Research ArticleClinical Studies
Open Access

Pembrolizumab Monotherapy Versus Pembrolizumab Plus Chemotherapy in Patients With Head and Neck Squamous Cell Carcinoma

MIOKO MATSUO, MUNEYUKI MASUDA, MORIYASU YAMAUCHI, MASAHIKO TAURA, KAZUKI HASHIMOTO, RYUNOSUKE KOGO, RINA JIROMARU, TAKAHIRO HONGO, TOMOMI MANAKO and TAKASHI NAKAGAWA
In Vivo September 2023, 37 (5) 2188-2196; DOI: https://doi.org/10.21873/invivo.13318

Abstract

Background/Aim: Pembrolizumab monotherapy and pembrolizumab with chemotherapy (combination therapy) are standard treatments for recurrent and metastatic head and neck squamous cell carcinoma (R/M-HNSCC). This study aimed to explore which of the two, pembrolizumab monotherapy or combination therapy is superior for long-term use. Patients and Methods: Participants of the study were 139 patients with histologically confirmed squamous cell carcinoma who had been treated with pembrolizumab monotherapy or combination therapy at the Kyushu University and related facilities. We analysed differences regarding long-term survival rate and adverse events (AEs) between the pembrolizumab monotherapy and combination therapy groups. Results: The overall 2-year progression-free survival and 2-year overall survival were 28.6% and 41.8%, respectively; these results were not significantly different between the two groups. Patients in the monotherapy group with AEs had a significantly better prognosis than those without AEs (in both the monotherapy and combination therapy groups). In the combination therapy group, there was no difference in prognosis between those with AEs and those without AEs (p=0.636). Conclusion: Considering the treatment of R/M-HNSCC from a long-term perspective, we identified that it is better to use pembrolizumab as monotherapy than to use it in combination with chemotherapy. Combination therapy did not improve prognosis; moreover, it can also cause additional adverse effects.

Key Words:

Head and neck squamous cell carcinoma (HNSCC) arises from the mucosa of the oral cavity, nasal or paranasal cavity, pharynx, and larynx (1). Most patients present with progressive disease (2). Locally advanced HNSCC recurs or metastasizes in approximately 50% of patients within two years of initial treatment, even with aggressive multimodality therapy (2, 3). The prognosis of patients with recurrent and metastatic HNSCC (R/M-HNSCC) is poor, with a median survival time of 4-5 months (4).

There are no surgical or radiotherapeutic treatment options for R/M-HNSCC, and the principal treatment primarily consists of systemic pharmacotherapy (2). The pharmacotherapy used until recently involved cytotoxic anticancer agents and molecular-targeted agents, resulting in minor improvements in the prognosis of R/M-HNSCC patients (2, 5); however, transient or cumulative adverse events often necessitate suspension or reduction of treatment. Disruption of treatment often results in a decreased quality of life and a reduced ability to eradicate tumours; therefore, long-term efficacy of systemic pharmacotherapy was not expected (2, 5-7).

Recently, the mean life expectancy of patients with R/M-HNSCC has markedly increased due to introduction of immune checkpoint inhibitors (ICIs) (2, 8, 9). Nivolumab and pembrolizumab are ICIs that are programmed cell death 1 (PD-1) monoclonal antibodies (10). In the CheckMate-141 (11) and KEYNOTE-048 (12) studies, nivolumab and pembrolizumab showed significant life-prolonging effects compared to traditional pharmacotherapy. Consequently, ICIs have been increasingly used in practice. Additionally, in a limited number of patients, ICIs are markedly beneficial for survival and have effects that are maintained for extended periods (13, 14).

In the KEYNOTE-048 study, patients with combined positive scores (CPS) for PD-L1, pembrolizumab monotherapy, and pembrolizumab combined with platinum/5-fluorouracil chemotherapy showed significantly improved overall survival (OS) (12). However, the long-term outcomes and AEs of the combination of pembrolizumab and cytotoxic anticancer agents are unknown. There have been few reports on the direct comparison of ICI monotherapy and ICI with cytotoxic anticancer agent combination therapy for any cancer (15), and there have been almost no reports comparing the efficacy and safety of pembrolizumab monotherapy and pembrolizumab with chemotherapy in patients with R/M-HNSCC (only one short study reported) (16).

We aimed to compare the long-term efficacy and safety of pembrolizumab monotherapy and pembrolizumab with chemotherapy (combination therapy) in patients with R/M-HNSCC. Several existing reports compare ICIs and conventional pharmacotherapy in patients with R/M-HNSCC (7, 10); however, this is the first long-term comparison between pembrolizumab monotherapy and combination therapy.

Patients and Methods

Patient cohort. We included patients with R/M-HNSCC and histological confirmation of squamous cell carcinoma, and who had received either pembrolizumab monotherapy or combination therapy between January 1, 2020, and December 31, 2022. Data were obtained from 139 patients treated at the Kyushu University, Kyushu Cancer Center, Saga University, and Fukuoka University. Retrospective analyses were performed. The observation period was until death or January 31, 2023, and the median duration was 10.8 months (range=0.4-35.9 months).

The study was approved by the Institutional Ethics Review Board of Kyushu University (No.22301-00) and each participating institution. The study was performed in accordance with the principles of the Declaration of Helsinki. Most subjects provided written informed consent; some refused to participate by opting out in response to an official announcement on the institution’s website.

Treatment. The patients were administered either (i) pembrolizumab monotherapy (200 mg, once every 3 weeks or 400 mg, once every 6 weeks) or (ii) combination therapy consisting of pembrolizumab, 5-FU (800 mg/m2/day, on days 1 to 5), and either cisplatin (80 mg/m2/day, on day 1) or carboplatin (area under the curve: 5/day, day 1). Combined chemotherapy was administered for 2-6 cycles (median: three cycles).

Endpoints and evaluation. The primary objective of this study was to verify the differences in long-term survival rates between two groups of R/M-HNSCC patients who were administered pembrolizumab monotherapy and combination therapy. The secondary objective was to ascertain the occurrence of AEs and their prognosis from a long-term perspective. The third objective was to ascertain whether CPS is an appropriate biomarker for pembrolizumab treatment.

OS was defined as the time from the start of pembrolizumab monotherapy or combination therapy until death. Progression-free survival (PFS) was defined as the time we started administering pembrolizumab monotherapy or combination therapy until either death or demonstration of progressive disease.

AEs were evaluated in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

The proportions of tumour cells that were PD-L1–positive tumour cells and PD-L1–positive immune cells were determined using PD-L1 protein immunostaining (22C3; PharmDx).

Statistical analysis. OS and PFS were calculated with the Kaplan-Meier method using JMP 14 software (SAS Institute, Cary, NC, USA). Differences were tested for statistical significance using the log-rank test for survival rate, Fisher’s exact test for nominal variables, and the Mann-Whitney U-test for continuous variables; differences were considered significant at p<0.05. Univariate and multivariate analyses of PFS and OS were performed using Cox proportional hazards models.

Results

Patient characteristics. Of the 139 patients with R/M-HNSCC, 87 were in the monotherapy group and 52 in the combination therapy group (Table I). The median age of the patients was 69 years in the monotherapy group (range=24-88 years) and 67 years in the combination therapy group (range=22-85 years). The proportion of patients with a performance status (PS) of 0-1 was 81.6% (71 of 87) in the monotherapy group and 86.5% (45 of 52) in the combination therapy group. The proportions with a CPS <1, 1-19, and ≥20 were 7.0% (6 of 87), 40.2% (35 of 87), and 47.1% (41 of 87), respectively, in the monotherapy group, and 13.5% (7 of 52), 44.2% (23 of 52), and 36.5% (19 of 52), respectively, in the combination therapy group. The number of patients who received combination therapy from first carcinoma onset was significantly higher than the number of those who started treatment for carcinoma recurrence (p<0.001).

View this table:
Table I.

Patient characteristics.

The proportion of patients who experienced AEs was 28.7% (25 of 87) in the monotherapy group and 42.3% (22 of 52) in the combination therapy group; however, the difference was not significant.

Treatment efficacy. The overall median PFS and OS were 5.0 and 16.9 months, respectively. The 2-year PFS and 2-year OS were 28.6% and 41.8%, respectively (Figure 1a and b). For patients with a CPS <1, 1-19, and ≥20, the 2-year OS rates were 26.3%, 45.0%, and 42.9%, respectively; however, this difference was not significant (Figure 2). The 2-year OS was significantly longer in the patients with AEs than those without AEs (55.9% vs. 33.7%, p=0.020; Figure 3).

Figure 1.
Figure 1.

Overall (a) and progression-free survival (b) curves for all 137 patients with recurrent and metastatic head and neck squamous cell carcinoma (R/M-HNSCC) who had received either pembrolizumab monotherapy or combination therapy.

Figure 2.
Figure 2.

Overall survival curves for all 137 patients with recurrent and metastatic head and neck squamous cell carcinoma (R/M-HNSCC) who had received either pembrolizumab monotherapy or combination therapy classified by combined positive score (CPS). PFS, Progression-free survival.

Figure 3.
Figure 3.

Overall survival curves for patients with adverse events (AEs) vs. without AEs. AE+, Patients with adverse events; AE-, patients without adverse events.

Effect of combination therapy on clinical outcomes. In the monotherapy and combination therapy groups, the 2-year OS rates were 46.1% and 33.1%, respectively; however, the difference was not significant (Figure 4). Patients in the monotherapy group and those with AEs had a significantly better prognosis than patients without AEs (with or without chemotherapy). In contrast, in the combination therapy group, there was no difference in prognosis between the participants with and without AEs (p=0.636; Figure 5).

Figure 4.
Figure 4.

Overall survival curves classified by monotherapy vs. combination therapy. CH-, Without combination chemotherapy; CH+; with combination chemotherapy.

Figure 5.
Figure 5.

Overall survival (OS) curves classified by monotherapy vs. combination therapy and with adverse events (AEs) vs. without AEs. In the combination therapy group, there was no difference in prognosis between the participants with and without AEs. AE+, Patients with adverse events; AE-, patients without adverse events; N.R: not reached; CH-, without combination chemotherapy, CH+, with combination chemotherapy.

The results of the univariate and multivariate analyses are presented in Table II. Additional chemotherapy (combination therapy) did not improve prognosis. Alternatively, patients who had a favourable PS or were AE+ had better prognoses in both the univariate and multivariate analyses.

View this table:
Table II.

Univariate and multivariate analyses of the clinical factors associated with overall survival.

Discussion

Our results showed that there is no long-term benefit to R/M-HNSCC receiving combination therapy. No difference in 2-year OS was found between pembrolizumab monotherapy and pembrolizumab with chemotherapy.

In the KEYNOTE-048 study, pembrolizumab monotherapy was compared to conventional pharmacotherapy. R/M-HNSCC patients with PD-L1-positive tumours had a significantly prolonged OS (CPS ≥1) that was non-inferior in the entire study population. When pembrolizumab with platinum formulation and 5-FU combination therapy was compared with conventional pharmacotherapy, OS was significantly prolonged with combination therapy in patients with PD-L1-positive tumours (CPS ≥1) and in the overall population (12). Regarding safety, pembrolizumab monotherapy was superior to pharmacotherapy in previous studies, and pembrolizumab with chemotherapy was approximately the same as pharmacotherapy in previous studies (12). Based on these results, both pembrolizumab monotherapy and pembrolizumab plus chemotherapy are recognised as appropriate systemic pharmacotherapies for patients with PD-L1–positive R/M-HNSCC (10, 12).

However, no direct assessment of whether pembrolizumab monotherapy or pembrolizumab plus chemotherapy is superior for treating R/M-HNSCC has been performed (10). When pharmacotherapy involving cytotoxic anticancer agents and molecular-targeted agents is administered for an extended time, the patient’s quality of life decreases due to cumulative toxicity, and it becomes necessary to reduce the dose or discontinue administration (6). This results in a decrease in anti-tumour efficacy; therefore, with the pharmacotherapy in previous use, even if temporary efficacy can be expected, long-term maintenance of efficacy is poor (6, 7). In contrast, patients who experience AEs with ICIs, that is, immune-related AEs, tend to have more favourable prognoses and can also be expected to show long-term maintenance of efficacy (13, 14). However, it is unknown whether patients undergoing therapy in combination with these agents, which have different properties, are observed for an extended period and suffer any disadvantages.

In this study, additional chemotherapy did not improve prognosis. Similar results to ours have already been reported. Matsumoto et al. compared pembrolizumab monotherapy and pembrolizumab with chemotherapy in patients with non-resectable and recurrent non-small cell lung cancer and found no significant difference in OS; in contrast, in patients with distant metastases, the benefits were greater with monotherapy (15). In addition, Nakano et al. administered pembrolizumab to patients with advanced head and neck cancer and found no difference in the 1-year OS between monotherapy and combination therapy (16). However, when the study was restricted to patients with distant metastases, the OS was significantly longer in the combination therapy group; therefore, it was concluded that if treatment is restricted to patients with distant metastases over a short treatment period (one year), combination therapy is advantageous (16). It is assumed that patients with distant metastases are more likely to respond to chemotherapy because they are native to chemotherapy.

Our results suggest from a long-term perspective that if pembrolizumab is used to treat patients with R/M-HNSCC, the efficacy of monotherapy will be approximately the same as that of combination therapy. This is supported by the findings in line with our second objective that was focused on AEs and prognosis. Although verification with all patients with R/M-HNSCC showed that patients with AEs had a better prognosis than patients without AEs, when verification was performed solely with patients in the combination therapy group, presence of AEs was not a factor for favourable prognosis. This finding is consistent with the report by Nakano et al. in which R/M-HNSCC patients who received pembrolizumab monotherapy and had AEs had a significantly more favourable prognosis than those without AEs; however, in the combination therapy group, there was no significant difference between the groups with and without AEs (16). The AEs associated with pharmacotherapy in previous use often lead to suspension or discontinuation of administration or dose reduction, and thus decreased antitumour efficacy. Alternatively, immune-related AEs due to ICIs are often associated with high antitumour efficacy, suggesting that the use of combined therapy cancels out the other.

Regarding our third objective, which was to ascertain the validity of the CPS as a biomarker, our findings also support the conclusion that both combination therapy and pembrolizumab monotherapy are appropriate for the treatment of patients with R/M-HNSCC. In this study, there was no difference in the proportions of patients with a CPS <1, 1-19, and ≥20 between the monotherapy and combination therapy groups. There was no significant difference in OS between these two groups. Our results suggest that if the CPS is low, combination therapy does not improve prognosis. Additionally, our study findings suggest that the CPS is an insufficient biomarker for choosing chemotherapy in combination with pembrolizumab. It was originally considered that PD-L1 expression in tumours has the potential to predict the clinical benefits of ICIs in patients with R/M-HNSCC (8, 12, 17); however, differences in cut-off levels, antibody assays, and inconsistencies in immune cell expression indicate that there is still debate about its use as a biomarker to predict ICI efficacy (8, 18, 19). Ito et al. reported that the tumour proportion score was a prognostic and predictive marker when nivolumab was administered to patients with R/M-HNSCC, but did not report the role of CPS as a biomarker (20). In addition, for all cancer types, the PD-L1 expression predictive value is not absolute, and PD-L1 expression status alone is insufficient to make treatment decisions. This has been confirmed where ICIs offer long-term clinical advantages in both PD-L1-positive and PD-L1-negative patients, and is therefore considered the better treatment option than the conventional pharmacotherapy (18, 19). It has also been reported that for the selection of patients with HNSCC who are likely to benefit from ICI treatment, it is preferable to determine the microsatellite instability and tumour mutation burden (21). Based on our results, we do not believe that CPS is an appropriate companion diagnostic test for pembrolizumab use in R/MHNSCC, and we believe that the use of chemotherapy according to CPS is of limited significance.

Study limitations. This study had two limitations: (i) the duration of the study was short and (ii) the number of subjects was small. We think that a larger number of cases and a longer observation period might rather result in the chemotherapy combination group having a predominantly poorer prognosis than pembrolizumab monotherapy. In future studies, we intend to investigate whether chemotherapy in combination with pembrolizumab is not only ineffective but also harmful for all patients with R/M-HNSCC.

Conclusion

Our results showed that combination therapy does not provide long-term benefit in R/M-HNSCC. With the possibility of prolongation of survival for patients with R/M-HNSCC if good treatment decisions are made, it has become more important to consider not only the temporary efficacy, but also long-term benefits of treatment options to the patient. From our study, we conclude that when considering the treatment of patients with R/M-HNSCC from a long-term perspective, if pembrolizumab is used, monotherapy may be more preferable than combination therapy. Additionally, the use of monotherapy may prevent the additional adverse effects that can occur with combination therapy.

Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing. We have no disclosures to declare and have received no financial support for this study.

Footnotes

  • Authors’ Contributions

    Mioko Matsuo: Writing (original draft), conceptualization, methodology, investigation; Muneyuki Masuda: Project administration; Moriyasu Yamauchi: Investigation; Masahiko Taura: Investigation; Kazuki Hashimoto: Validation; Ryunosuke Kogo: Validation; Rina Jiromaru: Data collection; Takahiro Hongo: Data collection; Tomomi Manako: Data collection; Takashi Nakagawa: Supervision.

  • Conflicts of Interest

    The Authors declare that there are no conflicts of interest.

  • Received May 8, 2023.
  • Revision received May 28, 2023.
  • Accepted June 19, 2023.

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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