Research ArticleExperimental Studies

PD-L1 Expression and Survival Rates Using TPS and CPS for Nivolumab-treated Head-and-Neck Cancer

TATSUYA ITO, ISAKU OKAMOTO, KUNIHIKO TOKASHIKI, HIROKI SATO, TAKURO OKADA, GAI YAMASHITA, TOSHITAKA NAGAO, HIDEAKI HIRAI, NATSUKI SAIGUSA and KIYOAKI TSUKAHARA
Anticancer Research March 2022, 42 (3) 1547-1554; DOI: https://doi.org/10.21873/anticanres.15628

Abstract

Background/Aim: This study investigated the expression and survival rates of programmed cell death ligand 1 using the tumor proportion score (TPS)and combined positive score (CPS) for recurrent/metastatic head and neck cancer administered nivolumab. Patients and Methods: Forty-seven patients with recurrent/metastatic head and neck cancer with a history of platinum-based chemotherapy who received nivolumab between June 1st, 2017, and January 31st, 2019 were included in this study. Results: TPS and CPS were strongly correlated (r=0.546). When the TPS was high (≥40%), overall and progression-free survival were significantly better. The median overall survival was 8.5 months, median progression-free survival was not reached, and the 1-year progression-free survival rate was 71.4%. However, there was no significant difference in overall and progression-free survival between the groups with high CPS (≥20). Conclusion: This is the first report to show a strong correlation between TPS and CPS. High TPS (40% or higher) may be used as a predictor of prognosis and efficacy. Further studies are warranted to determine the use of the CPS as a biomarker.

Key Words:

On March 24, 2017, the immune checkpoint inhibitor nivolumab became available for use in head and neck cancer with recurrence or distant metastasis (R/M-HNC) in Japan. Nivolumab is classified as a category 1 therapy in the National Comprehensive Cancer Network guidelines, as well as 5-fluorouracil with platinum and cetuximab (1). There are a few drugs that can be used in the treatment of cases of R/M-HNC, however, no established treatment protocol exists. Therefore, nivolumab is anticipated to be a new treatment option. An international joint phase III study, CheckMate-141, conducted with nivolumab reported a significant prolongation of overall survival (OS) in patients with platinum-resistant R/M-HNC compared with the control arm treated with anticancer drugs and cetuximab (2). Whilst the Checkmate 141 study confirmed OS prolongation, no large-scale reports have demonstrated the therapeutic effects.

Therapy using programmed cell death ligand 1 (PD-L1) inhibitor has shown efficacy in patients with recurrent or metastatic salivary gland carcinoma with long-term improved prognosis (3). Various biomarkers have been reported for other carcinoma types. The CheckMate-141 study compared a nivolumab-treated group with a group under an investigator-selected treatment for OS based on the PD-L1 expression status. Since the expression of PD-L1 differs spatially and temporally, its practicality as a biomarker is considered poor. At our Institution, the 28-8 antibody was used for assessing PD-L1 in all patients prior to the administration of nivolumab. The tumor proportion score (TPS), resulting from staining with 28-8 antibody, is used as a measurement of the PD-L1 expression in tumor cells. Okamoto et al. reported that OS was significantly better when the TPS was 40% or more in patients with R/M-HNC who were administered nivolumab (4).

The combined positive score (CPS) is a measurement of PD-L1 expressed in macrophages and lymphocytes, in addition to tumor cells. A randomised, open-label, phase 3 study, KEYNOTE-048, was a first-line study of platinum-sensitive R/M-HNC and showed an OS advantage in patients with CPS ≥20 and CPS ≥1 with pembrolizumab therapy compared to standard therapy (5). In Japan, when PD-L1 is measured for treatment of RM-HNC using pembrolizumab, the CPS is often measured. On the other hand, for use of nivolumab, TPS and CPS are rarely used. There are few reports on the relationship between TPS and CPS in HNC. Therefore, using samples for which TPS had already been measured, the CPS was also measured on the same samples. We investigated the survival of patients treated with nivolumab according to TPS and CPS. We also divided patients into three groups by CPS, as in the KEYNOTE-048 study, and compared the three groups, we also compared CPS to TPS.

Patients and Methods

Patients. The research period was from June 1, 2017–January 31, 2019. The participants were patients with R/M-HNC with a history of platinum-based chemotherapy who received nivolumab at our Institution. From the study cohort of Okamoto et al., five cases in which sample collection was not possible were excluded. Patients with no history of platinum-based chemotherapy, treated outside the health insurance system, or unwilling to participate in this study were also excluded. The follow-up period was from June 1, 2017– March 31, 2019.

The primary aim of this study was to compare OS based on the TPS and CPS for PD-L1 expression. Thus, we enrolled patients with R/M-HNC without considering the histopathological type and performed separate analyses for all the patients.

Administration of nivolumab. Nivolumab was administered by intravenous infusion of 3 mg/kg as per the package insert at 2-week intervals from June 1, 2017-August 31, 2018. After September 1, 2018, 240 mg per patient was infused intravenously at 2-week intervals. Image evaluation was performed following four to six cycles of therapy. The administration was continued until the appearance of overt progressive disease (PD) or unacceptable toxicity. However, the administration was continued even after the lesion progressed based on the clinical or imaging findings if the attending physician determined the clinical benefit to be high.

PD-L1 measurement. TPS was measured using Dako 28-8 antibody (Dako, Carpinteria, CA, USA). CPS was measured using 22C3 antibody (Agilent Technologies, Carpinteria, CA, USA). CPS was defined as the number of PD-L1-positive cells (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells ×100. At least 100 viable tumor cells had to be present for the specimen to be considered evaluable (6). Regarding PD-L1 measurement, other cancer guidelines do not specify tissue sampling sites or measurement timing. Therefore, wherever possible, the samples selected for measurement prior to the start of nivolumab treatment were taken when the tissue samples were abundant and there was no history of previous treatment.

Staging method. TNM classification was determined according to the Union for International Cancer Control version 7 criteria (7).

Study endpoints. The primary endpoint was the correlation between the TPS and CPS. Patients were divided into groups by TPS (1%, 5%, 10%, 20%, 30%, 40% and 50%). Similarly, patients were grouped by CPS values of <1, 1-<20, and ≥20. The correlation between TPS and CPS was calculated using Spearman’s rank correlation coefficient. Correlation coefficients of 0.7-1.0 were defined as representing strong correlation. The secondary endpoints were OS and progression-free survival (PFS). OS and PFS were evaluated using the Kaplan–Meier method, with an estimated hazard ratio (HR) and corresponding double-sided 95% confidence interval (CI). A Cox-proportional hazards model was used. Fisher’s exact test was used to compare the patient background factors between the groups. We performed statistical analysis using the log-rank test, with p<0.05 signifying a significant difference. The period for OS was defined as beginning with the initiation of nivolumab and ending with the date of last follow-up or death. The duration of PFS was defined as commencing from the onset of nivolumab administration and ending on the day when the overall response was determined to be PD or on the day of death from any cause, whichever occurred first.

Therapy evaluation was based on the Response Evaluation Criteria for Solid Tumors Guidelines Version 1.1 by a Board-certified HNC surgeon (8). In this study, the best overall response was determined to be stable disease when the overall response was not PD and was at least once stable disease or higher in cycle 4 and subsequent assessments. Pseudoprogression was defined as an initial assessment of PD followed by partial response or better at least once in the subsequent assessments. Overprogression was defined as an initial assessment of PD by Response Evaluation Criteria for Solid Tumors (9).

Statistical analysis and ethics. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for the R software environment for statistical computing and graphics (The R Foundation for Statistical Computing, Vienna, Austria). EZR is a modified version of R Commander designed to add statistical functions, which is frequently used in biostatistics (10). This study was approved by the Institutional Review Board (T2020-0403). We also adhered to the tenets of the Declaration of Helsinki and obtained written consent from all the patients for treatment.

Results

Background characteristics of the patients. Fifty-six patients received nivolumab at our Institution from June 1, 2017–March 31, 2019. We enrolled 52 out of the 56 patients who received nivolumab between June 1, 2017, and January 31, 2019, considering the follow-up period required to confirm the therapeutic effect. Five of them were referred from other facilities and were excluded because the CPS was not available, resulting in a total of 47 evaluable patients (Figure 1).

Figure 1.
Figure 1.

Study schema.

Age, sex, smoking history, alcohol usage history, Eastern Cooperative Oncology Group performance status (ECOG PS), TNM category, staging at the first visit, and histopathological type are presented in Table I. Patients ranged in age from 28 to 81 years, with an average of 61.8 years and a median of 65 years. Considering sex as a parameter, 41 men and six women were included. The primary tumor sites were the nasopharynx in three patients, oropharynx in 12, hypopharynx in 13, larynx in four, oral cavity in nine, sinuses in seven, salivary glands in two, and other sites in two patients. The patients had duplicate cancers that were recorded according to the primary site. The histological types were squamous cell carcinoma in the majority of patients (43/47, 91.5%). Thirty-five patients had ECOG PS of 0, the remaining patients having ECOG PS of 1 or 2. At the first visit, by the Union for International Cancer Control staging, tumors were stage IV in most patients (33/47, 70.2%) (Table II). Table III shows the distribution of patients by TPS and CPS.

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Table I.

Background characteristics of the study patients.

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Table II.

Union for International Cancer Control (UICC) classification of tumors in study patients.

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Table III.

Programmed cell death protein ligand 1 expression in patients using the tumor proportion score (TPS) and combined positive score (CPS).

Relationship between TPS and CPS. A strong positive correlation was found between the TPS and CPS, with a correlation coefficient of r=0.546 (Figure 2).

Figure 2.
Figure 2.

Correlation between tumor proportion score (TPS) and combined positive score (CPS). A strong correlation was found between TPS and CPS (correlation coefficient=0.546).

OS and PFS of the whole cohort. The median OS was 9.7 months (95% CI=6.3-13.0 months) considering the whole cohort of patients. The 1-year survival rate was 41.5% (95% CI=24.7-57.6%) (Figure 3). The median PFS for the whole cohort was 4.1 months (95% CI=1.6-6.6 months). The 1-year PFS rate was 20.1% (95% CI=1.9-51.9%) (Figure 4).

Figure 3.
Figure 3.

Overall survival (OS) for the whole patient cohort. The median OS was 9.7 months (95% confidence interval=6.3-13.0 months). The 1-year survival rate was 41.5% (95% confidence interval=24.7-57.6%).

Figure 4.
Figure 4.

Progression-free survival (PFS) for the whole patient cohort. The median PFS was 4.1 months (95% confidence interval=1.6-6.6 months). The 1-year PFS rate was 20.1% (95% confidence interval=1.9-51.9%).

Relationship between OS and PD-L1 expression by TPS and CPS. Using a cut-off for TPS of 40% as used by Okamoto et al. (4), the median OS was 8.5 months (95% CI=4.7-12.3 months) and the 1-year survival rate was 25% (95% CI=9-46%). In contrast, when the TPS was 40% or higher, the median OS was significantly better (not reached), and the 1-year survival rate was 71.4% (95% CI=39.8-88.5%) (p<0.05) (Figure 5A).

Figure 5.
Figure 5.

A: Overall survival (OS) according to the tumor proportion score (TPS). With a of TPS <40%, the median OS was 8.5 months (95% confidence interval=4.7-12.3 months). The 1-year survival rate was 25% (95% confidence interval=9-46%). In contrast, with a TPS ≥40%, the median OS was not reached, and the 1-year survival rate was 71.4% [95% confidence interval (CI)=39.8-88.5%]. This was a significant difference (p<0.05). B: OS according to the combined positive score (CPS). For CPS <1, the median OS was 9.0 months (95% CI=7.8-10.2 months) and the 1-year survival rate is 20% (95% CI=0.8-58.2%). With CPS ≥1 and <20, the median OS was 8.3 months (95% CI=2.9-13.8 months) and the 1-year survival rate was 42.8% (95% CI=19.1-64.8%). With CPS ≥20 and above, the median OS was 12 months (95% CI=4.5 months-not reached) and the 1-year survival rate was 47.5% (95% CI=19.9-71.0%). There was no clear significant difference in OS between those with CPS <1 and ≥20 (p=0.301).

When the CPS was <1, the median OS was 9.0 months (95% CI=7.8-10.2 months) and the 1-year survival rate was 20% (95% CI=0.8-58.2%). When the CPS was ≥1 and <20, the median OS was 8.3 months (95% CI=2.9-13.8 months) and the 1-year survival rate was 42.8% (95% CI=19.1-64.8%). When the CPS was 20 and above, the median OS was 12 months (95% CI=4.5 months-not reached) and the 1-year survival rate was 47.5% (95% CI=19.9-71.0%). These differences were not significant (p=0.301) (Figure 5B). Although not shown in the Figure, there was no significant difference in the OS on comparing CPS <1 and ≥1 (p=0.42).

Relationship between PFS and PD-L1 expression by TPS and CPS. When the TPS was <40%, the median PFS was 2.5 months (95% CI=1.4-3.6 months) and the 1-year survival rate was 24.9% (95% CI=10.8-42.0%). In contrast, when the TPS was 40% or above, the median PFS was not reached, and the 1-year PFS rate was 71.4% (95% CI=39.8-88.5%) (Figure 6A). When the CPS was <1, the median OS was 9.0 months (95% CI=7.8 -10.2 months) and the 1-year PFS rate was 20% (95% CI=0.8-58.2%). When the CPS was ≥1 to <20, the median PFS was 3.8 months (95% CI=1.7-5.7 months) and the 1-year survival rate was 32.8% (95% CI=13.1-54.2%). And finally, when the CPS was ≥20, the median PFS was not reached (95% CI=1.5 months-not reached) with a 1-year PFS rate of 51.9% (29.1-70.6%). There was no significant difference between the PFS when the CPS was <1 and CPS was >20 (p=0.223) (Figure 6B). Although not shown in the Figure, there was no significant difference in the PFS on comparing CPS <1 and ≥1 (p=0.316).

Figure 6.
Figure 6.

A: Progression-free survival (PFS) according to the tumor proportion score (TPS). For TPS <40%, the median PFS was 2.5 months (95% CI=1.4-3.6 months] and the 1-year survival rate was 24.9% (95% CI=10.8-42.0%). In contrast, for TPS>40%, the median PFS was not reached, and the 1-year PFS rate was 71.4% (95% CI=39.8-88.5%). B: PFS according to the combined positive score (CPS). For CPS<1, PFS was 9.0 months (95% CI=7.8-10.2 months) and the 1-year PFS rate was 20% (95% CI=0.8-58.2%). For CPS 1 to <20, the median PFS was 3.8 months (95% CI=1.7-5.7 months) and the 1-year survival rate was 32.8% (95% CI=13.1-54.2%). For CPS ≥20 and above, the median PFS was not reached (95% CI=1.5 months-not reached) with a 1-year PFS rate of 51.9% (29.1-70.6%). There was no significant difference in PFS between those with CPS <1 and ≥20 (p=0.223).

Clinical factors. We performed a multivariate analysis of the clinical factors related to the OS and PFS (Table IV). Multivariate analyses found significantly better OS (HR=0.19, 95% CI=0.05-0.76; p=0.019) and PFS (HR=0.23, 95% CI=0.07-0.72; p=0.011) for those with TPS ≥40%. Multivariate analysis also found poorer OS for patients with ECOG PS of 1-3 (HR=3.40, 95% CI=1.46-7.90; p=0.004). There was no significant difference in OS and PFS considering the sex, smoking and drinking habits, Union for International Cancer Control stage, platinum sensitivity and CPS.

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Table IV.

Multivariate analyses of the clinical factors associated with overall survival (OS) and progression-free survival (PFS) in patients with recurrent/metastatic head and neck cancer.

Discussion

Few reports have examined the predictors of nivolumab efficacy in patients with R/M-HNC. The main purpose of this study was to investigate the correlation between TPS and CPS in R/M-HNC immunotherapy and determine whether there is a change in OS or PFS owing to PD-L1 expression. In this study, we demonstrated a positive correlation between the TPS and the CPS. In addition, a significant prolongation of OS and PFS was observed in patients with TPS ≥40%. The results of this study suggest that TPS may be a useful biomarker. However, despite this correlation, CPS had no apparent association with OS and PFS. At this stage, TPS was considered to be a more effective predictor than CPS for efficacy of nivolumab treatment.

TPS represents PD-L1 expression solely of tumor cells, while CPS is an index additionally including PD-L1 expression in macrophages and lymphocytes. In small-cell lung cancer, Pedro et al. demonstrated equal predictive ability of TPS and CPS reporting a kappa coefficient of 0.85 among observers using both methods (11). There are reports that compared the rates of PD-L1 expression in other cancer types. 22C3 and SP263 were compared in gastric cancer and demonstrated a near-complete correlation [Pearson correlation coefficients of 0.965 (p<0.001) and 0.932 (p<0.001), respectively] (12). Currently, PD-L1 is used as a predictive biomarker for use of immune checkpoint inhibitors in patients with HNC. Neither TPS nor CPS have been reported to show a correlation similar to that of SP263 and 22C3. In this study, we have demonstrated for the first time that the TPS and CPS were strongly correlated (r=0.546). Previous studies have reported differences in TPS distribution between tumors and metastatic lymph nodes, showing the expression of PD-L1 changes depending on the site and time when the sample was collected. This heterogeneity in PD-L1 between tumors poses a challenge in treatment planning (13). From the positive correlation found between TPS and CPS in this study, it can be inferred that macrophages and lymphocytes have the same PD-L1 expression as the tumor cells in a single tissue. We believe this will help reveal tumor heterogeneity.

In this study, when the TPS was high (≥40%), the OS was significantly better (p=0.016) and the PFS also improved significantly (p=0.007). This finding was consistent with that reported by Okamoto et al. (4).

Most mechanisms of PD-L1 expression have been elucidated. PD1 is expressed in activated T-cells; when this protein binds to PD-L1 or PD-L2 expressed in cancer cells or antigen-presenting cells, it suppresses T-cell activation and allows cancer cells to evade the immune system (14). Antibody PD1 binds to PD1 on T-cells and inhibits the binding of PD-L1, and PD-L2 to block the suppression of signal transduction and activate T-cells, restoring and maintaining the antitumor effect (15, 16). Therefore, in theory, nivolumab is expected to be more effective under conditions of elevated PD-L1 expression. Furthermore, in gastric cancer, the CPS has been shown to be a more useful method of evaluation of PD-L1 expression than TPS as a predictive biomarker (17). The KEYNOTE-048 study classified CPS into <1, 1-<20, and ≥20, and reported a CPS of ≥1 as an effective predictor of response to pembrolizumab (5). However, our study did not demonstrate the usefulness of CPS as a biomarker. Comparing the three groups with CPS <1, 1-<20, and ≥20, OS and PS tended to be good for those with higher CPS; however, no significant difference was observed. In HNC, the CPS is divided into three groups based on the KEYNOTE-048 study to determine the therapeutic efficacy. However, Yamashita et al. demonstrated the effectiveness of CPS in gastric cancer (15), where it is subdivided into ≥5 and ≥10 for evaluation. In our study, there were 21 cases with CPS ≥20, and variations in TPS among those were observed. The median TPS for patients with a CPS of ≥20 was 40%. We consider that the effectiveness of CPS as a biomarker may be obtained by further subdividing and evaluating the CPS. Further classification and evaluation of CPS may help to define it as an effective biomarker.

There are no established and useful predictive biomarkers for nivolumab in clinical practice. In this study, TPS was considered to be a better predictor of therapeutic effect with nivolumab than CPS. Furthermore, in the group with TPS of 40% or more, it may be possible to show a greater antitumor effect. However, this is not just a recommendation for the continued administration of nivolumab. If a patient develops PD during treatment with nivolumab and PD-L1 expression is 40% or higher, switching to second-line treatment should be actively considered. It is important to use all available anticancer drugs to prolong OS.

This study has certain limitations. In this study, comparison used CPS groups, therefore, there was no strict direct correlation between TPS and CPS. Since this was a retrospective study from a single institution, large multicenter cohort studies are warranted in the future for establishing a standard assessment.

In conclusion, we investigated the PD-L1 expression and survival by comparing TPS and CPS in patients with R/M-HNC who received nivolumab. In this study, TPS and CPS were strongly correlated (r=0.546). To the best of our knowledge, this has not been reported in other studies on R/M-HNC. In addition, when TPS was high (≥40%), the OS was significantly better (p=0.016). The PFS also improved significantly when the TPS was high (≥40%) (p=0.07). However, there was no significant difference in OS and PFS between the groups with high a CPS (≥20). In considering treatment of patients with R/M-HNC with nivolumab, a high TPS (≥40%) may be useful as a predictor of prognosis and efficacy. Further studies are needed to determine whether CPS has any use as a biomarker.

Acknowledgements

The Authors would like to thank Editage (www.editage.com) for English language editing.

Footnotes

  • Authors’ Contributions

    Isaku Okamoto, Tatsuya Ito, and Kiyoaki Tsukahara designed the study. Tatsuya Ito wrote the main text of the article and prepared the figures. Tatsuya Ito, Isaku Okamoto, Hiroki Sato, Takuro Okada, Kunihiko Tokashiki, Gai Yamashita, Toshitaka Nagao, Hideaki Hirai, Natsuki Saigusa, and Kiyoaki Tsukahara were involved in the data collection. Isaku Okamoto and Tatsuya Ito performed the analyses. All the Authors discussed the results of the study, made comments on the article, and gave final approval of the version to be published.

  • Conflicts of Interest

    The Authors report no conflicts of interest.

  • Received January 12, 2022.
  • Revision received February 7, 2022.
  • Accepted February 8, 2022.

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PD-L1 Expression and Survival Rates Using TPS and CPS for Nivolumab-treated Head-and-Neck Cancer
TATSUYA ITO, ISAKU OKAMOTO, KUNIHIKO TOKASHIKI, HIROKI SATO, TAKURO OKADA, GAI YAMASHITA, TOSHITAKA NAGAO, HIDEAKI HIRAI, NATSUKI SAIGUSA, KIYOAKI TSUKAHARA
Anticancer Research Mar 2022, 42 (3) 1547-1554; DOI: 10.21873/anticanres.15628
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