A Single-center Prospective Study on the Ecacy of Nivolumab Against Platinum-sensitive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Nivolumab, an immune checkpoint inhibitor, reportedly benets patients with platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC). However, platinum-sensitive R/M-HNSCC has not yet been studied. Hence, this prospective study evaluated the ecacy and safety of nivolumab in patients with platinum-sensitive R/M-HNSCC. This prospective single-arm study was conducted in a single institution in Japan. Patients with platinum-sensitive R/M-HNSCC (dened as head and neck cancer that recurred or metastasized at least 6 months after platinum-based chemotherapy or chemoradiotherapy) were enrolled. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), overall response rate (ORR), immune-related adverse events (irAEs), and quality of life (QOL). This study was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN000031324). Twenty-two patients with platinum-sensitive R/M-HNSCC were enrolled. The median OS was 17.4, and the 1-year OS rate was 73%. The median PFS was 9.6 months, and the 1-year PFS rate was 48%. The ORR was 36%. In total, 16 irAEs were recorded in 12 patients; however, no grade 4 or 5 irAEs were observed. The QOL assessments revealed that nivolumab did not decrease the QOL of patients. Nivolumab is effective against platinum-sensitive R/M-HNSCC with acceptable safety. pembrolizumab rst-line treatment for platinum-sensitive R/M-HNSCC.


Introduction
The prognosis of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) is poor, with a median overall survival (OS) of less than 1 year 1-3 . In 2016, an international phase III trial (CheckMate-141) revealed that, compared with the standard-of-care, nivolumab (an immune checkpoint inhibitor) prolonged the OS of patients with platinum-refractory R/M-HNSCC. In the CheckMate-141 study, treatment with nivolumab led to a median OS of 7.5 months, median progressionfree survival (PFS) of 2.04 months, and an overall response rate (ORR) of 13.3% 4 . Thus, the National Comprehensive Cancer Network (NCCN) Guidelines recommend nivolumab along with the EXTREME regimen as a category 1 treatment for patients with R/M-HNSCC having a history of platinum therapy 5,6 . Several studies, including a real-world retrospective study, have reported the e cacy of nivolumab, with median OS ranging from 8.7 to 13.0 months, median PFS ranging from 1.9 to 3.7 months, and ORR ranging from 13% to 30% [7][8][9][10] .
The concept of platinum refractoriness initially used for treatment strategies for recurrent ovarian cancer 11,12 has recently been applied to R/M-HNSCC 13 . Tumors are considered platinum-refractory if they recur or metastasize within 6 months after platinum-based chemotherapy or chemoradiotherapy. In contrast, tumors are considered platinum-sensitive if they recur or metastasize more than 6 months after platinum-based chemotherapy or chemoradiotherapy. Notably, CheckMate-141 only enrolled patients with platinum-refractory R/M-HNSCC, and no prospective study has been conducted on the e cacy and safety of nivolumab for platinum-sensitive R/M-HNSCC. The KEYNOTE 048 trial suggested that pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, is effective against platinum-sensitive R/M-HNSCC 14 ; pembrolizumab is also considered a category 1 therapy in the NCCN Guidelines 5 . Nivolumab, similar to pembrolizumab, is a PD-1 inhibitor, and it may be effective against platinum-sensitive R/M-HNSCC. The aim of this study was to prospectively evaluate the e cacy and safety of nivolumab in patients with platinum-sensitive R/M-HNSCC.

Patient characteristics
From February 16, 2018, to December 31, 2019, 61 patients with recurrent or metastatic head and neck cancer received at least one cycle of nivolumab. Of these, 39 patients were excluded owing to platinum resistance (N = 35), non-squamous cell carcinoma (N = 3), and age >75 years (N = 1). Twenty-two patients who met the inclusion criteria were enrolled in this study. The data cutoff date was December 31, 2020. Detailed data of all patients are provided in Supplementary Information. Table 1 lists the age, sex, smoking history, drinking history, Eastern Cooperative Oncology Group performance status (ECOG PS), tumor-node-metastasis (TNM) classi cation and staging at recurrence or metastasis, and programmed cell death-ligand 1 (PD-L1) expression. The median age of patients was 63 years (range, 42-74 years). The primary tumor sites included the nasopharynx (N = 6) and maxillary sinus (N = 4). PD-L1 expression was <1% in 5 patients, ≥1% in 16 patients, ≥20% in 12 patients, ≥40% in 8 patients, and unmeasured in 1 patient. Treatment modalities prior to nivolumab administration are presented in Table 2. Previous exposure to platinum included induction chemotherapy (docetaxel/cisplatin/5-uorouracil, N = 3), de nitive concurrent chemoradiotherapy (N = 13), postoperative chemoradiotherapy (N = 6), and systemic therapy for recurrence or metastasis (cetuximab/cisplatin/5-uorouracil, N = 1). In addition, one patient underwent a duplicate platinumcontaining regimen. Cetuximab was used prior to nivolumab treatment as de nitive concurrent radiotherapy (N = 1) and as systemic therapy for countering the recurrence or metastasis of disease (cetuximab/paclitaxel, N = 3; cetuximab/cisplatin/5-uorouracil, N = 1). The median period between the date of the last administration of platinum and the date of disease progression was 351 days (range, 201-1,081 days), whereas the median period between the date of the last administration of platinum and the date of the rst administration of nivolumab was 397 days (range, 211-1,110 days). The median number of cycles of nivolumab administration was 9 (range, 1-57).
One patient, in whom the target lesions were assessed as CR, was evaluated as PD owing to the appearance of new distant metastatic lesions during follow-up ( Figure 2C). Table 3 lists the immune-related adverse events (irAEs) in all patients administered nivolumab. In total, 16 irAEs of different grades were detected in 12 patients: liver dysfunction (N = 5), interstitial lung disease (N = 4), hypothyroidism (N = 4), hyperthyroidism (N = 1), and dermatitis (N = 2). The following grade 3 or higher irAEs occurred in four patients: liver dysfunction (N = 3) and hypothyroidism (N = 1).

Quality of life assessments
Functional scales (physical, role, emotional, cognitive, and social functioning) and global health status were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 Module (QLQ-C30). Domain scales (pain, swallowing, sense problems, speech problems, trouble with social eating, trouble with social contact, and reduced sexuality) were assessed using the EORTC QLQ Head and Neck Cancer Module (QLQ-H&N35). Detailed data regarding the quality of life (QOL) scores are provided in Supplementary Information. The data of 19 patients, excluding the 3 patients who died by week 8, were analyzed. Figure 3 shows the QOL scores relative to baseline at 8 and 16 weeks after the initiation of nivolumab. There was no signi cant change in the QOL of patients treated with nivolumab.

Discussion
The aim of this study was to determine the e cacy and safety of nivolumab in patients with platinumsensitive R/M-HNSCC through a prospective study. The main outcomes of this study were the median OS of 19.3 months, median PFS of 9.3 months, ORR of 36%, and DCR of 68%. Considering that the prognosis of patients with R/M-HNSCC is poor at less than 1 year 1-3 , it is evident that treatment with nivolumab improved the OS. To the best of our knowledge, this is the rst prospective study to demonstrate the e cacy of nivolumab in patients with platinum-sensitive R/M-HNSCC only.
No prospective study has previously examined the effect of nivolumab in patients with platinum-sensitive head and neck cancer or with other carcinomas. The concept of platinum-resistant and platinumsensitive cancer was originally used to treat recurrent ovarian cancer and has recently been applied to R/M-HNSCC 11,12 . In recurrent ovarian cancer, patients with platinum-sensitive cancer are more likely to respond to subsequent chemotherapy and have a better prognosis than those with platinum-resistant cancer 11,12 . For R/M-HNSCC, the effects of the EXTREME regimen on the OS of two groups of patients with R/M-HNSCC, namely patients with platinum-resistant and platinum-sensitive R/M-HNSCC, have been  15 .
In contrast, Sano et al. showed that the OS of the non-platinum-refractory group was signi cantly higher than that of the platinum-refractory group (median OS: 7 vs. 13 months; P = 0.018) 16 19 . In our institution, we followed up the patients monthly after completing local treatment for head and neck cancer and performed imaging studies every 3-4 months. In patients with suspected recurrence, imaging was performed at relatively short intervals. In this study, tumor burden and growth rate were not measured. However, R/M-HNSCC was likely diagnosed at a relatively early stage, resulting in the immediate administration of nivolumab. We believe this is one of the reasons for the favorable OS and PFS observed in this study. Unlike multicenter studies, our study did not require a speci c time for the enrollment of patients, which enabled the rapid initiation of treatment, an advantage of single-arm studies conducted in a single institution.
In a sub-analysis of CheckMate-141, Ferris et al. compared the OS of patients with and without prior exposure to cetuximab 20 . They reported that patients without prior exposure were at a lower risk of death from nivolumab use. Cetuximab binds to the epidermal growth factor receptor on tumor cells but promotes the growth of immunosuppressive regulatory T cells in the tumor microenvironment 21 . Patients whose lesions worsen after cetuximab treatment are less likely to respond to immunotherapy owing to the proliferation of immunosuppressive regulatory T cells, such as regulatory T cells and myeloid-derived suppressor cells 21,22 . In our study, ve patients (22.7%) with a history of cetuximab treatment prior to nivolumab treatment could not attain an endpoint for previous cetuximab use. Therefore, it is not known whether previous cetuximab use had any effect on patient response. The CheckMate-141 QOL assessments showed that nivolumab does not reduce the QOL (compared with other chemotherapy or molecularly targeted drug treatments) 4,23 . This observation is not limited to R/M-HNSCC; it has also been reported for melanoma, non-small cell lung cancer, and renal cell carcinoma [24][25][26] . Our results also showed no reduction in the QOL of patients after treatment with nivolumab.
There were some limitations associated with the study. This was a single-arm study, and although the enrollment number was set at 50 patients, it was not reached. Sixty-one patients with R/M-HNSCC received nivolumab within the target period, but 35 were excluded due to platinum resistance. The effects of nivolumab in patients with platinum-resistant and platinum-sensitive R/M-HNSCC should be further examined in a multicenter prospective study with a higher number of patients. In addition, the outcomes of nivolumab and pembrolizumab as rst-line treatments for patients with platinum-sensitive R/M-HNSCC with a history of platinum use should be compared in future studies. These studies are necessary to establish more effective treatment strategies for patients with R/M-HNSCC.
In conclusion, our results suggest that nivolumab is highly effective in treating platinum-sensitive R/M-HNSCC, with no reduction in the QOL following treatment. These results may have implications for the current treatment regimen for R/M-HNSCC.

Study design
This was a single-institution, open-label, single-arm, phase II interventional study conducted in Japan to evaluate the e cacy of nivolumab in patients with R/M-HNSCC. The study was approved by the ethics committee at Tokyo Medical University (SH3946) and registered at the University Hospital Medical Information Network Clinical Trials Registry prior to the recruitment of patients (UMIN000031324, Date of rst registration;15/02/2018). The study adhered to the tenets of the Declaration of Helsinki, and informed consent was obtained from all the patients.

Patients
Patients with R/M-HNSCC were screened for eligibility for this study. The number of patients expected to be enrolled was 50, which was calculated based on the number of patients with R/M-HNSCC treated in our institution (approximately 60 patients per year), the expected rate of enrollment (40%), and the study period to enroll patients (2 years). The main exclusion criteria were prior exposure to nivolumab; platinum refractoriness, de ned as disease progression within 6 months after the last administration of platinum; non-squamous cell carcinoma; and age over 75 years. The full inclusion and exclusion criteria are provided in the Supplementary Protocol.

Outcomes and assessments
The primary endpoint was OS. The period of OS was de ned as the duration between the date of nivolumab initiation and the date of last follow-up or the patient's death. The secondary endpoints were PFS, ORR, and QOL. The period of PFS was de ned as the duration between the date of nivolumab initiation and the date of objective disease progression or patient's death from any cause, whichever occurred rst. Tumor response was assessed by three radiologists in our institution according to the Response Evaluation Criteria in Solid Tumors Guideline (version 1.1) 27 . The QOL was assessed using the EORTC QLQ-C30, a basic quality of life questionnaire used for patients with malignancies, and the EORTC QLQ-H&N35, a disease-speci c questionnaire 28,29 . The EORTC QLQ-C30 and QLQ-H&N35 were answered by the patients prior to treatment initiation and at 8 and 16 weeks after treatment initiation. These scores ranged from 0 to 100, with higher scores indicating higher functioning and symptom burden, except for the global health status items. Higher scores indicate lower functioning and symptom burden. TNM was classi ed using the Union for International Cancer Control stage, 7 th edition 30 . The discontinuation criteria for nivolumab were speci ed in the protocol based on the grade of irAEs, but no weight loss criterion was set 4 . The irAEs were assessed using the Common Terminology Criteria for Adverse Events version 4.0 31 .

Administration of nivolumab
Nivolumab was administered as a single intravenous dose (3 mg/kg body weight) every 2 weeks. A single treatment cycle lasted 2 weeks, and imaging assessment was carried out every 4-8 cycles. Treatment was continued until the con rmation of objective disease progression, the occurrence of unacceptable toxicity, or other reasons assessed by the attending physician. However, even after con rming progression based on clinical or imaging ndings, treatment continued when the attending physician thought that clinical bene t was likely 32 . Physician's choice 1 4.5 Table 3. Immune-related adverse events