Abstract
Objectives
We report 2-year results from CheckMate 141 to establish the long-term efficacy and safety profile of nivolumab and outcomes by tumor PD-L1 expression in patients with recurrent or metastatic (R/M),platinum-refractory squamous cell carcinoma of the head and neck (SCCHN).
Methods
Patients with R/M SCCHN with tumor progression/recurrence within 6 months of platinum therapy were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator’s choice (IC). Primary endpoint: overall survival (OS). Data cutoff: September 2017.
Results
With 24.2 months’ minimum follow-up, nivolumab (n =240) continued to improve OS vs IC (n = 121), hazard ratio (HR) = 0.68 (95% CI 0.54–0.86). Nivolumab nearly tripled the estimated 24-month OS rate (16.9%) vs IC (6.0%), and demonstrated OS benefit across patients with tumor PD-L1 expression ≥1% (HR [95% CI] = 0.55 [0.39–0.78]) and < 1% (HR [95% CI] =0.73 [0.49–1.09]), and regardless of tumor HPV status. Estimated OS rates at 18, 24, and 30 months with nivolumab were consistent irrespective of PD-L1 expression (< 1%/≥1%). In the nivolumab arm, there were no observed differences in baseline characteristics or safety profile between long-term survivors and the overall population. Grade 3–4 treatment-related adverse event rates were 15.3% and 36.9% for nivolumab and IC, respectively.
Conclusion
Nivolumab significantly improved OS at the primary analysis and demonstrated prolonged OS benefit vs IC and maintenance of a manageable and consistent safety profile with 2-year follow-up. OS benefit was observed with nivolumab irrespective of PD-L1 expression and HPV status. (Clinicaltrials.gov: NCT02105636)
Keywords: Nivolumab; Head and Neck Neoplasms; Carcinoma, squamous cell of head and neck; Immunotherapy; Papillomaviridae (HPV, Human Papillomavirus Viruses); Programmed Cell Death 1 Receptor; CD274 protein, human (PD-L1 Protein, Human); Clinical Trial, Phase III; Survival Analysis; Survivors (Long-term Survivors)
Introduction
Squamous cell carcinoma of the head and neck (SCCHN) includes neoplasms in the oral cavity, pharynx, and larynx, and accounts for 90% of all head and neck cancers [1–3]. Patients with recurrent/metastatic (R/M) SCCHN who progress within 6 months after platinumbased therapy have poor long-term prognosis and limited treatment options, with a median overall survival (OS) of ≤6 months [4,5]. In 2016, nivolumab was approved in the United States for the treatment of this patient population, with European approval following in 2017 [6,7].
CheckMate 141 evaluated the efficacy, safety, and patient-reported quality of life of nivolumab monotherapy vs standard single agent of investigator’s choice (IC) in patients with R/M SCCHN who experienced tumor progression or recurrence within 6 months of platinum-based therapy administered in the adjuvant, primary (ie, with radiation), recurrent, or metastatic setting [8,9]. Nivolumab is the only immunotherapy to significantly improve OS at the primary analysis in this patient population, hazard ratio (HR) vs IC = 0.70 (97.73% confidence interval [CI] 0.51–0.96); p=0.01 [8]. With 1-year follow-up, nivolumab continued to improve OS compared with IC; HR= 0.71 (95% confidence interval [CI]: 0.55, 0.90) [10]. The Kaplan-Meier–estimated 18-month OS rate with nivolumab was nearly triple that with IC (21.5% vs 8.3%). The objective response rate (ORR) with nivolumab was more than twice that of IC (13.3% vs 5.8%). The safety profile of nivolumab was manageable, with fewer grade 3–4 treatment-related adverse events (TRAEs) compared with IC. Nivolumab also stabilized quality-of-life measures, whereas clinically meaningful deterioration was observed with IC [9]. Here, we report long-term (2-year) follow-up of CheckMate 141 in the overall population, as well as in subgroups defined by baseline tumor programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status.
Patients and methods
Study design and patients
CheckMate 141 is a randomized, open-label, phase 3 trial (NCT02105636), the detailed study design of which has been described previously [8]. Briefly, eligible patients were 18 years of age or older, had histologically confirmed R/M SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx, and had tumor progression on or within 6 months after the last dose of platinum-based chemotherapy administered in the locally advanced, recurrent, or metastatic disease setting. Patients were randomized 2:1, stratified by prior cetuximab treatment, to receive nivolumab (3 mg/kg every 2 weeks) or standard single agent of IC (methotrexate 40–60 mg/m2 weekly, docetaxel 30–40 mg/m2 weekly, or cetuximab 400 mg/m2 once, then 250 mg/m2 weekly). Treatment continued until tumor progression or unacceptable toxicity. Patients in the nivolumab arm were allowed to continue nivolumab treatment beyond tumor progression if they met predefined, protocol-specified criteria [11].
CheckMate 141 was conducted in accordance with the ethical principles in the Declaration of Helsinki. All patients provided written informed consent prior to enrollment. The study was approved by the institutional review board or independent ethics committee at each center and was conducted in accordance with Good Clinical Practice guidelines defined by the International Conference on Harmonisation.
Outcomes
The primary endpoint was OS, defined as the time from randomization to death due to any cause. Secondary endpoints included progression-free survival (PFS) and ORR. Tumor responses were evaluated every 6 weeks from week 9 until progression or treatment discontinuation using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 [12]. Safety was evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. Adverse events with potential immunologic cause were classified as select adverse events.
Exploratory biomarker analyses
Fresh or archival pretreatment tumor specimens were obtained after the last therapy and prior to trial entry. Tumor PD-L1 membrane expression was evaluated centrally by immunohistochemical testing using the Dako PD-L1 IHC 28–8 pharmDx assay in a minimum of 100 evaluable tumor cells. Patients were defined as PD-L1 expressors if their tumor had ≥1% PD-L1 expression and non-expressors if their tumor had < 1% PD-L1 expression. Documented tumor HPV status, assessed by p16 immunohistochemical testing by local or central analysis, was required for patients with oropharyngeal cancer. Tumors were defined as HPV positive if diffuse staining was present in at least 70% of tumor cells.
Statistical analyses
The current analyses are based on a September 2017 data cutoff, representing a minimum follow-up of 24.2 months. Efficacy analyses were conducted in all randomized patients (intent-to-treat [ITT] population), and safety analyses were conducted in all treated patients.
OS and PFS were assessed using the Kaplan-Meier method, and HRs and corresponding 2-sided 95% CIs were estimated using a Cox proportional hazards model. A generalization of the Brookmeyer and Crowley method was used to compute CIs for median survival times, and a 2-sided Cochran-Mantel-Haenszel test was used to compute the odds ratio and associated CIs for tumor response.
Results
Patients
Baseline characteristics of the 361 randomized patients have been described previously [8]. Compared with the primary analysis [8], baseline tumor PD-L1 expression and HPV status were quantifiable in 15 and 8 additional patients, respectively (Table 1). At the time of this analysis, 8 (3.4%) patients remained on treatment in the nivolumab arm compared with 0 in the IC arm (Supplementary Table 1 and Supplementary Fig. 1). Sixteen patients in the nivolumab arm discontinued treatment between 1 and 2 years, most commonly due to disease progression (n =8); 2 patients discontinued nivolumab therapy after 2 years (1 each due to adverse events unrelated to study drug and patient request). No patient discontinued nivolumab therapy after 2 years due to disease progression or treatment-related toxicity. The median (range) duration of treatment was 1.9 (0 to 36+) months for nivolumab and 1.9 (0 to 13) months for IC. After treatment discontinuation, 5.3% of patients in the nivolumab arm and 10.1% of patients in the IC arm received subsequent immunotherapy (nivolumab, pembrolizumab, durvalumab, or urelumab) (Supplementary Table 2).
Table 1.
Baseline tumor PD-L1 expression and HPV status.
| Patients, n (%) | Nivolumab (n = 240) | IC (n = 121) |
|---|---|---|
| Tumor PD-L1 expression | 40 (33.1) | |
| Non-expressors (< 1%) | 76 (31.7) | 40 (33.1) |
| Expressors (≥1%) | 96 (40.0) | 63 (52.1) |
| Not quantifiable | 68 (28.3) | 18 (14.9) |
| Tumor HPV status | ||
| Positive | 64 (26.7) | 29 (24.0) |
| Negative | 56 (23.3) | 37 (30.6) |
| Unknown/not reported | 120 (50.0) | 55 (45.5) |
IC, investigator’s choice; HPV, human papillomavirus; PD-L1, programmed death ligand 1.
Efficacy in overall study population
Consistent with the primary analysis, nivolumab demonstrated sustained OS benefit compared with IC, with a 32% reduction in risk of death; HR =0.68 (95% CI 0.54–0.86) with long-term follow-up (minimum 24.2 months). Median (95% CI) OS was 7.7 (5.7–8.8) months in the nivolumab arm and 5.1 (4.0–6.2) months in the IC arm (Fig. 1). The Kaplan-Meier–estimated 24-month OS rate with nivolumab (16.9% [95% CI 12.4%–22.0%]) was nearly triple that of IC (6.0% [95% CI 2.7%–11.3%]). The estimates of the HR for death among prespecified demographic and clinical subgroups, including age, Eastern Cooperative Oncology Group (ECOG) performance status, tumor site, and prior lines of systemic therapy, were generally consistent with the ITT population, favoring nivolumab (Supplementary Fig. 2). With longer follow-up, PFS (HR = 0.87 [95% CI 0.68–1.11]) was similar to previous analyses [8,10].
Fig. 1.
Overall survival (OS) with a minimum follow-up of 24.2 months (intent-to-treat population). Symbols represent censored observations; dotted lines indicate OS rate time points. CI, confidence interval; HR, hazard ratio; IC, investigator’s choice; Nivo, nivolumab.
The ORR was unchanged from previous analyses (Table 2) [8,10]. In the nivolumab arm, 7 complete responses were observed, including 1 patient who had a partial response at the previous analysis, but since then converted to a complete response. The median (range) time to response remained unchanged in both treatment arms from previous follow-ups, 2.1 (1.8 to 7.4) months for nivolumab vs 2.0 (1.9 to 4.6) months for IC [8]. The median (range) duration of response with nivolumab treatment was more than double that with IC (9.7 [2.8 to 32.8+] vs 4.0 [1.5+ to 11.3]).
Table 2.
Best overall response.
| Nivolumab (n = 240) | IC (n = 121) | |
|---|---|---|
| Best overall response, n (%) | ||
| Complete response | 7 (2.9) | 1 (0.8) |
| Partial response | 25 (10.4) | 6 (5.0) |
| Stable disease | 55 (22.9) | 43 (35.5) |
| Progressive disease | 99 (41.3) | 42 (34.7) |
| Unable to determine | 54 (22.5) | 29 (24.0) |
| ORR,% (95% CI) | 13.3 (9.3–18.3) | 5.8 (2.4–11.6) |
| Time to response, median (range), mo | 2.1 (1.8–7.4) | 2.0 (1.9–4.6) |
| Duration of response, median (range), mo | 9.7 (2.8 to 32.8+) | 4.0 (1.5 + to 11.3) |
CI, confidence interval; IC, investigator’s choice; ORR, objective response rate.
Tumor PD-L1 expression and HPV status
OS benefit with nivolumab vs IC was demonstrated across PD-L1 expressors and non-expressors (Fig. 2). With long-term follow-up, nivolumab continued to provide OS benefit in PD-L1 expressors, with a consistent 45% reduction in the risk of death compared with IC (HR = 0.55 [95% CI 0.39–0.78]) (Fig. 2A). In PD-L1 non-expressors, nivolumab demonstrated a 27% reduction in the risk of death compared with IC (HR = 0.73 [95% CI 0.49–1.09] (Fig.2B). For these patients, HR (95% CI) trended lower as follow-up time increased: 0.83 (0.54–1.29) and 0.89 (0.54–1.45) at the 1-year (September 2016 data cutoff, Supplementary Fig. 3A) and primary analysis (December 2015 data cutoff, Supplementary Fig. 3B) [8], respectively. Kaplan-Meier estimated OS rates with nivolumab were consistent between PD-L1 expressors and non-expressors at 18 (24.0% and 26.2%, respectively), 24 (18.5% and 20.7%), and 30 (13.7% and 11.2%) months (Fig. 2). Median PFS for nivolumab was similar across PD-L1 subgroups and was not differentiated from IC in either subgroup, 2.1 (95% CI 2.0–3.4) months and 2.0 (95% CI 1.9–2.1) months in PD-L1 expressors and non-expressors, respectively, in the nivolumab arm, and 2.0 (95% CI 1.9–3.1) months and 2.7 (95% CI 2.0–4.6) months in PD-L1 expressors and non-expressors in the IC arm. The HR for PFS was 0.59 (95% CI 0.41–0.84) in PD-L1 expressors and 1.13 (95% CI 0.75–1.71) in PD-L1 non-expressors. Nivolumab improved ORR compared with IC in PD-L1 expressors; ORR was similar across treatment arms in PD-L1 non-expressors (Supplementary Table 3). Complete responses were observed across PD-L1 expressors (n =2), non-expressors (n =2), and PD-L1 non-quantifiable (n =3).
Fig. 2.
Overall survival (OS) in programmed death ligand 1 (PD-L1) expressors (A) and PD-L1 non-expressors (B). Symbols represent censored observations. CI, confidence interval; HR, hazard ratio; IC, investigator’s choice; Nivo, nivolumab.
OS benefit with nivolumab was observed in both patients with HPVpositive and HPV-negative tumors, and benefit was maintained with long-term (2-year) follow-up (Fig. 3). Nivolumab demonstrated approximately 40% reduction in the risk of death compared with IC in both the HPV-positive subgroup (HR =0.60 [95% CI 0.37–0.97]) as well as the HPV-negative subgroup (HR =0.59 [95% CI 0.38–0.92]). Nivolumab improved ORR compared with IC in patients with HPV-positive tumors; ORR was similar across treatment arms in patients with HPV-negative tumors (Supplementary Table 3).
Fig. 3.
Overall survival (OS) by tumor human papillomavirus (HPV) status, positive (A) and negative (B). Symbols represent censored observations. CI, confidence interval; HR, hazard ratio; IC, investigator’s choice; Nivo, nivolumab.
Overall survival was further analyzed in subgroups defined according to both tumor HPV status and PD-L1 expression (Supplementary Fig. 4). Nivolumab prolonged median OS vs IC in each of the 4 subgroups, with the greatest benefit (HR =0.39 [95% CI 0.18–0.81]) found among PD-L1 expressors with HPV-positive tumors. The results of this analysis should be interpreted with caution, as sample sizes and power were limited.
Safety
Among all treated patients (n =347), nivolumab demonstrated a favorable safety profile compared with IC with long-term follow-up. The safety profile remained manageable and consistent with previous analyses [8,10], with fewer grade 3–4 TRAEs in the nivolumab arm compared with the IC arm (Table 3). Most grade 3–4 TRAEs occurred within the first 6 months of initiating treatment; 19.5%, 2.5%, and 1.7% of patients in the nivolumab arm experienced grade 3–4 TRAEs within the first 6 months, between 6 and 12 months, and at or after 12 months of initiating study treatment, respectively. There were 6 patients with grade 3 TRAEs first occurring after 12 months of initiating therapy; 4 in the nivolumab arm (hyperlipasemia and hyperamylasemia; hyponatremia; deterioration of diabetes mellitus; and lipase increased and weight decreased), and 2 patients in the IC arm (hypothyroidism and increased aspartate aminotransferase); no patients experienced grade 4 TRAEs during this time frame. The most common select TRAEs in the nivolumab and IC arms were skin-related and gastrointestinal, respectively (Table 3). The incidence of serious TRAEs was lower in the nivolumab arm (7.2%) compared with the IC arm (15.3%). A greater proportion of patients in the IC arm compared with the nivolumab arm discontinued the study due to TRAEs at any time (9.0% vs 4.2%). Four TRAEs led to discontinuation between 1 and 2 years in the nivolumab arm: nephritis; pneumonitis; uncontrollable diabetes mellitus, chronic heart failure, and fatigue; and lipase elevation with progressive weight loss (n = 1 each). The number of treatment-related deaths remained unchanged from the primary analysis [8], (2 deaths in the nivolumab arm [1 each due to pneumonitis and hypercalcemia], and 1 death in the IC arm due to treatment-related lung infection).
Table 3.
Most common TRAEs (≥15% in any arm) and select TRAEs among all treated patients.
| Patients, n (%) | Nivolumab (n = 236) | IC (n = 111) | ||
|---|---|---|---|---|
| Any grade | Grade 3–4 | Any grade | Grade 3–4 | |
| Any TRAE | 146 (61.9) | 36 (15.3) | 88 (79.3) | 41 (36.9) |
| TRAEs in ≥15% of patients | 37 (15.7) | 5 (2.1) | 20 (18.0) | 3 (2.7) |
| Fatigue | 37 (15.7) | 5 (2.1) | 20 (18.0) | 3 (2.7) |
| Nausea | 22 (9.3) | 0 | 23 (20.7) | 1 (0.9) |
| Anemia | 12 (5.1) | 3 (1.3) | 19 (17.1) | 6 (5.4) |
| Asthenia | 10 (4.2) | 1 (0.4) | 17 (15.3) | 2 (1.8) |
| Select TRAEs | ||||
| Skin | 41 (17.4) | 0 | 14 (12.6) | 2 (1.8) |
| Endocrine | 22 (9.3) | 1 (0.4) | 1 (0.9) | 0 |
| Gastrointestinal | 20 (8.5) | 1 (0.4) | 16 (14.4) | 2 (1.8) |
| Hepatic | 7 (3.0) | 2 (0.8) | 5 (4.5) | 1 (0.9) |
| Pulmonary | 7 (3.0) | 2 (0.8) | 1 (0.9) | 0 |
| Hypersensitivity/infusion reactions | 3 (1.3) | 0 | 2 (1.8) | 1 (0.9) |
| Renal | 3 (1.3) | 0 | 2 (1.8) | 1 (0.9) |
IC, investigator’s choice; TRAEs, treatment-related adverse events.
Post hoc analysis of 2-year survivors
In the nivolumab arm, 37 patients (15.4%) were alive (in survival follow-up) at 2 years. There were no observed differences in baseline demographic or disease characteristics among patients in the nivolumab arm who were alive at 2 years compared with the nivolumab ITT population (Table 4). The safety profile of 2-year survivors in the nivolumab arm was consistent with all nivolumab-treated patients (Supplementary Table 4); however, a relatively higher rate of any-grade TRAEs was reported in 2-year survivors (89.2%) vs in all nivolumab-treated patients (61.9%). Fatigue was the most common TRAE among all nivolumab-treated patients and 2-year survivors. Disease progression was the most frequent primary cause of death in both study arms, both among patients who experienced late death (> 24 months after the first dose) and those who experienced early death.
Table 4.
Baseline characteristics in the nivolumab arm among the ITT population and 2-year survivors.
| Patients, n (%) | Nivolumab |
|
|---|---|---|
| ITT (n = 240) | 2-year survivors (n = 37) | |
| ECOG performance status | ||
| 0 | 49 (20.4) | 10 (27.0) |
| ≥1 | 190 (79.2) | 27 (73.0) |
| Not reported | 1 (0.4) | 0 |
| Tobacco use | ||
| Current/former | 191 (79.6) | 31 (83.8) |
| Never | 39 (16.3) | 6 (16.2) |
| Unknown | 10 (4.2) | 0 |
| Prior cetuximab use | 147 (61.3) | 19 (51.4) |
| Yes | 147 (61.3) | 19 (51.4) |
| No | 93 (38.8) | 18 (48.6) |
| Number of lines of prior systemic therapy | ||
| 1 | 106 (44.2) | 14 (37.8) |
| 2 | 80 (33.3) | 16 (43.2) |
| ≥3 | 54 (22.5) | 7 (18.9) |
| Site of primary tumor | ||
| Oral cavity | 108 (45.0) | 13 (35.1) |
| Pharynx | 92 (38.3) | 17 (45.9) |
| Larynx | 34 (14.2) | 5 (13.5) |
| Other | 6 (2.5) | 2 (5.4) |
| Tumor PD-L1 expression | ||
| Expressors (≥1%) | 96 (40.0) | 16 (43.2) |
| Non-expressors (< 1%) | 76 (31.7) | 15 (40.5) |
| Tumor HPV status | ||
| Positive | 64 (26.7) | 12 (32.4) |
| Negative | 56 (23.3) | 13 (35.1) |
| Unknown/not reported | 120 (50.0) | 12 (32.4) |
ECOG, Eastern Cooperative Oncology Group; HPV, human papillomavirus; ITT, intent-to-treat; PD-L1, programmed death ligand 1.
Discussion
With long-term (minimum 2-year) follow-up, nivolumab demonstrated prolonged OS benefit compared with IC and maintained a favorable safety profile in patients with R/M SCCHN post–platinum therapy. At the time of the current analysis, there were 8 patients (3.4%) continuing on nivolumab treatment and no patients continuing on IC.
Nivolumab is the only immunotherapy to demonstrate OS benefit across PD-L1 expressors/non-expressors in this patient population. Notably, Kaplan-Meier–estimated OS rates at 18, 24, and 30 months among nivolumab patients were consistent between PD-L1 expressors and non-expressors. Among PD-L1 expressors, OS benefit vs IC was observed at the primary analysis [8] and maintained at the 2-year follow-up. Among PD-L1 non-expressors, the HR for death consistently trended lower as follow-up time increased, suggesting a long-term benefit of nivolumab in this patient population. An assessment of the patients who had tumor PD-L1 data at the time of the primary analysis (excluding additional patients with quantifiable PD-L1 expression since the primary analysis) resulted in a HR of 0.77 (95% CI 0.51–1.15). In addition to the OS benefit seen, complete responses were observed across PD-L1 expressors/non-expressors.
Both patients with HPV-positive and HPV-negative tumors benefited from nivolumab therapy, and this was maintained with long-term follow-up. Notably, with current follow-up, Kaplan-Meier OS curves were similar between both HPV subgroups, and the HRs were nearly identical. Given the worse prognosis historically seen among patients with HPV-negative SCCHN [13], nivolumab helps address the unmet medical need in this population.
The median duration of response in the current analysis for each arm was similar to that of 1 year; however, the upper limit of the range for the nivolumab arm continued to increase, further suggesting that patients who remained on nivolumab continued to experience long-term benefit. Importantly, the OS benefit was seen despite approximately 10% of patients in the IC arm receiving subsequent immunotherapy.
There were no observed differences in baseline characteristics, including tumor PD-L1 expression and HPV status, among nivolumab-treated patients who were alive at 2 years compared with the nivolumab ITT population. Similarly, the safety profile of patients alive at 2 years in the nivolumab arm was consistent with all nivolumab-treated patients; this lack of new safety signals with long-term follow-up suggests a predictable safety profile. The slightly higher rate of any-grade TRAEs among 2-year survivors compared with all treated patients was likely due to these patients having longer follow-up, and thus having more time to experience TRAEs.
In CheckMate 141, nivolumab was dosed according to a weightbased regimen (3 mg/kg every 2 weeks), which was also the initial approved regimen in the United States and other countries. Recently, however, a flat dose of 240 mg every 2 weeks or 480 mg every 4 weeks via 30-min intravenous infusion was approved in the United States [14]. The 240 mg every 2 weeks via 30-min infusion dosing regimen was also recently recommended for approval by the Committee for Medicinal Products for Human Use of the European Medicines Agency (final decision pending) [15]. This added flexibility in dosing may provide health care professionals the flexibility to customize patient care.
Conclusion
Nivolumab is an established therapeutic option in R/M SCCHN postplatinum therapy and the only immunotherapy to demonstrate significant OS improvement in the primary analysis of a phase 3 study (CheckMate 141). Nivolumab is also the only immunotherapy to stabilize QoL in this patient population. With long-term follow-up, nivolumab demonstrated prolonged OS benefit compared with IC (methotrexate, docetaxel, or cetuximab) and maintained a favorable safety profile, with no new safety signals identified. Nivolumab demonstrated OS benefit across PD-L1 expressors/non-expressors and irrespective of HPV status in this patient population.
Supplementary Material
Acknowledgment
The authors thank the patients and their families, as well as the participating teams, for making this study possible. This study was sponsored by Bristol-Myers Squibb (Princeton, NJ) and ONO Pharmaceutical Company, Ltd. (Osaka, Japan). Writing and editorial assistance was provided by Qiong Wang, PhD, and Beth Burke, PhD, CMPP, of Evidence Scientific Solutions Inc, funded by Bristol-Myers Squibb.
Financial support
The work was supported by Bristol-Myers Squibb.
Conflict of interest
R.L.F. reports consultancy role for AstraZeneca, Bristol-Myers Squibb, Celgene, Lilly, Merck, and Pfizer; grants from AstraZeneca, Bristol-Myers Squibb, and VentiRx. G.B.Jr. reports grants from Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Immatics, Macrogenics, Merck, Novartis, and Xcovery; consultancy fees from ARIAD, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Clovis, Genentech, Immatics, Merck, Novartis, and Xcovery; advisory board participation for Bayer. J.F. reports personal fees from AstraZeneca and Bristol-Myers Squibb. J.G. reports consultancy role for AstraZeneca, Bristol-Myers Squibb, Innate Pharma, and Merck Serono; grants from Bristol-Myers Squibb, GlaxoSmithKline, and Merck Serono. L.Licitra reports grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Merck Serono, Merck Sharpe & Dohme, Novartis, and Roche; personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Debiopharm, Eisai, Merck Serono, Merck Sharpe & Dohme, Novartis, and Roche; travel arrangements from Bayer, Debiopharm, Merck Serono, and Sobi. K.J.H. reports honoraria from AstraZeneca, Bristol-Myers Squibb, Merck, Merck Sharpe & Dohme, and Pfizer; grants from AstraZeneca and Merck Sharpe & Dohme. S.K. reports honoraria and grants from Bristol-Myers Squibb and Roche/Genentech. E.E.V. reports personal fees from AbbVie, Amgen, ARIAD, AstraZeneca, Bayer, Biolumia, and Bristol-Myers Squibb. F.W. reports advisory board fees from Fusion and Merck; grants from Bayer, Bristol-Myers Squibb, Eisai, and Merck. N.F.S. reports advisory board fees from Bristol-Myers Squibb, Eli Lilly, Genentech, Kura Oncology, and Merck. L.C.I.D. reports personal fees from Bristol-Myers Squibb, Merck KGaA, and Merck Sharp & Dohme. R.H. reports personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Merck, and Pfizer. T.R. reports advisory board fees from Bristol-Myers Squibb and Merck KGaA. N.K. reports honoraria from Bayer, Bristol-Myers Squibb, Eisai, Merck Serono, and ONO Pharmaceuticals; grants from AstraZeneca, Pfizer, and ONO Pharmaceuticals. M.T. reports advisory board fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharpe & Dohme, ONO Pharmaceuticals, and Pfizer; honoraria from Bayer, Bristol-Myers Squibb, Eisai, and Otsuka; grants from AstraZeneca, Boehringer Ingelheim, Eisai, Merck Sharpe & Dohme, NanoCarrier, Novartis, ONO Pharmaceuticals, and Pfizer. M.L., L.Li, and V.J. are employees of Bristol-Myers Squibb. M.L.G. reports consultancy role for Amgen, AstraZeneca, Aspyrian Therapeutics, Bristol-Myers Squibb, Celgene, and Merck. A.D.C. and C.E. report no conflicts of interest.
Footnotes
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.oraloncology.2018.04.008.
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