Abstract
Background/Aim: The advent of immune checkpoint inhibitor (ICI) treatment has transformed the treatment of recurrent or metastatic head and neck cancer; however, nasopharyngeal carcinoma (NPC) has not been included in major phase III trials. The clinical outcomes of ICI for NPC in real-world practice remain to be fully elucidated. Patients and Methods: We retrospectively reviewed 23 patients with recurrent or metastatic NPC treated with nivolumab or pembrolizumab at 6 institutions from April 2017 to July 2021 and investigated the correlation of clinicopathological factors and immune-related adverse events with the effects of ICI therapy and the prognosis. Results: The objective response rate was 39.1% and the disease control rate was 78.3%. The median progression-free survival was 16.8 months and overall survival has not been reached. As with other treatment procedures, the efficacy and the prognosis tended to be better in EBER-positive cases than in EBER-negative cases. The rate of significant immune-related adverse events that necessitated discontinuation of treatment was only 4.3%. Conclusion: ICI monotherapy (e.g., nivolumab and pembrolizumab) was effective and tolerable for NPC in a real-world setting.
Nasopharyngeal carcinoma (NPC) is a rare epithelial carcinoma arising from the nasopharyngeal mucosa (1). According to the International Agency for Research on Cancer, in 2020, there were about 133,000 new cases of NPC, accounting for only 0.7% of all cancers diagnosed in 2020. However, approximately 85% of them occur in Asia, and the distribution is known to be uneven (2).
Previous reports on NPC have shown that latent infection of the nasopharyngeal mucosa with Epstein-Barr virus (EBV) is an important factor in its development (3, 4). It is also suggested that EBV-encoded small RNA (EBER), which can be detected by in situ hybridization (ISH), is highly sensitive in detecting the presence of EBV infection, and that nasopharyngeal carcinomas that express EBER have a better prognosis than those that do not express EBER (5, 6).
According to the WHO classification, NPC is pathologically classified as keratinizing (type I), nonkeratinizing (type II), or undifferentiated (type III), and the nonkeratinizing subtype is suggested to be associated with EBV infection (1, 4).
Recently, immune checkpoint inhibitors (ICI) have achieved breakthroughs in the treatment of recurrent metastatic head and neck cancer. The major phase III trials of ICI therapy in head and neck cancer, CheckMate141 and KEYNOTE048, did not include nasopharyngeal cancer, and reports of ICI therapy in NPC are limited (7-9). Therefore, we conducted the present study to clarify the efficacy of ICI therapy in the treatment of NPC in real-world clinical practice.
Patients and Methods
We retrospectively analyzed 23 patients with recurrent or metastatic NPC (RMNPC) who received nivolumab or pembrolizumab monotherapy for the first time at 6 institutions (Kyushu University Hospital, National Hospital Organization Kyushu Cancer Center, Fukuoka University Hospital, Hamanomachi Hospital, Saga University Hospital and Kitakyushu Municipal Medical Center) from April 2017 to July 2021. The observation period ended on May 31, 2022. Patients were pathologically diagnosed with NPC before starting the first treatment.
Medical records were reviewed for the following characteristics: age when ICI therapy was started, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS) prior to the use of ICIs, histological type, EBV status, TNM classification of NPC 8th edition at the time of first visit and start of ICIs, therapies prior to starting ICIs, the PD-L1 expression as the combined positive score (CPS), the number of chemotherapy lines, the type of regimen: nivolumab or pembrolizumab monotherapy, duration of ICI administration, immune-related adverse events (irAEs), post-ICI salvage chemotherapy, and the date of the last follow-up visit or death.
Biopsied or surgically resected formalin-fixed paraffin embedded tumor tissues were used for PD-L1 immunohistochemical staining (IHC) and in situ hybridization for EBV-encoded small nuclear RNA (EBER). In situ hybridization for EBER was carried out using the Inform EBER Probes (800-2842, Ventana Medical Systems, Roche Diagnostics GmbH, Mannheim, Germany) to analyze EBV expression. IHC for PD-L1 was performed using a PD-L1 IHC 22C3 pharmDx assay according to manufacturer’s instructions. The CPS was determined as the total number of PD-L1-stained cells (tumor cells, lymphocytes, macrophages), divided by the total number of viable tumor cells, multiplied by 100.
Nivolumab was administered at a dose of 3 mg/kg body weight every 2 weeks at first, and then administered at a fixed dose of 240 mg every 2 weeks, according to the change in guidelines approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) in August 2018.
Pembrolizumab was administered at a dose of 200 mg every 3 weeks or at a dose of 400 mg every 6 weeks. ICI treatment was continued until the judgment of progressive disease (PD), intolerable adverse events, or a poor general condition.
The treatment response was assessed every 2-3 months by computed tomography (CT) or magnetic resonance imaging (MRI), in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) (10). Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (11).
To evaluate the efficacy of ICI treatment for NPC, we calculated overall survival (OS): time from the first cycle of ICI therapy to death or last follow-up visit; and progression-free survival (PFS): time from the first cycle of ICI therapy to PD or last follow-up visit. The objective response rate (ORR) was defined as the percentage of patients with a complete or partial response (CR or PR, respectively) as the best overall response (BOR); and the disease control rate (DCR) was defined as the percentage of patients with a CR, PR, or stable disease (SD). We also analyzed whether the expression of EBER, the CPS, occurrence of irAE, and palliative chemotherapy after ICI therapy are factors that influence the efficacy of ICIs and the prognosis.
We used Fisher’s exact test for comparisons between two groups. OS and PFS were calculated using the Kaplan-Meier method. The log-rank test was used to test for statistical significance in the subgroup analysis. p-Values of <0.05 were considered to indicate statistical significance. Data analyses were carried out using the JMP Statistical Discovery software program (ver. 16; SAS, Cary, NC, USA).
Results
Patient characteristics. The characteristics of 23 patients with RMNPC who received ICI therapy are shown in Table I. The median age at the initiation of ICI therapy was 56 years (range=37-79 years of age) and there were 19 males and 4 females. Prior to the use of ICIs, one (4.3%) patient had an ECOG PS score of two, one (4.3%) patient had PS one, and the other 21 patients had PS zero. Five (21.7%) patients had keratinizing carcinoma, and 18 (78.3%) had nonkeratinizing carcinoma. Nineteen patients were examined for the expression of EBV; 16 (84.2%) were EBER-positive, whereas three (15.8%) were EBER-negative. The CPS was also examined in 21 patients; two (9.5%) showed a score of <1, five (23.8%) patients had a score of ≥1 to <20 and 14 (66.7%) patients had a score of ≥20. Radical chemoradiotherapy (CRT) was performed prior to ICI therapy in 22 (96.3%) patients. In eight of these cases, induction chemotherapy (IC) was administered before CRT. Twenty (87.0%) patients received ICI therapy as the first systemic therapy after the recognition of RMNPC. The regimens administered for RMNPC prior to ICI therapy included the EXTREME regimen (platinum-fluorouracil-cetuximab), weekly paclitaxel and cetuximab (PTX+Cet), and tegafur-gimestat-otastat potassium (S-1). Eighteen (78.3%) patients received nivolumab monotherapy and five (21.7%) patients received pembrolizumab monotherapy.
Patient characteristics.
Although the median duration of ICI therapy was 9.9 months (range=1.4-35.5 months), nine (39.1%) patients continued ICI therapy for >1 year, and three (13.0%) patients continued ICI therapy for over two years. At the time of cut-off, death had occurred in nine (39.1%) patients, and three (13.0%) patients were continuing ICI therapy. One (4.3%) patient had discontinued ICI therapy because of irAEs. A total of 13 (56.5%) patients received chemotherapy after ICI therapy, among whom four patients received PTX+Cet, four received S-1, 3 patients received PTX+Cet and S-1, one patient received PTX and S-1, and one patient received only PTX. Two patients received conversion surgery (neck dissection and abdominal lymphadenectomy). In two cases, ICI treatment resulted in a CR, and treatment was terminated at the patient’s request.
irAEs. The irAEs that occurred in this study are shown in Table II. Five patients experienced adverse events of any grade, with grade 3 hypoadrenocorticism in one patient, grade 2 hypoadrenocorticism in two patients, grade 3 encephalitis in one patient, and grade 2 hypothyroidism in one patient. The administration of ICIs was stopped because of encephalitis.
Immune-related adverse events occurring in this study.
The analysis of CPS and clinicopathological factors. The association between the expression of EBER, CPS, occurrence of irAEs, and histological type were compared (Table III). In agreement with previous reports, the proportion of nonkeratinizing carcinoma cases tend to be higher in EBER-positive cases than in EBER-negative cases, but there was no correlation between EBER, CPS, and irAEs.
Association between combined positive score (CPS) and clinicopathological factors.
Efficacy and prognosis. The best therapeutic response was a CR in four patients (17.4%), PR in five patients, SD in nine patients, and PD in five patients. Thus, the ORR of all patients was 39.1% and the DCR was 78.3%.
The 1-year survival rate of all patients was 77.8%, and the 2-year OS rate was 62.2%. The median of OS has not been reached. The median PFS of all patients was 16.8 months (95%CI=3.7-25.5), and the 1-year PFS rate was 52.2% (Figure 1A and B).
The Kaplan-Meier analysis for overall survival (OS) (A), progression-free survival (PFS) (B) in all 23 nasopharyngeal carcinoma patients and OS (C), PFS (D) in patients according to the expression of EBV-encoded small RNA (EBER). The 1-year OS rate of all patients was 77.8%, and the 2-year OS rate was 62.2% (A). The median of OS has not been reached. The median PFS of all patients was 16.8 months, and the 1-year PFS rate was 52.2% (B). EBER-positive patients had better PFS in comparison to EBER-negative patients (p=0.039) (D). PFS tended to be preserved in the high CPS group, but no significant difference was observed (p=0.078) (F). Among patients who completed ICI therapy, those who received palliative chemotherapy after ICI therapy tended to have better OS after the initiation of ICI therapy; however, the difference was not statistically significant (p=0.44) (G). No significant difference was found between the occurrence of irAEs and the prognosis (H, I).
The analysis of the association between EBER and the prognosis in these patients revealed that EBER-positive cases showed significantly better PFS (Figure 1D, p=0.039) and tended to have better OS (Figure 1C, p=0.12). In EBER-positive/negative cases, ORR and DCR were 50.0%/33.3% and 81.3%/66.7%, respectively.
When patients were classified into the low CPS group (<20) and the high CPS group (≥20), OS and PFS tended to be preserved in the high CPS group; however, the difference was not statistically significant (Figure 1E and F, p=0.56 and p=0.078, respectively).
Of the 13 patients who received palliative chemotherapy after ICI therapy, the DCR was 36.4% in the 11 patients for whom the evaluation of treatment efficacy was possible. Although there was no significant difference, those who received palliative chemotherapy after ICI therapy tended to have better OS from the initiation of ICI therapy among patients who completed ICI therapy (Figure 1G, p=0.44).
The association between the occurrence of irAEs and the effectiveness and prognosis of ICI therapy were analyzed, but no significant differences were found (Table IV, Figure 1H and I).
Best therapeutic respose according to clinicopathological valuables.
The effectiveness of ICI therapy was comparable between the ICI regimens (nivolumab or pembrolizumab) (Table III).
The association between the best therapeutic response and clinicopathological variables is shown in Table III. There was no correlation between them.
Discussion
This is the largest study in Japan to examine the effect of ICI therapy on nasopharyngeal carcinoma in clinical practice. Hanai et al., Sato et al., Sato et al., and Kim et al. previously reported real-world data on ICI therapy in NPC, and compared to those, the ORR and DCR of our study was comparable or better (Table V) (12-16). Additionally, it is reported that the OS is approximately 15.7-19.3 months and the PFS is approximately 7.6-8.0 months in RMNPC patients treated with systemic chemotherapy. The results in the present report are more favorable in comparison to these previous reports (17). Recently, effective chemotherapy for RMNPC has been reported as FP (5-FU+platinum), GP (gemcitabine + platinum), TP (taxane+platinum), and multi-agent therapy including platinum agents, such as triple therapy (1, 18). In the phase III study on the efficacy of GP and FP therapy as 1st line treatment reported by Hong et al., the 1-year OS rates were 79.9% and 71.8%, respectively, and the median PFS was 7.0 and 5.6 months (19). In comparison to these reports, the 1-year OS in our study was comparable and the median PFS in our study was better. These results indicate that ICI monotherapy is also effective for NPC.
Immune checkpoint inhibitor (ICI) studies for recurrent or metastatic nasopharyngeal carcinoma (RMNPC).
As severe AEs often disrupt the continuation of treatment and lead to death, the frequency of AEs is also important when selecting treatment. Zhang et al. reported that among patients receiving GP and FP therapy, grade ≥3 treatment-related AEs were observed in 36% and 43% of patients, respectively (20). In real-world clinical practice, chemotherapy [e.g., PTX+Cet and EXTREME regimen (5-FU+plutinam+Cet)] may be used as it is used in the treatment of other recurrent or metastatic head and neck cancers. The frequency of grade ≥3 AEs in patients receiving these regimens has been reported to be 18.4-57% in patients receiving PTX+Cet (21-23) and 42-83% in patients receiving EXTREME (8, 22, 24). In contrast, AEs were clearly less frequent in this study. In addition, pembrolizumab with chemotherapy has been reported to cause grade ≥3 AEs in 20-85% of patients, which is more common than the rate observed in patients treated with pembrolizumab monotherapy (8, 25). Thus, considering the low frequency and severity of AEs, we regard ICI therapy as a useful treatment that can be better tolerated by patients in a poor general condition and older patients in comparison to other chemotherapy regimens.
There have been no previous reports regarding the association with EBER and the effect of ICI therapy on RMNPC in a real-world setting. This study showed that EBER-positive cases respond better to ICI therapy, which may be a factor in choosing ICI monotherapy. Economopoulou et al. reported a correlation between ORR to pembrolizumab therapy and a decrease in plasma EBV DNA levels after immunotherapy (16). Therefore, EBV-related RMNPC cases can be considered for ICI treatment since they are more likely to benefit from ICI therapy.
There are few reports on CPS for ICI therapy in RMNPC, and Chan et al. reported no impact on OSS or ORR for PDL-1 CPS ≥1 in the KEYNOTE-122 phase 3 study (26). There are no other reports on CPS for ICI therapy in RMNPC in the real world, and this report is the first. Also, there have also been no reports on high CPS groups, such as the group with CPS ≥20, as was reported in this study. Although no significant difference in the relationship between CPS and the prognosis was found in this study, both OS and PFS tended to be better in the high CPS group than in the low CPS group, and a significant difference could be obtained by increasing the number of cases and following them for a longer period. Alternatively, although the patients were classified into two groups on the CPS in the present study, if absolute CPS values were obtained, cutoff values associated with the prognosis may be found. Also, since there are many inflammatory cells in the nasopharyngeal tissue, which may affect the CPS, it may be necessary to establish new criteria for evaluating PD-L1 IHC to determine the correlation with the therapeutic efficacy of ICI therapy in NPC.
Our group previously reported that palliative chemotherapy with/without Cet after nivolumab treatment might be useful in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (27). There have been no reports on the benefit of palliative chemotherapy in ICI therapy for RMNPC. Our study also showed that palliative chemotherapy after ICI therapy might have a beneficial effect on RMNPC, although this study did not show a statistically significant benefit of palliative chemotherapy after ICI therapy. Given the large proportion of cases with ongoing treatment, the prognosis should be reexamined after a longer follow-period up and larger study population.
There have been no previous reports on the occurrence of irAEs and the efficacy of ICI therapy in RMNPC in a real-world setting. Although there have been many reports on the positive association between the occurrence of irAEs and the efficacy of ICI therapy in various carcinomas, including head and neck squamous cell carcinoma, we found no association in this study (28). However, the frequency of irAEs in this study was lower in comparison to other reports (Table V), and it is necessary to analyze a larger study population.
In this study, nivolumab was used more frequently than pembrolizumab. This is because nivolumab was started earlier, and since the introduction of pembrolizumab based on KEYNOTE-048, nivolumab is often chosen for platinum-resistant cases, and pembrolizumab monotherapy or in combination therapy is chosen for other cases according to the CPS. Therefore, it is possible that efficacy could differ between pembrolizumab-treated and nivolumab-treated cases; however, in the present study, the efficacy was comparable (Table IV). Further studies with a larger population are needed to compare the efficacy of pembrolizumab and nivolumab in RMNPC.
The present study is associated with several limitations. First, this was a retrospective observational study, and there was no control group. In addition, this was a multi-center observational study, and the choice of regimen and the decision of whether to continue the drug was made by each physician based on the patient’s condition and intention, which may not necessarily be constant. Second, this study only included cases treated with ICI monotherapy. Combination chemotherapy was excluded due to the small number of cases and the short follow-up period.
Conclusion
ICI monotherapy (e.g., nivolumab or pembrolizumab) was an effective and tolerable treatment for RMNPC in a real-world setting.
Acknowledgements
The Authors thank all clinicians for their involvement and contribution to the study and Brian Quinn (Japan Medical Communication: www.japan-mc.co.jp) for English language editing.
Footnotes
Authors’ Contributions
RY and TN substantially contributed to the study conceptualization. TT, MT, AT, MY and KT were involved in data acquisition. TN and MM significantly contributed to data analysis and interpretation. TM wrote the manuscript text and prepared the figures. All Authors critically reviewed and revised the manuscript draft and approved the final version for submission.
Conflicts of Interest
The Authors declare no conflicts of interest associated with this manuscript.
- Received December 14, 2022.
- Revision received December 21, 2022.
- Accepted December 22, 2022.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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