Introduction

Oncology Letters

1792-1074 1792-1082

D.A. Spandidos

10.3892/ol.2024.14486

OL-28-2-14486

Articles

First‑line programmed cell death 1 inhibitor plus chemotherapy vs. standard treatment in patients with recurrent or metastatic oral squamous cell carcinoma: A retrospective cohort study

Cheng

Lei

1 Chai

Congna

2 Liu

Yingqi

1 Jiao

Jianjun

1Department of Stomatology, Handan Central Hospital, Handan, Hebei 056001, P.R. China 2Department of Oral and Maxillofacial Surgery, Handan Central Hospital, Handan, Hebei 056001, P.R. China

Correspondence to: Dr Congna Chai, Department of Oral and Maxillofacial Surgery, Handan Central Hospital, 59 North Congtai Road, Handan, Hebei 056001, P.R. China, E-mail: nagangguanlil@163.com

08 2024

03 06 2024

28 2

352

07082023 28022024

2024

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Programmed cell death 1 (PD-1) inhibitor revives the killing effect of immune cells to prevent tumor progression. The present study aimed to evaluate the efficacy and safety of first-line PD-1 inhibitor + chemotherapy vs. standard treatment in recurrent or metastatic (R/M) oral squamous cell carcinoma (OSCC). A total of 51 patients with R/M OSCC were reviewed and divided into the PD-1 inhibitor + chemotherapy (n=21) and standard treatment (n=30) groups based on their actual treatments. The results of the present study demonstrated that the objective response rate (52.4 vs. 36.7%, P=0.265) and disease control rate (81.0 vs. 70.0%, P=0.377) were numerically elevated in the PD-1 inhibitor + chemotherapy group compared with those in the standard treatment group; however, the results did not reach statistical significance. The progression-free survival (PFS) was numerically increased (without statistical significance) in the PD-1 inhibitor + chemotherapy group compared with that of the standard treatment group (P=0.057). Specifically, the PD-1 inhibitor + chemotherapy group and the standard treatment group exhibited a median [95% confidence interval (CI)] PFS duration of 6.7 (1.6–11.8) and 5.2 (3.4–7.0) months, respectively. In addition, the PD-1 inhibitor + chemotherapy group demonstrated increased overall survival (OS) compared with that of the standard treatment group (P=0.032). Specifically, the PD-1 inhibitor + chemotherapy group and the standard treatment group exhibited a median (95% CI) OS duration of 18.3 (11.9–24.7) and 10.3 (7.9–12.7) months, respectively. Furthermore, multivariate Cox regression analysis indicated that PD-1 inhibitor + chemotherapy was independently associated with improved PFS [hazard ratio (HR)=0.308, P=0.002] and OS (HR=0.252, P=0.003). In addition, the incidence of grade 3–5 adverse events (AEs) was relatively low in both groups and the incidence of any grade of each AE was not significantly different between groups (all P>0.050). In conclusion, the first-line PD-1 inhibitor + chemotherapy group had improved efficacy and comparable safety compared with those of the standard treatment in patients with R/M OSCC.

recurrent/metastatic oral squamous cell carcinoma programmed cell death 1 inhibitor chemotherapy treatment efficacy safety profile

Funding: No funding was received.

Introduction

Oral cavity cancer ranks sixth among the most commonly diagnosed cancer types; the most prevalent pathological subtype is oral squamous cell carcinoma (OSCC), accounting for >90% of all reported diagnoses (1–3). OSCC is associated with various factors, including tobacco consumption, alcohol abuse, exposure to human papillomavirus and genetic predisposition (4). Surgery is the preferred radical treatment option for OSCC. However, surgery in patients with recurrent/metastatic (R/M) OSCC has limited feasibility, and systemic therapy for palliation with active drugs, such as cetuximab, platinum, 5-fluorouracil and paclitaxel, is recognized as the standard treatment (5–7). Despite the use of standard treatment, a proportion of patients with R/M OSCC develop further tumor progression, resulting in a dismal prognosis of the disease (5). Therefore, the exploration of certain different treatment options with the potency to improve the treatment response or survival of patients with R/M OSCC is urgent.

Programmed cell death 1 (PD-1) inhibitor binds to the PD-1 checkpoint receptor to avoid its interaction with the programmed cell death ligand 1 (PD-L1), which restores the recognition and cytotoxic effect of immune cells, preventing the immune escape of tumor cells and inhibiting tumor progression (8,9). Available evidence suggests that the use of PD-1 inhibitors is effective for certain tumor types. In recent years, the efficacy of the PD-(L)1 inhibitors (including camrelizumab, nivolumab, pembrolizumab and durvalumab) in OSCC has been reported in several studies (10–14). For instance, a previous study has shown that nearly 60% of patients with recurrent/unresectable/metastatic OSCC treated with pembrolizumab achieve objective response (10). An additional study has revealed that the 1-year progression-free survival (PFS) rate is 25.4% in nivolumab-treated patients with R/M OSCC (11). Another study showed that durvalumab was able to achieve numerically higher 12-, 18- and 24-month survival rates compared to standard of care in R/M head and neck squamous cell carcinoma (HNSCC) (lacking statistical significance) (13). However, certain patients do not have a durable clinical benefit and the efficacy of the PD-1 inhibitors can be improved by rational combination with other therapies, which results in overcoming potential resistance (10,11,15–18). To date, only one study has suggested that PD-1 inhibitor combined with concurrent chemoradiotherapy treatment is able to achieve satisfactory efficacy [median overall survival (OS), 19 months] for Chinese patients with R/M HNSCC (19). However, the previous study is single-arm and the potential of PD-1 inhibitor + chemotherapy in Chinese patients with R/M OSCC requires further exploration (19).

In this light, the present study intended to assess the efficacy and safety of PD-1 inhibitors (pembrolizumab, camrelizumab and nivolumab) + chemotherapy as first-line treatment compared with the standard treatment in Chinese patients with R/M OSCC.

Materials and methods <sec> <title>Study population and treatment

In the present retrospective cohort study, 51 patients with R/M OSCC who were treated with PD-1 inhibitor + chemotherapy or standard treatment as the first-line treatment from August 2020 to February 2023 were included. The inclusion criteria were the following: i) Patients diagnosed as R/M OSCC by histopathology; ii) age >18 years; iii) patients who received PD-1 inhibitor + chemotherapy or standard treatment as the first-line treatment; iv) patients who had at least one clinical response result and follow-up data. If the patients had active autoimmune disease with serious lesions in important organs, such as the heart, lungs and kidneys, they were excluded. Females during pregnancy or lactation were also excluded. All patients received first-line PD-1 inhibitor + chemotherapy or standard treatment. The regimen details of PD-1 inhibitor + chemotherapy included the following: Pembrolizumab (200 mg per cycle) + platinum + 5-fluorouracil (5-FU); camrelizumab (200 mg per cycle) + platinum + 5-FU; and nivolumab (3 mg/kg every 2 weeks) + platinum + 5-FU. PD-1 inhibitors were continued until disease progression, death or toxicity-based intolerance. The chemotherapy lasted 4 to 6 cycles with a 3-week cycle and the conventional doses used were identical to those reported in a previous study (18). The regimen of standard treatment involved the following: Cetuximab + platinum + 5-FU; cetuximab + cisplatin + docetaxel; platinum + 5-FU; and cetuximab + paclitaxel. The doses of the drugs used were based on the Chinese Society of Clinical Oncology diagnosis and treatment guidelines for head and neck cancer 2018 (7).

Data collection and assessment

Age, gender, current or former smoking status, Eastern Cooperative Oncology Group performance status (ECOG PS) score (20), primary tumor location according to the 4th edition of the World Health Organization Classification of Head and Neck Tumors (21), disease status and PD-L1 combined positive score (CPS) were collected. PD-L1 expression was determined by immunohistochemical staining (22), and the staining was performed according to the manufacturer's protocol. Antibodies used included PD-L1 polyclonal antibody (cat. no. PA5-88105; dilution, 1:100; Thermo Fisher Scientific, Inc.) and goat anti-rabbit IgG (H+L) secondary antibody, HRP (cat. no. 31460; dilution, 1:100; Thermo Fisher Scientific, Inc.). The PD-L1 CPS was calculated via the following formula (23): PD-L1 CPS=No. PD-L1-stained cells (tumorcells, lymphocytes, macrophages)Total No. of viable tumor cells×100

PD-L1 CPS <1 was defined as PD-L1-negative (Fig. S1A), while PD-L1 CPS ≥1 was defined as PD-L1-positive (Fig. S1B). In addition, the clinical response results were collected and assessed via the response evaluation criteria in solid tumors version 1.1 (24). The disease progression or death statuses were obtained as well. In addition, adverse events (AEs) were recorded.

The objective response rate (ORR) and disease control rate (DCR) were calculated according to the clinical response results after 4 cycles (~2.8 months) of treatment. The PFS and OS rates were calculated based on the disease statuses and survival durations. PFS was defined as the time from the start of treatment in the study until disease progression or death of any cause; OS was defined as the time from the start of treatment in the study until any-cause death of any cause. AEs were graded via the Common Terminology Criteria for Adverse Events (v.5.0) (25).

Statistical analysis

SPSS v.26.0 (IBM Corp.) was used for data analyses. Student's t-test, the χ² test or Fisher's exact test were applied for comparisons as appropriate. Kaplan-Meier curves were plotted to illustrate PFS and OS of the groups and the log-rank test was used for statistical comparison. Enter-method multi-variable Cox regression analyses were performed to identify factors affecting PFS and OS in patients with OSCC, in which PD-1 inhibitor plus chemotherapy, age, male sex, current or former smoking, ECOG PS score, primary tumor location, and disease status were included in the analyses. P<0.05 was considered to indicate a statistically significant difference.

Results <sec> <title>Patient characteristics

The mean age of the PD-1 inhibitor + chemotherapy group and the standard treatment group was 59.9±11.9 years and 61.8±10.0 years (P=0.524), respectively. There were 17 (81.0%) males in the PD-1 inhibitor + chemotherapy group and 21 (70.0%) males in the standard treatment group (P=0.377). A total of 10 (47.6%), 1 (4.8%) and 5 (23.8%) patients in the PD-1 inhibitor + chemotherapy group had a history of surgery, chemotherapy and radiotherapy, respectively. In comparison, in the standard treatment group, 13 (43.3%), 8 (26.7%) and 12 (40.0%) patients had a history of surgery, chemotherapy and radiotherapy, respectively. In the PD-1 inhibitor + chemotherapy group, all 21 (100%) patients were rated as PD-L1 CPS ≥1, while in the standard treatment group, 8 (26.7%) and 9 (30.0%) patients were classified as PD-L1 CPS <1 and ≥1, respectively; the PD-L1 CPS status of the remaining 13 (43.3%) patients in that group was unknown (P<0.001). In addition, current or former smoking, primary tumor location, disease status and ECOG PS score did not exhibit any differences between the two groups (all P>0.050). The specific information is displayed in Table I.

Treatment information

In the PD-1 inhibitor + chemotherapy group, 14 (66.7%) patients, 4 (19.0%) patients and 3 (14.3%) patients received pembrolizumab + platinum + 5-FU, nivolumab + platinum + 5-FU and camrelizumab + platinum + 5-FU, respectively. In the standard treatment group, 20 (66.7%), 4 (13.3%), 5 (16.7%) patients and 1 (3.3%) patient were treated with cetuximab + platinum + 5-FU, cetuximab + cisplatin + docetaxel, platinum + 5-FU and cetuximab + paclitaxel, respectively (Table II).

ORR and DCR

The ORR was numerically elevated (without statistical significance) in the PD-1 inhibitor + chemotherapy group compared with that in the standard treatment group (52.4 vs. 36.7%, P=0.265). In addition, the DCR exhibited an elevated trend (lacking statistical significance) in the PD-1 inhibitor + chemotherapy group compared with that in the standard treatment group (81.0 vs. 70.0%, P=0.377; Fig. 1).

PFS and OS

The PFS exhibited a prolonged trend (lacking statistical significance) in the PD-1 inhibitor + chemotherapy group compared with that in the standard treatment group (P=0.057). In detail, the median [95% confidence interval (CI)] PFS duration of the PD-1 inhibitor + chemotherapy group and the standard treatment group was 6.7 (1.6–11.8) months and 5.2 (3.4–7.0) months, respectively. The 12-month PFS rate in the PD-1 inhibitor + chemotherapy group and in the standard treatment group was 38.5 and 8.1%, respectively. Furthermore, the 24-month PFS rate in the two groups was 14.4 and 4.0%, respectively (Fig. 2A).

The OS was prolonged in the PD-1 inhibitor + chemotherapy group compared with that in the standard treatment group (P=0.032). Specifically, the median (95% CI) OS duration of the PD-1 inhibitor + chemotherapy group and that of the standard treatment group was 18.3 (11.9–24.7) months and 10.3 (7.9–12.7) months, respectively. Furthermore, the 12-month OS rate of the PD-1 inhibitor + chemotherapy group and that of the standard treatment group was 68.2 and 30.6%, respectively, while the 24-month OS rate was 34.1 and 10.9% in the corresponding groups (Fig. 2B).

In addition, neither PFS (P=0.869; Fig. S2A) nor OS (P=0.834; Fig. S2B) was different among R/M OSCC patients with different primary tumor locations.

Subgroup analysis

In patients who received treatment between 2020 and 2022, PFS exhibited a prolonged trend (without statistical significance) in the PD-1 inhibitor + chemotherapy group in comparison with that in the standard treatment group (P=0.054; Fig. S3A). OS was prolonged in the PD-1 inhibitor + chemotherapy group compared to the standard treatment group (P=0.031; Fig. S3B). However, in patients who received treatment in 2023, neither PFS (P=0.918; Fig. S3C) nor OS (P=0.705; Fig. S3D) was different between the two groups.

Independent factors affecting PFS and OS

PD-1 inhibitor in addition to chemotherapy was independently associated with longer PFS [hazard ratio (HR): 0.308, P=0.002]. In addition, male sex (HR: 4.309, P=0.005) and a higher ECOG PS score (HR: 4.040, P=0.002) were independently related to reduced PFS. Whereas higher age, current or former smoking, primary tumor location in the gingiva (vs. tongue), mouth floor (vs. tongue), other locations (vs. tongue), metastatic disease only (vs. recurrent metastatic disease) and recurrent disease only (vs. recurrent metastatic disease) were not independently associated with PFS (all P>0.050) (Fig. 3). Furthermore, PD-1 inhibitor in addition to chemotherapy (HR: 0.252, P=0.003) and recurrent disease only (vs. recurrent metastatic disease; HR: 0.232, P=0.019) were independently associated with longer OS, whereas male sex (HR: 6.502, P=0.004) and higher ECOG PS score (HR: 4.871, P=0.003) were independently associated with reduced OS. However, higher age, current or former smoking, primary tumor location in gingiva (vs. tongue), mouth floor (vs. tongue), other locations (vs. tongue) and metastatic disease only (vs. recurrent metastatic disease) were not independent related factors for OS (Fig. 4).

AEs

The most common AEs of any grade in the PD-1 inhibitor + chemotherapy group were fatigue (42.9%), anemia (28.6%), neutropenia (28.6%), nausea (28.6%), leukopenia (23.8%) and liver dysfunction (23.8%). In addition, the incidence of grade 3–5 AEs in the PD-1 inhibitor + chemotherapy group was relatively low, including neutropenia (9.5%), fatigue (4.8%), anemia (4.8%), nausea (4.8%), leukopenia (4.8%) and liver dysfunction (4.8%). In the standard treatment group, fatigue (36.7%), nausea (33.3%), anemia (26.7%), diarrhea (26.7%), rash (26.7%), thrombocytopenia (23.3%), neutropenia (20%), leukopenia (20.0%), liver dysfunction (20.0%) and vomiting (20.0%) were common AEs of any grade. Grade 3–5 AEs in the standard treatment group included neutropenia (6.7%), fatigue (3.3%), nausea (3.3%), leukopenia (3.3%), liver dysfunction (3.3%), diarrhea (3.3%) and vomiting (3.3%). Overall, the incidence of each AE of any grade was not significantly different between the PD-1 inhibitor + chemotherapy and the standard treatment group (all P>0.050; Table III).

Discussion

Various studies have reported on the utilization of PD-1 inhibitors in patients with R/M HNSCC (26–28). For instance, a previous study revealed that patients with R/M HNSCC receiving nivolumab exhibited an ORR of 13.3%, which was superior to that noted in the standard therapy group (5.8%) (26). An additional study demonstrated that pembrolizumab caused a numerical elevation in the ORR (14.6 vs. 10.1%) compared with methotrexate, docetaxel or cetuximab following platinum drug treatment in patients with R/M HNSCC (28). However, the efficacy of the application of PD-1 inhibitor + chemotherapy lacked sufficient evidence. In the present study, the results did not demonstrate a statistically significant benefit of treatment response in patients with PD-1 inhibitor + chemotherapy compared to standard treatment as the first-line treatment in patients with R/M OSCC, which may be due to the relatively small sample size. However, the ORR (52.4 vs. 36.7%) and DCR (81.0 vs. 70.0%) were numerically elevated in patients with R/M OSCC treated with PD-1 inhibitor + chemotherapy compared with those receiving standard treatment. The potential explanations may be as follows: PD-1 inhibitor was assumed to potentiate the cytotoxic effect of chemotherapy on tumor cells by altering the tumor microenvironment (29–31), and to facilitate death of tumor cells through reviving the cytotoxic activity of T lymphocytes (32). Therefore, PD-1 inhibitor + chemotherapy achieved a numerically higher ORR and DCR in patients with R/M OSCC compared with those on standard treatment; however, the findings require further validation in large-scale studies. In addition, it is worth mentioning that although the salvage operation was an optimal choice for locally recurrent OSCC, certain patients were not suitable for salvage operation due to overload tumor burden or rejection of salvage operation for various reasons. Thus, for this population in the present study, conservative treatment was chosen. Furthermore, the treatment decision is made by the oncological board, which is based on the Chinese Society of Clinical Oncology guidelines (7) combined with the patient's condition and choice.

The application of PD-1 inhibitors has improved the survival profile of patients with HNSCC, including cancer of the hypopharynx, larynx, oral cavity and oropharynx (18,33,34). For instance, a previous study indicated that the OS was increased in patients with R/M HNSCC receiving pembrolizumab + chemotherapy (13.0 months) compared with those receiving cetuximab + chemotherapy (10.7 months) (18). An additional study suggested that nivolumab effectively improved the 24-month OS rate of patients with R/M HNSCC compared with that of patients treated with methotrexate, docetaxel or cetuximab (16.9 vs. 6.0%) (33). Another study found that PD-1 inhibitor in combination with paclitaxel and cisplatin achieved a 12-month PFS rate of 80.4% and 12-month OS rate of 94.1% in patients with locally advanced laryngeal and hypopharyngeal squamous cell carcinoma (34). In the current study, PFS indicated a numerically elevated trend and OS was prolonged in patients with R/M OSCC who underwent PD-1 inhibitor + chemotherapy compared with those who underwent standard treatment. In addition, PD-1 inhibitor + chemotherapy was independently related to higher PFS and OS of patients with R/M OSCC. The possible explanation may be as follows: Inhibition of PD-1 had a favorable anti-tumor effect and its combination with chemotherapy further impeded the progression of OSCC, contributing to improved survival (16). Consequently, the PD-1 inhibitor + chemotherapy combination was an independent factor for prolonged PFS and OS (vs. standard treatment) of patients with R/M OSCC. Of note, in comparison with previous studies (18,33), patients administered with PD-1 inhibitor + chemotherapy in the current study achieved a relatively longer OS, which may be explained by the following etiology: Clinically, PD-1 inhibitors are recommended for patients with PD-L1 CPS≥1 (35); in addition, all of the patients receiving PD-1 inhibitor + chemotherapy in the present study were classified as PD-L1 CPS≥1 and thus benefited more from the immunotherapy. It is interesting to note that male sex was independently associated with worse PFS and OS in the present study, which was consistent with a previous study (36).

In line with previous studies (18,37), fatigue, nausea, neutropenia and anemia were the most common AEs associated with PD-1 inhibitor + chemotherapy in the present study. Furthermore, fatigue, nausea, anemia, diarrhea and rush were the most common AEs in the standard treatment group of the current study, which was similar to the results noted in previous studies (18,38). More importantly, the incidences of all AEs did not vary between patients who received PD-1 inhibitor + chemotherapy and standard treatment. In addition, the majority of AEs in the present study were of grade 1-2; the incidence of grade 3–5 AEs was relatively low, indicating that the systematic toxicity of both PD-1 inhibitor + chemotherapy and standard treatment in patients with R/M OSCC was controllable.

Certain limitations were inevitable in the present study: First, the current retrospective study was conducted at a single center and it was difficult to avoid selection bias. Furthermore, this was a retrospective study; therefore, the documentation of AEs may have been inadequate, which may have potentially led to an underestimation of AEs in both groups. In addition, the present study had a relatively small number of enrolled patients and it was difficult to summarize useful information, such as the association of various tumor localizations with treatment response. Finally, the follow-up duration of the present study was not adequate and the findings required more verification in studies with a longer follow-up period.

In conclusion, the present study indicated that PD-1 inhibitor + chemotherapy achieved numerically elevated treatment response and was an independent factor for prolonged PFS and OS with comparable safety compared to standard treatment in patients with R/M OSCC. The findings suggest that PD-1 inhibitor + chemotherapy may serve as a potential first-line therapeutic regimen for patients with R/M OSCC. Further validation through multi-center randomized, controlled studies with a large sample size is necessary.

Supplementary Material

Supporting Data

Acknowledgements

Not applicable.

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

LC, CC, YL and JJ contributed to the study conception and design. Material preparation, data collection and analysis were performed by LC, CC and YL. The first draft of the manuscript was written by LC. LC, CC, YL and JJ commented on previous versions of the manuscript. YL and JJ confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

The Ethics Committee of Handan Central Hospital (Handan, China) gave approval for this study (approval date, 2023/02/10; no approval number was provided). Oral informed consent for analysis and publication of personal information was obtained from each patient via telephone. Besides, the PD-L1 IHC staining was performed for treatment purposes.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References 1

Xie

Shang

Oral cancer incidence, mortality, and mortality-to-incidence ratio are associated with human development index in China, 1990-2019

Biomed Res Int202264578402022

10.1155/2022/6457840

35800221

Rivera

Essentials of oral cancer

Int J Clin Exp Pathol811884118942015

26617944

Sarode

Maniyar

Sarode

Jafer

Patil

Awan

Epidemiologic aspects of oral cancer

Dis Mon661009882020

10.1016/j.disamonth.2019.100899

32605720

Chamoli

Gosavi

Shirwadkar

Wangdale

Behera

Kurrey

Kalia

Mandoli

Overview of oral cavity squamous cell carcinoma: Risk factors, mechanisms, and diagnostics

Oral Oncol1211054512021

10.1016/j.oraloncology.2021.105451

34329869

Chow

LQM

Head and neck cancer

N Engl J Med38260722020

10.1056/NEJMra1715715

31893516

Johnson

Burtness

Leemans

Lui

VWY

Bauman

Grandis

Head and neck squamous cell carcinoma

Nat Rev Dis Primers6922020

10.1038/s41572-020-00224-3

33243986

Chinese society of clinical oncology (CSCO) diagnosis and treatment guidelines for head and neck cancer 2018 (english version)

Chin J Cancer Res3184982019

10.21147/j.issn.1000-9604.2019.01.05

30996568

Bagchi

Yuan

Engleman

Immune checkpoint inhibitors for the treatment of cancer: Clinical impact and mechanisms of response and resistance

Annu Rev Pathol162232492021

10.1146/annurev-pathol-042020-042741

33197221

Tang

Chen

Long

Shi

Han

Wang

The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers

Front Immunol139644422022

10.3389/fimmu.2022.964442

36177034

Tao

Yang

Shang

Song

Efficacy and safety of pembrolizumab monotherapy for recurrent/unresectable/metastatic oral squamous cell carcinoma: A single-center study in China

J Oncol202272839462022

37261276

Yamakawa

Umeda

Yoshii

Mitsudo

Noguchi

Kusukawa

Katakura

Nakayama

Sasaki

Noguchi

Multicenter retrospective study of nivolumab for recurrent/metastatic oral squamous cell carcinoma

Oral Dis302472582022

10.1111/odi.14471

36519515

Xia

Zhu

Dou

Zhu

Dong

Wang

Sun

Zhao

Zhou

A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma

Nat Commun1353782022

10.1038/s41467-022-33080-8

36104359

Ferris

Haddad

Even

Tahara

Dvorkin

Ciuleanu

Clement

Mesia

Kutukova

Zholudeva

Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study

Ann Oncol319429502020

10.1016/j.annonc.2020.04.001

32294530

Hsieh

Borson

Tsagianni

Zandberg

Immunotherapy in recurrent/metastatic squamous cell carcinoma of the head and neck

Front Oncol117056142021

10.3389/fonc.2021.705614

34540672

Upadhaya

Neftelino

Hodge

Oliva

Campbell

Combinations take centre stage in PD1/PDL1 inhibitor clinical trials

Nat Rev Drug Discov201681692021

10.1038/d41573-020-00204-y

33177720

Meric-Bernstam

Larkin

Tabernero

Bonini

Enhancing anti-tumour efficacy with immunotherapy combinations

Lancet397101010222021

10.1016/S0140-6736(20)32598-8

33285141

Oliva

Spreafico

Taberna

Alemany

Coburn

Mesia

Siu

Immune biomarkers of response to immune-checkpoint inhibitors in head and neck squamous cell carcinoma

Ann Oncol3057672019

10.1093/annonc/mdy507

30462163

Burtness

Harrington

Greil

Soulières

Tahara

de Castro

JrPsyrri

Basté

Neupane

Bratland

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study

Lancet394191519282019

10.1016/S0140-6736(19)32591-7

31679945

Chen

Yan

Guo

Fan

Lan

Lai

Zhou

Huang

Initial analysis of the synergy of programmed cell death-1 (PD-1) inhibitor and concurrent chemoradiotherapy treatment for recurrent/metastatic head and neck squamous cell carcinoma patients

Radiat Oncol181092023

10.1186/s13014-023-02310-8

37403098

Oken

Creech

Tormey

Horton

Davis

McFadden

Carbone

Toxicity and response criteria of the eastern cooperative oncology group

Am J Clin Oncol56496551982

10.1097/00000421-198212000-00014

7165009

El-Naggar

Chan

JKC

Grandis

Takata

Slootweg

WHO classification of head and neck tumours

IARC Press

Lyon

2032602017

Cho

Sorensen

Choi

Feng

Kim

Choi

Georgsen

Dolled-Filhart

Emancipator

Meldgaard

Programmed death ligand 1 expression in paired non-small cell lung cancer tumor samples

Clin Lung Cancer18e473e4792017

10.1016/j.cllc.2017.04.008

28669849

Kulangara

Zhang

Corigliano

Guerrero

Waldroup

Jaiswal

Shah

Hanks

Wang

Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer

Arch Pathol Lab Med1433303372019

10.5858/arpa.2018-0043-OA

30028179

Schwartz

Litière

de Vries

Ford

Gwyther

Mandrekar

Shankar

Bogaerts

Chen

Dancey

RECIST 1.1-update and clarification: From the RECIST committee

Eur J Cancer621321372016

10.1016/j.ejca.2016.03.081

27189322

Freites-Martinez

Santana

Arias-Santiago

Viera

Using the common terminology criteria for adverse events (CTCAE-version 5.0) to evaluate the severity of adverse events of anticancer therapies

Actas Dermosifiliogr (Engl Ed)11290922021(In English, Spanish)

10.1016/j.ad.2019.05.009

32891586

Ferris

Blumenschein

JrFayette

Guigay

Colevas

Licitra

Harrington

Kasper

Vokes

Even

Nivolumab for recurrent squamous-cell carcinoma of the head and neck

N Engl J Med375185618672016

10.1056/NEJMoa1602252

27718784

de Sousa

Ferrarotto

Pembrolizumab in the first-line treatment of advanced head and neck cancer

Expert Rev Anticancer Ther21132113312021

10.1080/14737140.2021.1996228

34689660

Cohen

EEW

Soulieres

Le Tourneau

Dinis

Licitra

Ahn

Soria

Machiels

Mach

Mehra

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): A randomised, open-label, phase 3 study

Lancet3931561672019

10.1016/S0140-6736(18)31999-8

30509740

Xue

Gao

Gou

Yin

Wang

Zhang

Tang

Platinum-based chemotherapy in combination with PD-1/PD-L1 inhibitors: Preclinical and clinical studies and mechanism of action

Expert Opin Drug Deliv181872032021

10.1080/17425247.2021.1825376

32954856

Saleh

Khalifeh-Saleh

Kourie

Nasr

Chahine

Do immune checkpoint inhibitors increase sensitivity to salvage chemotherapy?

Immunotherapy101631652018

10.2217/imt-2017-0153

29370724

Melo-Alvim

Neves

Santos

Abrunhosa-Branquinho

Barroso

Costa

Ribeiro

Radiotherapy, chemotherapy and immunotherapy-current practice and future perspectives for recurrent/metastatic oral cavity squamous cell carcinoma

Diagnostics (Basel)13992022

10.3390/diagnostics13010099

36611391

Wakabayashi

Lee

Luh

Kuo

Chang

Yen

Development and clinical applications of cancer immunotherapy against PD-1 signaling pathway

J Biomed Sci26962019

10.1186/s12929-019-0601-2

31801525

Ferris

Blumenschein

JrFayette

Guigay

Colevas

Licitra

Harrington

Kasper

Vokes

Even

Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of checkMate 141 with analyses by tumor PD-L1 expression

Oral Oncol8145512018

10.1016/j.oraloncology.2018.04.008

29884413

Fang

Cao

Liu

PD-1 Inhibitors combined with paclitaxel (albumin-bound) and cisplatin for larynx preservation in locally advanced laryngeal and hypopharyngeal squamous cell carcinoma: A retrospective study

Cancer Immunol Immunother72416141682023

10.1007/s00262-023-03550-z

37804437

Cohen

EEW

Bell

Bifulco

Burtness

Gillison

Harrington

Lee

Leidner

Lewis

The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC)

J Immunother Cancer71842019

10.1186/s40425-019-0662-5

31307547

Asher

Veness

Smee

Goldstein

Gopalakrishna Iyer

Balasubramanian

Low

Palme

Gupta

Clark

Effect of age and gender in non-smokers with oral squamous cell carcinoma: Multi-institutional study

Oral Oncol1161052102021

10.1016/j.oraloncology.2021.105210

33618102

Hato

Khong

de Vries

Lesterhuis

Molecular pathways: The immunogenic effects of platinum-based chemotherapeutics

Clin Cancer Res20283128372014

10.1158/1078-0432.CCR-13-3141

24879823

Pontes

Garcia

Domingues

João Sousa

Felix

Amorim

Salgueiro

Mariano

Teixeira

Survival predictors and outcomes of patients with recurrent and/or metastatic head and neck cancer treated with chemotherapy plus cetuximab as first-line therapy: A real-world retrospective study

Cancer Treat Res Commun271003752021

10.1016/j.ctarc.2021.100375

33882378

Figure 1.

Clinical response in patients with recurrent or metastatic oral squamous cell carcinoma. DCR, disease control rate; ORR, objective response rate; PD-1, programmed cell death 1.

Figure 2.

Survival of patients with R/M OSCC. (A) The PFS indicated a numerically elevated trend (lacking statistical significance) in patients with R/M OSCC receiving PD-1 inhibitor + chemotherapy compared with those receiving standard treatment. (B) Patients with R/M OSCC who were treated with PD-1 inhibitor + chemotherapy exhibited better OS compared with those who were treated with standard treatment. R/M, recurrent or metastatic; OSCC, oral squamous cell carcinoma. PFS, progression-free survival; PD-1, programmed cell death 1; OS, overall survival.

Figure 3.

Independent factors for PFS of patients with recurrent or metastatic oral squamous cell carcinoma. PFS, progression-free survival; PD-1, programmed cell death 1; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio.

Figure 4.

Independent factors for OS of patients with recurrent or metastatic oral squamous cell carcinoma. OS, overall survival; PD-1, programmed cell death 1; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio.

Table I.

Clinical features of patients with oral squamous cell carcinoma.

Item	PD-1 inhibitor plus chemotherapy (n=21)	Standard treatment (n=30)	P-value
Age, years	59.9±11.9	61.8±10.0	0.524
Male sex	17 (81.0)	21 (70.0)	0.377
Current or former smoker	16 (76.2)	20 (66.7)	0.463
History of surgery	10 (47.6)	13 (43.3)	0.783
History of chemotherapy	1 (4.8)	8 (26.7)	0.064
History of radiotherapy	5 (23.8)	12 (40.0)	0.366
ECOG PS score			0.530
0	6 (28.6)	11 (36.7)
1	14 (66.7)	19 (63.3)
2	1 (4.8)	0 (0.0)
Differentiation			0.604
Poor	4 (19.0)	9 (30.0)
Moderate	13 (61.9)	18 (60.0)
Well	4 (19.0)	3 (10.0)
Primary tumor location			0.672
Tongue	8 (38.1)	16 (53.3)
Gingiva	8 (38.1)	9 (30.0)
Mouth floor	3 (14.3)	4 (13.3)
Others	2 (9.5)	1 (3.3)
Disease status			0.568
Metastatic disease only	11 (52.4)	14 (46.7)
Recurrent disease only	4 (19.0)	10 (33.3)
Recurrent metastatic disease	6 (28.6)	6 (20.0)
Metastatic site
Lymph nodes	7 (33.3)	16 (53.3)	0.253
Lung	9 (42.9)	11 (36.7)	0.773
Bone	7 (33.3)	5 (16.7)	0.196
Liver	1 (4.8)	6 (20.0)	0.217
Other	5 (23.8)	7 (23.3)	>0.999
Recurrence site			0.886
Tongue	5 (50.0)	7 (43.8)
Gingiva	3 (30.0)	4 (25.0)
Mouth floor	2 (20.0)	5 (31.3)
PD-L1 CPS			<0.001
<1	0 (0.0)	8 (26.7)
≥1	21 (100.0)	9 (30.0)
Unknown	0 (0.0)	13 (43.3)

Values are expressed as the mean ± standard deviation or n (%). PD-1, programmed cell death 1; ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1 CPS, programmed death-ligand 1 combined positive score.

Table II.

Treatment regimens for patients with oral squamous cell carcinoma.

Treatment	N (%)
Programmed cell death 1 inhibitor plus chemotherapy
Pembrolizumab + platinum + 5-FU	14 (66.7)
Nivolumab + platinum + 5-FU	4 (19.0)
Camrelizumab + platinum + 5-FU	3 (14.3)
Standard treatment
Cetuximab + platinum + 5-FU	20 (66.7)
Cetuximab + cisplatin + docetaxel	4 (13.3)
Platinum + 5-FU	5 (16.7)
Cetuximab + paclitaxel	1 (3.3)

5-FU, 5-fluorouracil.

Table III.

AEs [n (%)].

	Programmed cell death 1 inhibitor plus chemotherapy (n=21)			Standard treatment (n=30)

AE	Any grade	Grade 1-2	Grade 3-5	Any grade	Grade 1-2	Grade 3-5	P-value
Fatigue	9 (42.9)	8 (38.1)	1 (4.8)	11 (36.7)	10 (33.3)	1 (3.3)	0.656
Anemia	6 (28.6)	5 (23.8)	1 (4.8)	8 (26.7)	8 (26.7)	0 (0.0)	0.881
Neutropenia	6 (28.6)	4 (19.0)	2 (9.5)	6 (20.0)	4 (13.3)	2 (6.7)	0.518
Nausea	6 (28.6)	5 (23.8)	1 (4.8)	10 (33.3)	9 (30.0)	1 (3.3)	0.718
Leukopenia	5 (23.8)	4 (19.0)	1 (4.8)	6 (20.0)	5 (16.7)	1 (3.3)	0.744
Liver dysfunction	5 (23.8)	4 (19.0)	1 (4.8)	6 (20.0)	5 (16.7)	1 (3.3)	0.744
Thrombocytopenia	4 (19.0)	4 (19.0)	0 (0.0)	7 (23.3)	7 (23.3)	0 (0.0)	>0.999
Stomatitis	4 (19.0)	4 (19.0)	0 (0.0)	5 (16.7)	5 (16.7)	0 (0.0)	>0.999
Diarrhea	4 (19.0)	4 (19.0)	0 (0.0)	8 (26.7)	7 (23.3)	1 (3.3)	0.739
Hypothyroidism	3 (14.3)	3 (14.3)	0 (0.0)	1 (3.3)	1 (3.3)	0 (0.0)	0.293
Vomiting	3 (14.3)	3 (14.3)	0 (0.0)	6 (20.0)	5 (16.7)	1 (3.3)	0.720
Pyrexia	2 (9.5)	2 (9.5)	0 (0.0)	3 (10.0)	3 (10.0)	0 (0.0)	>0.999
Rash	2 (9.5)	2 (9.5)	0 (0.0)	8 (26.7)	8 (26.7)	0 (0.0)	0.167
Pneumonitis	1 (4.8)	1 (4.8)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0.412
Renal dysfunction	1 (4.8)	1 (4.8)	0 (0.0)	2 (6.7)	2 (6.7)	0 (0.0)	>0.999

AE, adverse event. The P-values pertain to the comparison of ‘any grade’ AEs between the two groups.