with different efficacy and prognosis of PD-1/PD-L1–related therapy in HNC, relative risk (RR) and 95% CI (95% CI) were pooled. Our meta-analysis assigned the OS at 6 and 12 months and the ORR for the primary end points. The secondary end points were based on the subdivision of ORR, including partial response (PR), complete response (CR), stable disease (SD), and progression disease (PD). Subgroup analyses were based on PD-1 inhibitors or PD-L1 inhibitors, two kinds of PD-L1 evaluation criteria, and two definitions for PD-L1 positive. Two kinds of PD-L1 evaluation criteria included the tumor cells' proportion score (TC/TPS) and combined positive score (CPS). TC or TPS was defined as the percentage of TCs with membranous PD-L1 expression. CPS was defined as the number of PD-L1–positive TCs, lymphocytes, and macrophages divided by the total number of TCs multiplied by 100. Two definitions for PD-L1 positive included TC/TPS ≥1% and CPS ≥1%. TC/TPS ≥1% meant that more than 1% of TCs had membranous PD-L1 expression. CPS ≥1% meant that the percentage of PD-L1–positive TCs, lymphocytes, and macrophages divided by the total number of TCs multiplied by 100 was >1%. The category of R/M head and neck squamous cell carcinoma (HNSCC) was also extracted to include in the subgroup analysis. The subgroup analyses were all about ORR due to the insufficient number of studies offering OS data that can be obtained. The ORR and secondary end points were evaluated according to the standards of RECIST v1.1 (Response Evaluation Criteria in Solid Tumors version 1.1).

The detailed methods of statistical analyses can be referred to our previously published study.[8] Review Manager 5.3 (Cochrane Collaboration, Oxford, UK) and STATA 14.0 (StataCorp, College Station, TX, USA) acted as the main software that performed statistical analyses. The pooled RR and 95% CI were calculated by the Review Manager. Heterogeneity was assessed by the Chi-square test and I2 statistic. If the P < 0.1 in the Chi-square test or I2 >50%, it indicated that heterogeneity exists among the corresponding studies.[14] Therefore, the random-effects model will be utilized in this situation. Otherwise, the fixed-effects model will be applied. The purpose of the subgroup analysis is to seek the source of heterogeneity. When the pooled RR and 95% CI are >1, it proved that PD-L1–positive cases benefit more than PD-L1–negative cases from PD-L1/PD-1 ICIs. Moreover, Begg's and Egger's tests were used to evaluate the publication bias. Bilateral P < 0.05 was considered statistically significant.


 > Results Top


Study selection

Initially, we obtained 1554 relevant studies according to retrieval methods. Then, 473 duplicates have been removed. We thoroughly evaluated the residual 1081 papers' titles and abstracts. We then ruled out 1016 articles that did not satisfy our inclusion and exclusion criteria. Full-text scanning was done in the remaining 65 articles. Twenty subgroup reports and 34 researches offering unavailable data have been ruled out. Finally, 11 clinical trials were included. The detailed selection procedure is shown in [Figure 1].
Figure 1: Selection flowchart of the included studies

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Study characteristics

In total, 11 clinical trials (1663 patients) were included in our study.[6],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] [Table 1] lists the major features in clinical trials. All the trials included have been registered in advance in ClinicalTrials.gov. Patients were recruited from 2014 to 2018. The publication year was the last 4 years. PD-1 ICIs involved nivolumab and pembrolizumab, while PD-L1 ICIs involved atezolizumab and durvalumab. PD-1/PD-L1 ICIs involved in these clinical trials were all approved by the FDA to be applied in various indications. The median OS varied between 6 and 17.5 months. The ORR had a wide range of fluctuation, with a minimum value of 6.5% and a peak value of 60%. The definitions for PD-L1 positive vary between studies. All included researches offered accessible ORR data based on the PD-L1 expression levels, of which six provided available data concerning OS. All trials used the RECIST v1.1 to evaluate the efficacy of tumor response.

End points of meta-analysis

The pooled results revealed that the higher or positive expression of PD-L1 predicted better 6- and 12-month OS in HNC (RR 1.30, 95% CI: 1.02–1.65, P = 0.03; and RR 1.31, 95% CI: 1.05–1.62, P = 0.01). No obvious heterogeneity was discovered (I2 = 0%, P = 0.83; I2 = 0%, P = 0.63) [Figure 2]. PD-L1 positivity was also found to be relevant with a higher ORR in HNC patients who had treatment of PD-1/PD-L1 inhibitors than PD-L1–negative groups (RR 1.84, 95% CI: 1.41–2.41, P < 0.00001). It also showed no obvious heterogeneity (I2 = 0%, P = 0.85) [Figure 3]. The meta-analysis results for secondary end points demonstrated that PD-L1 positive was relevant to a better PR (RR 1.53, 95% CI: 1.09–2.17, P = 0.02), better CR (RR 3.05, 95% CI: 1.15–8.11, P = 0.03), and less PD (RR 0.76, 95% CI: 0.60–0.98, P = 0.03) [Figure 4]. The fixed-effects model was used in both primary end points and secondary end points because no statistical heterogeneity was discovered from the pooling data. Moreover, no relationship existed in PD-L1 positive and SD (RR 0.77, 95% CI: 0.58–1.02, P = 0.07). Besides, secondary end points included 4–6 studies that are data available. The detailed data of secondary end points are shown in [Table 2].
Figure 2: Forest plot of risk ratio for 6- and 12-month overall survival between programmed cell death ligand-1–positive and programmed cell death ligand-1–negative head and neck squamous cell carcinoma patients

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Figure 3: Forest plot of risk ratio for objective response rates between programmed cell death ligand-1–positive and programmed cell death ligand-1–negative head and neck cancer patients

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Figure 4: Forest plot of risk ratio for secondary end points between programmed cell death ligand-1–positive and programmed cell death ligand-1–negative head and neck cancer patients

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Table 2: Subgroup analysis and secondary end points of included studies in this meta-analysis

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Subgroup analysis

Table 2 displays the pooled data of the subgroup analysis. Subgroup analyses showed a statistical correlation between the high expression level of PD-L1 and better ORR in patients who received PD-1 ICIs (RR 1.91, 95% CI: 1.42–2.56, P < 0.0001) [Figure 5]. In contrast, the clinical efficacy of PD-L1 ICIs did not relate to the PD-L1 expression [Figure 5]. Two kinds of PD-L1 evaluation criteria included the TC/TPS and CPS. PD-L1–positive patients in both of the standards showed better ORR (RR 1.66, 95% CI: 1.21–2.27, P = 0.002; RR 1.86, 95% CI: 1.23–2.82, P = 0.003) [Figure 6]. Providing that CPS ≥1% was regarded as the definition for PD-L1 positive, an improved ORR favored to appear in a high expression of PD-L1 HNC cases (RR 1.91, 95% CI: 1.25–2.92, P = 0.003) [Figure 7]. Likewise, the subdivision of R/M HNSCC with PD-L1 positive could gain better clinical efficacy from PD-1/PD-L1 ICIs than the PD-L1–negative cases (RR 1.84, 95% CI: 1.39–2.44, P < 0.0001) [Figure 8].
Figure 5: Forest plot of risk ratio for objective response rates between programmed cell death ligand-1–positive and programmed cell death ligand-1–negative head and neck cancer patients treated with PD-1 or programmed cell death ligand-1 inhibitors

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Figure 6: Forest plot of risk ratio for objective response rates between programmed cell death ligand-1–positive and programmed cell death ligand-1–negative head and neck cancer patients in different programmed cell death ligand-1 evaluation criteria

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Figure 7: Forest plot of risk ratio for objective response rates between programmed cell death ligand-1–positive and programmed cell death ligand-1–negative head and neck cancer patients in different definitions of programmed cell death ligand-1 positivity

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Figure 8: Forest plot of risk ratio for objective response rates between programmed cell death ligand-1–positive and programmed cell death ligand-1–negative recurrent or metastatic head and neck squamous cell carcinoma cancer

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Publication bias

[Figure 9] shows the publication bias. The statistics about 12 months of OS and ORR were used in the Begg's and Egger's tests. Both funnel plots of the Begg's test have been examined and found approximately symmetrical. On the other hand, the P value of the Begg's and Egger's tests was all >0.05. Therefore, no publication bias existed in our meta-analysis.
Figure 9: Begg's funnel plot for 12-month overall survival (a) and objective response rates (b). Publication bias tests for 12-month overall survival (c) and objective response rates (d)

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 > Discussion Top


Our meta-analysis incorporated 11 studies to clarify whether the biomarker of PD-L1 could predict the treatment efficacy and prognosis of PD-1/PD-L1 ICIs in HNC patients. The outcomes indicated that PD-L1–positive cases treated with PD-1/PD-L1 ICIs had a superior OS in 6 and 12 months. An increased ORR also favored to appear in high PD-L1 expressions of HNC and R/M HNSCC who received PD-1/PD-L1 ICIs.

Immunotherapy could strengthen the immune reaction of patients and destroy cancer cells by stimulating the immune signaling pathway. Moreover, chemotherapy drugs act on different cycles of TCs to inhibit growth, regeneration, and cell death. The mechanism of immunotherapy is different from chemotherapy.[26] Recently, more clinical trials concerning PD-1/PD-L1 ICIs are ongoing or have been completed worldwide. It showed encouraging clinical efficacy and tolerant side effects in some kinds of tumors, such as melanoma and NSCLC. It also makes that PD-1/PD-L1 ICIs become the highlight in the field of cancer treatment and the frontiers of immunotherapy.[27] Although studies regarding PD-1/PD-L1 ICIs were performed worldwide, the treatment efficacy and prognosis varied in different cancer categories. The KEYNOTE-006 trial showed a 2-year OS of 55% and an ORR of 37%, which strongly supported the use of pembrolizumab as the standard treatment for advanced melanoma.[28] CheckMate-057 demonstrated that a 1-year OS was approximately 51% and an ORR was 19% in advanced nonsquamous NSCLC treated with nivolumab.[29] CheckMate-017 revealed a rate of 42% for 1-year OS and 20% for ORR in advanced squamous NSCLC received nivolumab.[30] In our meta-analysis, HNSCC who received durvalumab had a minimum ORR of 6.5%.[20] The worst median OS is approximately 6 months, and it appears in HNC treated with durvalumab and atezolizumab, both belonging to PD-L1 ICIs.[17],[21] The best immune monotherapy efficacy among included studies occurred in metastatic HNSCC treated with nivolumab, with the best ORR of 34.5% and median OS of 14.2 months.[23] For immunotherapy combined with other treatments, the KEYNOTE-048 showed that pembrolizumab combined with chemotherapy had a superior ORR of 36% in R/M HNSCC.[15] In 2016, pembrolizumab and nivolumab have been approved by the US FDA for the treatment of R/M HNSCC with disease progression during or after platinum-based treatment, given the encouraging antitumor clinical efficacy and tolerant toxicity shown by KEYNOTE-048 and CheckMate-141.[31],[32],[33]

It is debated that PD-L1 is an appropriate biomarker that predicts the efficacy of PD-1/PD-L1 ICIs. PD-L1–positive melanoma has been proved to be more associated with the superior OS when treated with PD-1 ICIs.[34] A pooled study on NSCLC stated that PD-L1 positive would have improved the clinical antitumor efficacy with PD-1/PD-L1 ICIs.[10] In contrast, another NSCLC meta-analysis showed that PD-L1–negative patients were also associated with enhanced OS using PD-1/PD-L1 ICIs.[35] For NSCLC patients with PD-L1 expression on at least 50% of TCs, combination therapy and pembrolizumab monotherapy are better than chemotherapy.[36] In our meta-analysis, RR and 95% CI in most of the studies showed no relationship between the PD-L1 expression status and efficacy in HNC treated with PD-1/PD-L1 ICIs. However, the pooled data revealed that PD-L1–positive cases treated with PD-1/PD-L1 ICIs had a superior OS and ORR. Cohen et al.[37] indicated that PD-L1–positive R/M HNSCC leads to more clinical benefits by independently summarizing every relevant study. In contrast, our meta-analysis proved it by evidence-based medicine and statistics.

Wang et al.[38] compared the clinical efficacy of the standard treatment and PD-1 ICIs in HNC. They include two clinical trials and revealed that PD-L1–positive HNC had superior antitumor efficacy from PD-1 inhibitors than the standard treatment. Nevertheless, PD-L1–negative HNC obtained a similar clinical efficacy in the two groups. In contrast, our meta-analysis incorporated 11 studies and revealed that the biomarker of PD-L1 could predict the treatment efficacy and prognosis of PD-1/PD-L1 ICIs in HNC patients. The present meta-analysis only included clinical trials on HNC that received PD-1/PD-L1 ICIs relevant immunotherapy. It effectively prevents the interference of non-PD-1/PD-L1–related therapy, which is the highlight and uniqueness of our meta-analysis.

The secondary end points analysis of our study indicated that PD-L1–positive cases were more likely to have a tumor partial and CR, with less tumor progression. It further approved our main conclusion from the analysis of primary end points. CRs mainly come from the KEYNOTE-048 study, which were PD-L1–positive cases who received pembrolizumab and chemotherapy.[39] This indicated that the chemo-IO (chemotherapy and immunotherapy) is indispensable for a CR in R/M HNSCC.[39]

PD-L1 evaluation criteria and the definitions for PD-L1 positive varied between studies. The criteria of TC and TPS had the same interpretation, which was the percentage of TCs with membranous PD-L1 expression.[6],[25] When the PD-L1 evaluation criterion is TC/TPS or CPS, PD-L1 expressors showed favored ORR against PD-L1 nonexpressors. Besides, better ORR in PD-L1 expressors was related to the subgroup of CPS ≥1% than TC/TPS ≥1%, indicating that CPS may be the useful evaluation criterion for PD-L1 in predicting the clinical efficacy of PD-1/PD-L1 ICIs in HNC. The KEYNOTE-048 clinical trial proved that HNC with CPS ≥1% or CPS ≥ 20% would gain better clinical benefits from PD-1 ICIs.[15] It was in accordance with our pooled results in the subgroup study.

Only three included studies were not strictly concerning R/M HNSCC.[17],[19],[24] Thus, the statistics were collected from the remaining eight studies regarding R/M HNSCC. Moreover, it proved that a PD-L1–positive R/M HNSCC had favored ORR from PD-1/PD-L1 ICIs than PD-L1–negative cases. In our primary end point analysis, studies included in OS focused only on R/M HNSCC. Combining the two analyses above, we conclude that PD-L1–positive R/M HNSCC indicated better OS and ORR.

In the meantime, our meta-analysis has some limits. On the one hand, HNC includes a variety of cancer types. However, the R/M HNSCC was in the majority of our study. It may limit our findings to be utilized in other types of HNC. Therefore, it would be better if more clinical trials can be included in the meta-analysis to make the outcomes more robust and reliable. On the other hand, the PD-L1 evaluation criteria and the definitions for PD-L1 positive vary in clinical trials. Subgroup analysis based on two kinds of PD-L1 evaluation criteria and the definitions for PD-L1 positive both showed that PD-L1 positive patients had better ORR. Besides, no heterogeneities were found in the subgroup of different PD-L1 evaluation criteria and the definitions of PD-L1 positivity. However, it would be better to have a unified global standard to assess the PD-L1 positive in HNC cases.


 > Conclusion Top


In summary, PD-L1–positive HNSCC patients indicate a favorable OS at 6 and 12 months from PD-1/PD-L1 ICIs. Increased ORR also favored to appear in PD-L1 expressors of HNC or R/M HNSCC who received PD-1/PD-L1 ICIs. Therefore, PD-L1 proved to be an appropriate biomarker to predict the clinical efficacy and prognosis of PD-1/PD-L1 ICIs in HNC. To better use the biomarker of PD-L1, it would be better to have a unified global standard to assess the PD-L1 positive in HNC cases.

Financial support and sponsorship

This work was supported by The National Natural Science Funds (Grant No. 81872464) and The Science Development Program of Guangzhou (NO. 201707020001).

Conflicts of interest

There are no conflicts of interest.



 
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