Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non-small cell lung cancer
Funding Information
This medical writing assistance was funded by Ono Pharmaceutical Co., Ltd, Osaka, Japan
Abstract
Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4–25.4), 2.7 (range 1.2–5.5) and 4.2 (95% CI 1.4–7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. Clinical trial registration number: JapicCTI-132072
Lung cancer is one of the leading causes of cancer-related death worldwide.1 Non-small cell lung cancer (NSCLC) accounts for up to 85% of lung cancers2 and is classified based on histology as either squamous or non-squamous cell carcinoma.3 Squamous NSCLC accounts for approximately 30% of NSCLC cases.4 Guidelines recommend using combination therapy for the first-line treatment of patients with stage IIIB/IV squamous NSCLC unsuited to radical radiotherapy,5, 6 consisting of a platinum agent plus a third-generation agent such as carboplatin/paclitaxel or cisplatin/gemcitabine. As for second-line therapy, docetaxel has been a standard treatment in patients with squamous NSCLC for more than a decade, with a median progression-free survival (PFS) of 2.7 months and median overall survival of 7.4 months.7
It has been shown that combination chemotherapy as second-line treatment in NSCLC improves the overall response rate (ORR) and PFS compared with single-agent chemotherapy. However, combination chemotherapies have failed to improve overall survival (OS) in these patients and have been associated with more adverse events (AE) than single-agent therapy.8 Therefore, there is an unmet need for newer agents with better efficacy and safety.
Programmed cell death-1 (PD-1) is a receptor present on cytotoxic T cells which binds to its natural ligands PD ligand-1 (PD-L1) and PD ligand-2 (PD-L2) and is activated in response to inflammation or infection.9, 10 Binding of PD-L1 to its receptor causes deactivation of T cells leading to immunosuppression. Expression of PD-L1 in NSCLC generates an immunosuppressive tumor microenvironment and promotes tumor immune escape, thus leading to poor prognosis of the disease.11
Nivolumab is a fully human immunoglobulin G4 monoclonal antibody, which inhibits the PD-1 receptor and has been approved in the USA, EU and Japan for the treatment of advanced NSCLC.12, 13 Studies have demonstrated the efficacy and tolerability of nivolumab in Caucasian patients with advanced NSCLC.14-16 The aim of the present study was to investigate the efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy.
Materials and Methods
Study design
This was a multicenter, open-label phase II study (Fig. S1a). The study protocol was reviewed and approved by the institutional review board of each study site before the study and the study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent. The data cut-off date was 17 December 2015. Clinical trial registration number: JapicCTI-132072.
Patients enrolled in this study were aged ≥20 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and had histologically or cytologically confirmed squamous NSCLC, stage IIIB/IV disease (according to UICC-TNM classification [7th edition])17 or recurrent NSCLC after surgical resection. Further inclusion criteria included: (i) ≥1 measurable lesion by RECIST guideline (version 1.1); (ii) a history of prior treatment of at least one regimen of platinum-containing chemotherapy; (iii) percutaneous oxygen saturation (SpO2) ≥94%; and (iv) adequate organ function. Patients were excluded if they had hypersensitivity to antibody products, a history of autoimmune disease and interstitial lung disease or pulmonary fibrosis, were treated with any systemic corticosteroid or immune suppressant in the last 28 days, or had active diverticulitis or symptomatic gastrointestinal ulcerative disease.
Nivolumab 3 mg/kg was given i.v. every 2 weeks in each 6-week cycle until progressive disease (PD) or unacceptable toxicity was observed. At the end of each cycle, patients underwent diagnostic imaging and patients who met the criteria for the start of the next cycle continued the treatment. Criteria for the start of the next cycle were: (i) no ≥grade 3 AE; (ii) no ≥grade 2 increase in aspartate aminotransferase, alanine aminotransferase, or total bilirubin from baseline (for which a causal relationship with nivolumab cannot be ruled out); and (iii) no occurrence of an autoimmune disease, as indicated by signs/symptoms or general laboratory test data. Patients who met at least one of the criteria for discontinuation discontinued treatment and moved to the follow-up period; criteria for discontinuation included: tumor response of PD according to the RECIST guideline (version 1.1); aggravation of clinical symptoms caused by disease progression; ≥grade 2 interstitial lung disease; ≥grade 2 eye pain or reduced visual acuity which did not resolve to ≤grade 1 with local treatment for which a causal relationship with nivolumab could not be ruled out; or ≥grade 3 bronchospasm, hypersensitivity reaction, injection reaction, or uveitis, for which a causal relationship with nivolumab could not be ruled out. Patients were allowed to continue treatment after initial disease progression if they had gained clinical benefit from the treatment without any unacceptable treatment-related AE, as reported by the investigator. Treatment-related AE were followed up every 2 weeks until these events resolved, were resolving, or had stabilized. Laboratory tests and diagnostic imaging were repeated as necessary to ensure patient safety.
Efficacy assessments
The primary efficacy endpoint was independent radiology review committee (IRC)-assessed confirmed ORR, evaluated based on tumor response assessed according to RECIST guidelines (version 1.1). Secondary endpoints included study site-assessed confirmed ORR, OS, PFS, duration of response (DOR), time to response, best overall response (BOR), and change in tumor size. ORR was calculated as the proportion of patients with a BOR of complete response (CR) or partial response (PR).
Safety assessments
Adverse events were evaluated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Select AE (those with a potential immunological cause) were grouped according to pre-specified categories.
Subgroup analysis
A pre-specified subgroup analysis for ORR and a post-hoc subgroup analysis for OS and PFS were carried out to determine the association between these efficacy variables and the patient age, gender, ECOG performance status, brain metastasis, disease stage and smoking status.
Biomarker analysis
Tumor PD-L1 expression was assessed retrospectively in pretreatment (archival or recent) tumor-biopsy specimens using a validated, automated immunohistochemical assay (Dako North America Santa Clara, CA, USA) that used a rabbit anti-human PD-L1 antibody (clone 28–8; Epitomics Cambridge, MA, USA). Tumor PD-L1 expression was confirmed when the tumor-cell membranes were stained (at any intensity) at predetermined expression levels of ≥1%, ≥5%, and ≥10% in a section that included at least 100 tumor cells that could be evaluated.
Statistical analysis
The expected response rate for nivolumab was set at 26%. Assuming a threshold response rate of 9% for nivolumab,18 30 patients were needed in order to ensure a power of ≥80% at a one-sided significance level of 0.025 in binominal tests (normal approximation). If a tumor response is achieved in at least six of 30 patients, the null hypothesis is rejected. To allow for several non-evaluable patients, 35 patients were planned to be enrolled in the study.
Baseline characteristics of patients enrolled in the study were summarized using frequency distributions and summary statistics. Primary efficacy and safety analyses were conducted in all patients who received at least one dose of nivolumab. AE and grade observed after first giving nivolumab and 28 days after the last dose or the start date of subsequent anticancer therapy after the last dose (whichever came first) were also tabulated.
Results
The study enrolled 35 patients from 17 sites in Japan (Fig. S1b). The majority of patients were male (91.4%), had no brain metastasis (91.4%), had undergone one prior systemic regimen (94.3%) and were current/former smokers (97.1%; Table 1). During the study, a median of eight doses of nivolumab were given (range 2–62) and 11 patients received >12 doses. The median duration of therapy was 3.6 months (range 0.5–29.3) and the median overall survival was 16.3 months (range 1.7–29.3). After discontinuation of treatment, 68.6% of the patients received subsequent systemic cancer therapy. 48.6% of the patients received subsequent docetaxel (Table S1).
| Characteristic | N = 35 |
|---|---|
| Age, years | |
| Median | 65.0 |
| Range | 31–85 |
| <65, n (%) | 15 (42.9) |
| ≥65, n (%) | 20 (57.1) |
| Gender, n (%) | |
| Male | 32 (91.4) |
| Female | 3 (8.6) |
| ECOG performance status, n (%) | |
| 0 | 18 (51.4) |
| 1 | 17 (48.6) |
| Disease stage, n (%) | |
| IIIB | 6 (17.1) |
| IV | 24 (68.6) |
| Recurrent | 5 (14.3) |
| Brain metastasis, n (%) | |
| Yes | 3 (8.6) |
| No | 32 (91.4) |
| Prior systemic regimens, n (%) | |
| 1 | 33 (94.3) |
| 2 | 2 (5.7) |
| Smoking status, n (%) | |
| Never smoked | 1 (2.9) |
| Former smoker | 29 (82.9) |
| Current smoker | 5 (14.3) |
| Prior treatment for NSCLC, n (%) | |
| Platinum-based therapy | 35 (100.0) |
| Carboplatin | 17 (48.6) |
| Cisplatin | 16 (45.7) |
| Nedaplatin | 2 (5.7) |
| EGFR-TKI | 2 (5.7) |
| Erlotinib | 2 (5.7) |
- ECOG, Eastern Cooperative Oncology Group; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; NSCLC, non-small cell lung cancer.
Efficacy
Nine patients had IRC-assessed response to treatment, resulting in an ORR of 25.7% (95% CI 14.2, 42.1) and seven patients had study site-assessed response to treatment with an ORR of 20.0% (95% CI 10.0, 35.9; Table 2). IRC-assessed BOR was PR for nine patients (25.7%), SD for 10 patients (28.6%), and PD for 16 patients (45.7%; Table 2, Fig. 1c). Study site-assessed BOR was PR for seven patients (20.0%), SD for 10 patients (28.6%), and PD for 18 patients (51.4%).
| IRC assessed n (%) | Study site assessed n (%) | |
|---|---|---|
| Best overall response | ||
| Complete response | 0 (0.0) | 0 (0.0) |
| Partial response | 9 (25.7) | 7 (20.0) |
| Stable disease | 10 (28.6) | 10 (28.6) |
| Progressive disease | 16 (45.7) | 18 (51.4) |
| ORR (CR + PR), % (95% CI) | 25.7 (14.2, 42.1) | 20.0 (10.0, 35.9) |
| Progression-free survival (IRC assessed) | ||
| Median, months (95% CI) | 4.2 (1.4, 7.1) | |
| Range, months | 0.6–25.5a | |
| Rate at 1 year, % (95% CI) | 24.5 (10.7, 41.3) | |
| Overall survival | ||
| Median, months (95% CI) | 16.3 (12.4, 25.4) | |
| Range, months | 1.7–29.3a | |
| Rate at 1 year, % (95% CI) | 71.4 (53.4, 83.5) | |
| Time to response | ||
| Responders, n | 9 | |
| Median, months (range) | 2.7 (1.2–5.5) | |
| Duration of response | ||
| Median, months (range) | NR (3.0a–22.9a) | |
- CI, confidence interval; CR, complete response; IRC, independent radiology review committee; NR, not reached; ORR, overall response rate; PR, partial response.
- a Censored value.
The lower limit of the 95% CI of the ORR with nivolumab exceeded the threshold response rate of 9% which was based on the ORR (8.8%) for docetaxel.18 Kaplan–Meier plots for OS and PFS are shown in Figure 1a and b. The median OS with nivolumab treatment was 16.3 months (95% CI 12.4, 25.4) and the OS rate at 1 year was 71.4% (95% CI 53.4, 83.5). The median IRC-assessed PFS was 4.2 months (95% CI 1.4, 7.1) and the median site-assessed PFS was 2.7 months (95% CI 1.5, 5.6). The median DOR has not been reached (range 3.0–22.9). The median time to response was 2.7 months (range 1.2–5.5) in the nine patients who responded to study treatment. A change in tumor size (tumor shrinkage) was seen in more than half of the study population and the antitumor effect of nivolumab was sustained for a long period of time in these patients (Fig. 1d).
Safety
Treatment-related AE were reported in 24 patients (68.6%). The incidence of treatment-related AE of all grades and ≥Grade 3 reported in ≥5% of patients is shown in Table 3. Grade 3 treatment-related AE included decreased lymphocyte count (2 patients, 5.7%), and no ≥Grade 3 treatment-related select AE were reported. Serious treatment-related AE occurred in two patients (5.7%); one patient experienced both atrial fibrillation and pneumonitis (2.9%) and one patient experienced interstitial lung disease (2.9%) (Table S2). An article discussing clinical findings and imaging characteristics of pneumonitis and interstitial lung disease cases reported in the present study has been published.19
| Treatment-related adverse events, n (%) | All grades | Grade 3 or higher |
|---|---|---|
| Total | 24 (68.6) | 2 (5.7) |
| Malaise | 5 (14.3) | 0 (0.0) |
| Pyrexia | 5 (14.3) | 0 (0.0) |
| Rash | 5 (14.3) | 0 (0.0) |
| Decreased appetite | 5 (14.3) | 0 (0.0) |
| Diarrhea | 3 (8.6) | 0 (0.0) |
| Lymphocyte count decreased | 3 (8.6) | 2 (5.7) |
| Nausea | 3 (8.6) | 0 (0.0) |
| Anemia | 2 (5.7) | 0 (0.0) |
| Arthralgia | 2 (5.7) | 0 (0.0) |
| Aspartate aminotransferase increased | 2 (5.7) | 0 (0.0) |
| Blood creatine phosphokinase increased | 2 (5.7) | 0 (0.0) |
| Dermatitis acneiform | 2 (5.7) | 0 (0.0) |
| Erythema | 2 (5.7) | 0 (0.0) |
| Hypersensitivity | 2 (5.7) | 0 (0.0) |
| Hypoalbuminemia | 2 (5.7) | 0 (0.0) |
| Edema peripheral | 2 (5.7) | 0 (0.0) |
| Peripheral sensory neuropathy | 2 (5.7) | 0 (0.0) |
| Pulmonary hemorrhage | 2 (5.7) | 0 (0.0) |
| Rash maculopapular | 2 (5.7) | 0 (0.0) |
| Autoimmune thyroiditis | 2 (5.7) | 0 (0.0) |
| Treatment-related select adverse events, n (%) | ||
| Endocrine disorders | 5 (14.3) | 0 (0.0) |
| Infusion reactions | 2 (5.7) | 0 (0.0) |
| Gastrointestinal toxicity | 3 (8.6) | 0 (0.0) |
| Hepatotoxicity | 2 (5.7) | 0 (0.0) |
| Pulmonary toxicity | 2 (5.7) | 0 (0.0) |
| Nephrotoxicity | 1 (2.9) | 0 (0.0) |
| Skin toxicity | 10 (28.6) | 0 (0.0) |
- AE and grades observed between the start date of the first dose of nivolumab and 28 days after the last dose or the start date of subsequent anticancer therapy after the last dose, whichever comes first, are tabulated.
Treatment-related AE led to treatment interruption in six patients (17.1%), of which three patients (8.6%) discontinued treatment as a result of secondary adrenocortical insufficiency, hypersensitivity, and interstitial lung disease (n = 1; 2.9% each) (Table S3). There were no deaths as a result of AE during the study. However, one patient died of respiratory failure which occurred 31 days after the last dose of nivolumab without resolution of pneumonitis, after docetaxel treatment was initiated following nivolumab discontinuation. This event was not included in the analysis as it occurred beyond 28 days after the last dose or shortly after starting post-study treatment after the last dose.
Subgroup analysis
The post-hoc subgroup analysis indicated an association between ORR, OS, and PFS and patient age, gender, ECOG performance status, brain metastasis, disease stage and smoking status (Table 4; Table S4). The correlation between response and OS was also examined. The OS at 24 months was 74.1% in the PR (n = 9) group, 15.0% in the SD (n = 10) group and 31.3% in the PD (n = 16) group (Fig. S2). Median OS of patients with CR/PR, SD and PD with nivolumab treatment was 27.5 months, 15.3 months and 12.8 months, respectively. Patients who responded to nivolumab treatment (n = 9) included those aged ≥70 years (n = 4), with an ECOG performance status of 1 (n = 3) and never smoked (n = 1) (Table S5).
| Baseline characteristics | No. responders (n/N) | ORR (%) | 95% CI | Odds ratiob | 95% CI |
|---|---|---|---|---|---|
| Age, years | |||||
| <65 | 2/15 | 13.3 | 3.7, 37.9 | 0.29 | 0.05, 1.64 |
| ≥65 | 7/20 | 35.0 | 18.1, 56.7 | ||
| Gender | |||||
| Male | 9/32 | 28.1 | 15.6, 45.4 | NA | NA, NA |
| Female | 0/3 | 0 | 0.0, 56.1 | ||
| ECOG performance status | |||||
| 0 | 6/18 | 33.3 | 16.3, 56.3 | 2.33 | 0.48, 11.40 |
| 1 | 3/17 | 17.6 | 6.2, 41.0 | ||
| Brain metastasis | |||||
| Yes | 0/3 | 0 | 0.0, 56.1 | 0.0 | NA, NA |
| No | 9/32 | 28.1 | 15.6, 45.4 | ||
| Disease stage | |||||
| III B | 0/6 | 0 | 0.0, 39.0 | – | – |
| IV | 6/24 | 25.0 | 12.0, 44.9 | ||
| Recurrent | 3/5 | 60.0 | 23.1, 88.2 | ||
| Smoking statusa | |||||
| Yes | 8/34 | 23.5 | 12.4, 40.0 | ||
| No | 1/1 | 100 | 20.7, 100.0 | 0.0 | NA, NA |
- CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; NA, not applicable; ORR, overall response rate.
- a Smoking status was classified as current/former smokers (Yes) or never smoked (No).
- b Odds ratio of first category relative to second category.
Biomarker analysis
Of the 35 patients included in the study, 19 (54.3%) had a tumor tissue specimen collected at baseline, all of which had quantifiable PD-L1 levels. Of these 19 patients, 78.9%, 68.4% and 57.9% of patients were positive for PD-L1 expression of 1%, 5% and 10%, respectively. Although the subgroup analysis showed that the ORR and PFS outcomes were greater for PD-L1-positive patients, no significant association between the PD-L1 expression levels and the efficacy outcomes was determined (Table 5).
| PD-L1 expression level | No. responders (n/N) | ORR, % (95% CI) | OR (95% CI) |
|---|---|---|---|
| ≥1% | 7/15 | 46.7 (24.8, 69.9) | NA |
| <1% | 0/4 | 0.0 (0.0, 49.0) | |
| ≥5% | 5/13 | 38.5 (17.7, 64.5) | 1.25 (0.16, 9.54) |
| <5% | 2/6 | 33.3 (9.7, 70.0) | |
| ≥10% | 4/11 | 36.4 (15.2, 64.6) | 0.95 (0.14, 6.28) |
| <10% | 3/8 | 37.5 (13.7, 69.4) |
| PD-L1 expression level | No. patients | PFS, months (95% CI) | HR (95% CI) |
|---|---|---|---|
| ≥1% | 15 | 7.1 (1.2, NA) | 0.34 (0.10, 1.18) |
| <1% | 4 | 1.4 (1.2, 7.9) | |
| ≥5% | 13 | 8.8 (1.2, NA) | 0.49 (0.15, 1.64) |
| <5% | 6 | 4.3 (1.2, 7.9) | |
| ≥10% | 11 | 8.8 (1.2, NA) | 0.49 (0.16, 1.48) |
| <10% | 8 | 4.3 (1.0, 18.2) |
| PD-L1 expression level | No. patients | OS, months (95% CI) | HR (95% CI) |
|---|---|---|---|
| ≥1% | 15 | 12.6 (6.3, 27.5) | 0.67 (0.21, 2.20) |
| <1% | 4 | 14.6 (6.6, 18.6) | |
| ≥5% | 13 | 12.6 (6.3, 27.5) | 0.71 (0.25, 2.06) |
| <5% | 6 | 14.6 (6.6, 22.1) | |
| ≥10% | 11 | 12.6 (5.3, NA) | 0.89 (0.31, 2.54) |
| <10% | 8 | 14.6 (6.6, 22.1) |
- CI, confidence level; HR, hazard ratio; NA, not applicable; OR, odds ratio; ORR, overall response rate; OS, overall survival; PD-L1, programmed cell death ligand-1; PFS, progression-free survival.
Discussion
The present study demonstrated that nivolumab was effective and safe in Japanese patients with advanced or recurrent squamous NSCLC. In the present study, nivolumab was associated with an ORR of 25.7%, a median OS of 16.3 months and a median PFS of 4.2 months. The IRC-assessed BOR was PR for nine patients (25.7%), SD for 10 patients (28.6%), and PD for 16 patients (45.7%). The results of present study are consistent with those observed in the phase III randomized controlled CheckMate 017 trial that compared the efficacy of nivolumab with docetaxel in a Caucasian population with advanced squamous NSCLC.14 The ORR of nivolumab was 20% (27/135 patients) [95% CI 14, 28] and the median PFS was 3.5 months (95% CI 2.1, 4.9). Median OS was 9.2 months (95% CI 7.3, 13.3) with nivolumab compared with 6.0 months (95% CI 5.1, 7.3) with docetaxel, indicating superiority of nivolumab over docetaxel. Furthermore, nivolumab also reduced the risk of death by 41% compared with docetaxel (hazard ratio 0.59, 95% CI 0.44, 0.79).14 Other studies of nivolumab have also shown similar ORR and PFS in previously treated patients with advanced squamous NSCLC.15, 20 In summary, the present study highlights the effectiveness of nivolumab in the treatment of Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy.
Nivolumab was well tolerated in this study; treatment-related AE were reported in 68.6% of patients. The most common treatment-related AE were malaise, pyrexia, rash, decreased appetite, diarrhea, lymphocyte count decreased, and nausea. Serious treatment-relates AE were atrial fibrillation (n = 1, 2.9%), interstitial lung disease (n = 1, 2.9%), and pneumonitis (n = 1, 2.9%). Atrial fibrillation resolved with appropriate treatment and interstitial lung disease resolved with steroid pulse therapy. The AE reported in this study were consistent with those observed in previous trials of nivolumab in patients with advanced NSCLC.14, 15, 20
PD-L1 expression is considered as a potential predictive biomarker in patients with NSCLC.21 In the CheckMate 017 trial, a PD-L1 subgroup analysis indicated that tissue PD-L1 expression is neither a prognostic nor predictive factor for nivolumab in squamous NSCLC.14 The OS was significantly longer with nivolumab than with docetaxel regardless of PD-L1 status. In addition, there was no clear association between OS and ORR stratified by PD-L1 expression at different cut-off levels (1%, 5% and 10%). The efficacy profile of nivolumab stratified by PD-L1 expression status in our study coincided with the CheckMate 017 study, with no clear association between the efficacy of nivolumab with PD-L1 expression status.
There are a few limitations to the present study, including the relatively small sample size and the absence of a comparator group. Also, the lack of heterogeneity in the characteristics of the patients (mostly male, relatively older population) may influence the results of this study.
The results of the present study are in line with the outcomes of the CheckMate 017 study and demonstrate that nivolumab is associated with clinical efficacy and manageable tolerability in Japanese patients with advanced or recurrent squamous NSCLC progressed after platinum-containing chemotherapy, which is expected to be clinically useful. Early diagnosis and treatment of treatment-related AE can ensure safety during treatment.
Acknowledgments
The authors thank all patients who participated in this study and their families, as well as all investigators, physicians, nurses and clinical research coordinators who were involved in this study. The authors would also like to thank Dr Hironobu Minami (Kobe University, Hyogo) who was the medical consultant as well as Dr Noriyuki Masuda (Kitasato University, Kanagawa), Dr Yoichi Nakanishi (Kyusyu University, Fukuoka), Dr Masashi Takahashi (Yujin-Yamazaki Hospital, Shiga) and Dr Terufumi Kato (Kanagawa Cancer Center, Kanagawa) for their critical contribution as members of Independent Data-Monitoring Committee. The authors also acknowledge statistical support from Akira Takazawa (Ono Pharmaceutical Co., Ltd, Osaka). The authors thank Nishad Parkar, PhD, and Cécile Duchesnes, PhD, of Springer Healthcare Communications for preparing the outline and the first and subsequent drafts of this manuscript. This medical writing assistance was funded by Ono Pharmaceutical Co., Ltd, Osaka, Japan.
Disclosure Statement
The study was designed under the responsibility of Ono Pharmaceutical Co., Ltd in conjunction with the steering committee. The study was funded by Ono Pharmaceutical Co., Ltd; Nivolumab was provided by Ono Pharmaceutical Co., Ltd; Ono Pharmaceutical Co., Ltd collected and analyzed the data and contributed to the interpretation of the study. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. Toyoaki Hida received research funding from Ono Pharmaceutical Co., Ltd, Bristol-Meyers Squibb, MSD, Chugai Pharmaceutical Co., Ltd, AstraZeneca, Pfizer, and Merck Serono. Makoto Nishio received honoraria from Ono Pharmaceutical Co., Ltd, and Bristol-Myers Squibb. Naoyuki Nogami received honoraria from AstraZeneca, Ono Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd, Kyowa Hakko Kirin, Eli Lilly, and Pfizer. Yuichiro Ohe received research grants from Chugai Pharmaceutical Co., Ltd, Eli Lilly, Taiho Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd, AstraZeneca, Bristol-Myers Squibb, Pfizer, Kyorin Pharmaceutical Co. Ltd, and Dainippon-Sumitomo Pharma Co. Ltd. Ohe Y. also received honoraria from Chugai Pharmaceutical Co., Ltd, Eli Lilly, Taiho Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd, AstraZeneca, Daiichi-Sankyo Co., Ltd, and Boehringer Ingelheim. Hiroshi Nokihara received research funding from Merck Serono, Pfizer, Taiho Pharmaceutical Co., Eisai Co., Ltd, Chugai Pharmaceutical Co., Ltd, Eli Lilly, Novartis, Daiichi-Sankyo Co., Ltd, GlaxoSmithKline, Yakult Co. Ltd, Quintiles, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim and Ono Pharmaceutical Co., Ltd. Hiroshi Sakai received research funding from Chugai Pharmaceutical Co., Ltd, Eli Lilly, Taiho Pharmaceutical Co., Ltd, MSD, AstraZeneca, Ono Pharmaceutical Co., Ltd, Yakult Co., Ltd, Merck Serono, and Bristol-Meyers Squibb. Sakai H. also received honoraria from Ono Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd, Eli Lilly, Taiho Pharmaceutical Co., Ltd, and Bristol-Myers Squibb. Miyako Satouchi received funding from Ono Pharmaceutical Co., Ltd, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd, AstraZeneca, Eli Lilly, Pfizer, Taiho Pharmaceutical Co., Ltd, MSD, Novartis, and Astellas Pharma Inc. Satouchi M. also received honoraria from Ono Pharmaceutical Co., Ltd, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd, AstraZeneca, Eli Lilly, Pfizer, Taiho Pharmaceutical Co., Ltd, and Boehringer Ingelheim. Kazuhiko Nakagawa received research funding from Chugai Pharmaceutical Co., Ltd, Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd, OncoTherapy Science, MSD, Eisai Co, Ltd, EPS Associates Co., Ltd, Takeda Pharmaceutical Co., Ltd, Japan Clinical Research Operations, Quintiles, Boehringer Ingelheim, Pfizer, Daiichi-Sankyo Co., Ltd, Kyowa Hakko Kirin Co., Ltd, Astellas Pharma Inc., and PPD-SNBL. Nakagawa K. also received honoraria from Chugai Pharmaceutical Co., Ltd, Eli Lilly, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, and Astellas Pharma Inc. Mitsuhiro Takenoyama received research funding from Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd, Eli Lilly, Daiichi-Sankyo Co., Ltd, Boehringer Ingelheim, Novartis, and Eli Lilly. Takenoyama M. also received honoraria from Chugai Pharmaceutical Co., Ltd. Hiroshi Tanaka received research funding from Ono Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd, AstraZeneca, MSD, and Eli Lilly. Tanaka H. also received honoraria from Ono Pharmaceutical Co., Ltd. Koichi Minato received research funding from Ono Pharmaceutical Co., Ltd and Chugai Pharmaceutical Co., Ltd. Toshiaki Takahashi received research funding from AstraZeneca, Eli Lilly, Chugai Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd, Pfizer, Takeda Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, and MSD. Takahashi T. also received honoraria from AstraZeneca, Eli Lilly, Chugai Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd, and Boehringer Ingelheim. Makoto Maemondo received research funding from Boehringer Ingelheim. Maemondo M. also received honoraria from Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd, AstraZeneca, and Pfizer. Koji Takeda received research funding from Abbvie, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd, Eli Lilly, Eisai Co. Ltd, GlaxoSmithKline, Kyowa Hakko Kirin Co. Ltd, Merck Serono, Ono Pharmaceutical Co. Ltd, Quintiles Transnational Japan, and Taiho Pharmaceutical Co. Ltd. Hideo Saka received research funding from AstraZeneca, Taiho Pharmaceutical Co, Ltd, Ono Pharmaceutical Co., Ltd, MSD, Linical Co., Ltd, Eli Lilly, Bristol-Myers Squibb, Sanofi, and Daiichi-Sankyo Co., Ltd. Koichi Goto received research funding and honoraria from Ono Pharmaceutical Co., Ltd, and Bristol-Myers Squibb. Shinji Atagi received research funding from Ono Pharmaceutical Co., Ltd. Tomonori Hirashima received research funding from MSD, AstraZeneca, Eisai Co. Ltd, Daiichi-Sankyo Co., Ltd, Ono Pharmaceutical Co., Ltd, Merck Serono, Eli Lilly, Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Boehringer Ingelheim, Kyowa Hakko Kirin, Co., Ltd and Takeda Pharmaceutical Co., Ltd. Hirashima T. also received honoraria from Ono Pharmaceutical Co., Ltd. Naoki Sumiyoshi is an employee of Ono Pharmaceutical Co. Ltd. Tomohide Tamura received honoraria from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Eli Lilly, Eisai Co., Ltd, and Yakult Co., Ltd.
