Abstract
Background/Aim: There are no real-world comparative data of nivolumab doses of 3 mg/kg and 240 mg/body for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). We investigated the efficacy and safety of nivolumab in treating recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) at different doses using real-world data. Patients and Methods: R/M SCCHN patients who received nivolumab were divided into the 3 mg/kg and 240 mg/body groups and retrospectively examined for efficacy and safety. Results: A total of 199 patients (3 mg/kg and 240 mg/body, 88 and 111 patients, respectively) were included. The 3 mg/kg vs. 240 mg/body groups had similar overall response rates (15% vs. 25, p=0.15), disease control rates (46% vs. 57%, p=0.15), overall survival (9.5 months vs. 10.9 months), and progression-free survival (3.7 months vs. 3.8 months, p=0.95). The incidence of immune-related adverse events was also similar in both groups. Conclusion: In R/M SCCHN patients, nivolumab showed similar efficacy and safety at doses of 3 mg/kg and 240 mg/body.
Unresectable recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) has a poor prognosis, and the survival time is usually approximately one year (1). R/M SCCHN has been treated using systemic chemotherapy, with the first choice consisting of an extreme regimen that includes a platinum-based anticancer agent as the key drug (5-fluorouracil plus cisplatin/carboplatin plus cetuximab) (2). In the international phase III Checkmate 141 study, patients administered the immune checkpoint inhibitor nivolumab, an anti-human programmed cell death 1 (PD-1) monoclonal antibody, at 3 mg/kg for platinum-resistant R/M SCCHN, exhibited a longer overall survival (OS) than those administered the investigator’s choice of treatment (3). Consequently, nivolumab has been indicated for the treatment of R/M head and neck cancer.
Nivolumab was initially administered at a dose based on body weight (BW). However, challenges associated with the laborious calculation of the BW conversion, the complexity of infusion preparation, and disposal of the leftover amounts of this expensive drug prompted development of a fixed-dose method. In the large phase Ib ascending dose CA209003 study, the upper limit of tolerability for nivolumab was 10 mg/kg (4). Computer simulations were used for the clinical pharmacological evaluation, whereas population pharmacokinetic (PPK) analysis was used for pharmacokinetic (PK) determinations in the body, and exposure-response (ER) analysis was used to predict efficacy and safety.
PPK analysis was used to predict blood levels of nivolumab following the administration of 3 mg/kg and 240 mg/body doses; steady-state mean blood, maximum blood, and serum trough levels did not rise above the 10 mg/kg upper limit of tolerability, and there were no differences among cancers (5-7). In addition, ER analysis showed that OS, response rate, and adverse events (AEs) with nivolumab were similar at 3 mg/kg and 240 mg/body doses (8). Based on this result, the dose of nivolumab was changed from 3 mg/kg to 240 mg/body for all cancers. In computer simulations, efficacy and safety were similar at 3 mg/kg and 240 mg/body, although no clinical studies have solely reported on R/M SCCHN (9, 10). Therefore, in this study, we investigated the efficacy and safety of nivolumab in treating R/M SCCHN at different doses using real-world data.
Patients and Methods
This four-centre retrospective cohort study was conducted at Tokyo Medical University Hospital, Tokyo Medical University Hachioji Medical Center, International University of Health and Welfare Mita Hospital, and Kitasato University Hospital. The participants were R/M SCCHN patients who had been treated with platinum-based anticancer agents and received nivolumab at least once from May 2017 to March 2020. This study was approved by the institutional review boards of the various hospital (approval no. T2020-0386, 5-21-33, C21-009) and was conducted in accordance with the Declaration of Helsinki.
From May 2017 to August 2018 nivolumab was administered at 3 mg/kg every two weeks (Q2W) and from September 2018 to March 2020 the dose was 240 mg/body Q2W. The target lesion was evaluated using computed tomography (CT) or magnetic resonance imaging (MRI) every 2-3 months. Treatment continued until the lesions increased in size, unacceptable AEs occurred, or the physician in charge decided to discontinue administration for some other reason. The observation period for the 3 mg/kg- and 240 mg/body-treated patients was until October 2018 and March 2020, respectively.
The primary endpoint was the overall response rate (ORR) [complete response (CR) + partial response (PR)]. The secondary endpoints were disease control rate (DCR) [CR + PR + stable disease (SD)], OS, progression-free survival (PFS), and immune-related AEs (irAEs). The therapeutic effect on the target lesion was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Furthermore, irAEs were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. ORR and DCR were only evaluated in patients who could be evaluated using RECIST, whereas patients who exhibited clinically obvious disease progression before the initial imaging evaluation were evaluated using progressive disease (PD) calculations. OS was defined as the period from the start of drug administration to death or the date of final follow-up, whereas PFS was the period from the start of the administration to disease progression or death.
Efficacy and safety were examined in the 3 mg/kg- and 240 mg/body-treated groups. In addition, OS was comparatively analysed by dividing patients into high and low BW groups based on median weight. Because BW comparisons may not reflect body physique, we also compared OS based on body mass index (BMI) using the World Health Organization (WHO) criteria (BMI <18.5 underweight, 18.5-24.9 normal range, >25 obese) (11). We also calculated the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) using neutrophil, platelet, and lymphocyte values measured before nivolumab administration to determine their potential correlations with BW.
Differences in patient characteristics, ORR, DCR, and AEs were analysed using Fisher’s exact test. Body weight distributions were analysed using the t-test. OS and PFS were evaluated using the Kaplan–Meier method and the log-rank test. Survival was analysed using the Cox proportional-hazards model. Spearman’s correlation coefficients were calculated to assess correlation. For all the analyses, values with a p<0.05 were considered significantly different.
All statistical analyses were performed using Easy R (EZR, Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). EZR is a modified version of R commander designed to include statistical functions frequently used in biostatistics (12).
Results
Of the 201 R/M SCCHN patients treated with nivolumab at the four institutions, 199 were eligible for this study. Two patients were excluded because they were not treated with platinum-based anticancer agents. Finally, 88 and 111 patients were treated with 3 mg/kg and 240 mg/body, respectively. Table I shows the patients’ characteristics and there were no significant differences between the groups in age, sex, performance status (PS), primary site, or platinum resistance/susceptibility. Figure 1 shows the BW and BMI distributions. The median BW of the 3 mg/kg and 240 mg/kg groups was 51 kg and 53 kg, respectively, which was not significantly different (p=0.71). The BMI of most patients indicated they were underweight or within the normal range, whereas few patients were obese and none had a BMI >30.
Patient characteristics.
Distribution of (a) body weight (BW) and (b) body mass index (BMI) of all patients.
Table II shows the best overall response, and the ORR values of the 3 mg/kg and 240 mg/body groups were not significantly different (p=0.15) at 15% and 25%, respectively. The DCR values of the 3 mg/kg and 240 mg/body groups were also not significantly different (p=0.15) at 46% and 57%, respectively. The median OS of the 3 mg/kg group was 9.5 [95% confidence interval (CI)=7.9-11.8] months and that of the 240 mg/body group was 10.9 (95% CI=8.7-21.7) months, which were not significantly different [hazard ratio (HR)=0.89; 95% CI=0.57-1.37; p=0.59; Figure 2a]. The median PFS of the 3 mg/kg group was 3.7 (95% CI=2.5-5.1) months and of the 240 mg/body group was 3.8 (95% CI=2.7-5.7) months, which were not significantly different (HR=1.01; 95% CI=0.71-1.44; p=0.95; Figure 2b).
Best overall response.
Kaplan-Meier curves of (a) overall survival (OS) and (b) progression-free survival (PFS). Black line: 3 mg/kg group. Red line: 240 mg/body group. HR: Hazard ratio; CI: confidence interval.
The OS of the 240 mg/body group was compared between patients with BW ≥53 kg and <53 kg, and that of the latter was significantly worse (HR=0.44; 95% CI=0.14-0.81; p=0.006; Figure 3a). The comparison based on BMI showed that the OS was significantly worse in underweight patients than it was in those who were obese or within the normal range (HR=0.55; 95% CI=0.32-0.90; p=0.02; Figure 3b). Similarly, in the 3 mg/kg group OS tended to be worse in patients with a BW <53 kg (HR=0.50; 95% CI=0.25-1.01; p=0.054; Figure 3c) than it was in those with a BW ≥53 kg. The comparison based on BMI showed that OS was significantly worse in underweight patients (HR=0.56; 95% CI=0.33-0.95; p=0.03; Figure 3d), than it was in those who were within the normal range or obese.
Kaplan-Meier curves for the overall survival of (a, b) 240 mg/body and (c, d) 3 mg/kg groups. (a, c) Black line: <53 kg patients. Red line: ≥53 kg patients. (b, d) Black line: underweight patients. Red line: normal range patients. Green line: obese patients.
Table III summarizes the irAEs: there were 33 in 25 patients in the 3 mg/kg group, whereas 31 occurred in 23 patients in the 240 mg/body group. Interstitial lung disease, hypothyroidism, and liver dysfunction were frequent events in both groups. There was one case of grade 5 interstitial lung disease in the 240 mg/body group. The incidence of irAEs was not significantly different (p=0.24) between the groups.
Immune-related adverse events.
Figure 4 shows diagrams illustrating the correlation of BW with NLR and PLR and the correlation coefficients were 0.01 (p=0.93) and –0.09 (p=0.36), respectively. These findings indicated there was no correlation between BW and these markers.
Correlation between body weight and (a) neutrophil-to-lymphocyte ratio and (b) platelet-to-lymphocyte ratio.
Discussion
The present study did not identify any significant differences in ORR, DCR, OS, PFS, or irAEs between the 3 mg/kg and 240 mg/body groups. At 3 mg/kg, the dose per unit BW is the same and, thus, no differences are expected in efficacy depending on BW. However, at a fixed dose of 240 mg/body, the dose per unit BW varies. For example, the dose for a patient with a BW of 40 kg is 6 mg/kg, whereas that for a patient with BW 80 kg is 3 mg/kg, or half the amount. Higher doses per unit BW could be more effective but could also lead to more adverse events.
The findings of our comparisons of the OS between patients with different BW and BMI administered both doses indicated that the OS was worse when the dose per unit BW was higher in both groups. In addition, the incidence of higher than grade 3 irAEs that may lead to discontinuation of treatment was not significantly different between the two groups, indicating that irAEs did not worsen OS. These findings indicate that the dose per unit BW was not directly related to the occurrence of irAEs or the deterioration of OS, which suggests that OS was worse when the BW was low.
Pre-chemotherapy nutritional status is known to be associated with OS. Many tumour-bearing patients, especially those with R/M SCCHN who have difficulty eating, have malnutrition and low BW because of these and other factors. AEs are more likely to occur with chemotherapy when the patient is undernourished, which can necessitate dose reduction and lead to poorer survival rates (13-15). Neutrophils and platelets are involved in local inflammation (16-19), and lymphocytes are involved in local immunity and nutritional status (20, 21). NLR and PLR, which are calculated using these data, have been found to be useful biomarkers for predicting the prognosis of various cancers (22-26). In the present study, our investigation of the relationship between BW and both NLR and PLR showed no correlations.
A 240 mg/body dose is equivalent to that for a patient with BW 80 kg when converted at 3 mg/kg. Of the 199 patients we examined, only one had BW ≥80 kg, which indicates that the doses for the other patients were ≥3 mg/kg. A 240 mg/body dose was selected because the median BW in a study from the United States was 78 kg and, thus, 80 kg was adopted as an approximate value (8). However, Japanese patients are usually smaller than Western patients, and the median BW in the present study was 53 kg, which is considerably lower than 80 kg. The incidence of irAEs was similar in smaller Japanese patients at both 3 mg/kg and 240 mg/body, which indicates that the 240 mg/body dose is safe.
Conclusion
We retrospectively compared the differences in efficacy and safety of two different doses of nivolumab for R/M SCCHN. The analysis of real-world data showed no significant differences in OS, PFS, ORR, DCR, or irAEs between the 3 mg/kg and 240 mg/body groups, which was similar to the results of the computer simulations. Patients with lower BW exhibited a worse OS than those with a higher BW but did not have more irAEs. Safety was also maintained at a dose of 240 mg/body. The flat dose eliminates the need to calculate the dose for each patient and simplifies the process up to administration. The dose of 240 mg/body has provided convenience and safety to healthcare professionals and patients. Similar results to the clinical pharmacology approach were obtained in terms of usefulness and safety, making it a better dosing option. A limitation of our study was the retrospective analysis and the dosing period differed between the 3 mg/kg and 240 mg/body groups.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
TO, CF, TM, IO and HS contributed to the conception and design of the study. TK, TI, GY, YA, KH, YK, KM and TY were responsible for the data collection. GO, HT and NO contributed to data analysis. TO, CF, TM, IO, HS, TK and KT were in charge of drafting the manuscript. TM, YT, KM and TY revised the manuscript critically for important intellectual content. The final version was read and approved by all the Authors.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received December 27, 2021.
- Revision received January 20, 2022.
- Accepted January 26, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.