From March 24, 2017, to March 31, 2020, 5944 patients with head and neck cancer were registered; we analyzed 632 patients who planned to start nivolumab treatment by June 30, 2017, because the prespecified number of patients to be included in the study were assembled by then (Fig. 1). Of those, 24 were excluded from the safety analysis, predominantly because they did not receive nivolumab by June 30, 2017, and one was excluded because of the lack of permission for this report. Thus, the case report forms of 607 eligible patients were analyzed as the safety analysis set. In this set, nine patients were excluded from the effectiveness analysis, because they had not received platinum-containing chemotherapy before the nivolumab treatment; ultimately, 598 patients constituted the effectiveness analysis set.
In the safety analysis set, 454 patients (74.8%) were male (Table 1). The median age was 64 years, and 76 (12.5%) were ≥ 75 years. Most patients (78.7%) had ECOG PS 0 or 1; meanwhile, 129 patients (21.3%) had ECOG PS ≥ 2, which is an ineligibility criterion for CheckMate 141, and 40 patients (6.6%) had ECOG PS ≥ 3. The majority (84.5%) suffered from stage IV head and neck cancer, with the pharynx as the most common primary site (47.0%).
The median frequency of nivolumab administration was 6 (range 1–18). The average dose of each administration was 157.7 (SD 32.6) mg and 3.0 (SD 0.03) mg/kg. The median duration of administration was 85 (range 1–302) days.
In the safety analysis set, nivolumab treatment was continued in 169 patients (27.8%) for ≥ 6 months but discontinued in 438 patients (72.2%) within 6 months (Fig. 1). Major reasons for discontinuation were as follows: a successful nivolumab response in 4 patients, disease progression or death in 281, unsatisfactory response in 154, and adverse events in 81.
The incidence of any TRAEs was 36.1%, and that of grade ≥ 3 TRAEs was 12.5% (Table 2). The most common TRAE was hypothyroidism (7.6%) (Online Resource 1: Supplementary Table S1), while the most common grade ≥ 3 TRAEs were ILD (1.2%), diarrhea (0.8%), and hepatic function abnormal (0.7%). Possible relationships between death and the nivolumab treatment could not be ruled out in 16 patients (2.6%) (Table 2).
Online Resource 1: Supplementary Table S2 summarizes the incidences of TRAEs in patient subpopulations classified by patients’ baseline characteristics. Patients with medical history had a higher TRAE incidence than those without medical history (42.7% vs. 26.4%). Regarding medical history for each organ, patients with medical history of hepatic, renal, or thyroidal diseases had higher TRAE incidences than those without the corresponding medical history. With regard to lung medical history, the incidence of TRAEs demonstrated no statistically significant difference. Moreover, patients with hepatic medical history had a higher incidence of hepatobiliary disorders including hepatic function abnormal than those without hepatic medical history (6.0% vs. 2.3%) (Online Resource 1: Supplementary Table S3). Likewise, the incidence of endocrine disorders including hypothyroidism and thyroid disorder was higher in patients with thyroidal medical history (20.3%) than those without thyroidal medical history (8.9%). For renal medical history, hypothyroidism was the only TRAE observed in three or more patients (9.4%).
The most common TRAEs of special interest were thyroid dysfunction in 62 (10.2%), hepatic dysfunction in 32 (5.3%), and ILD in 25 (4.1%) patients (Table 3). The incidence of these TRAE categories was ≥ 1 percentage point higher than those reported in the whole population of CheckMate 141 (Online Resource 1: Supplementary Table S4). No incidences of encephalitis, venous thromboembolism, or immune thrombocytopenic purpura were reported. Online Resource 1: Supplementary Table S5 lists the exploratory analysis-identified risk factors for these common TRAE categories. Current or former smoking history was a possible risk factor for thyroid dysfunction (HR 2.38) and hepatic dysfunction (HR 3.10). Patients with a medical history of pulmonary infection (HR 5.11) or with a medical history of emphysema or chronic obstructive pulmonary disease (HR 5.64) had a high risk of developing ILD. Although the median time to the onset of each TRAE of special interest were mostly 1–2 months, most of the TRAEs occurred throughout the observation period of 6 months (Fig. 2). Nonetheless, with appropriate treatment including steroid treatment, most patients recovered or remitted from TRAEs of special interest (Table 4).
In the effectiveness analysis set, at least 334 out of 598 patients (55.9%; 95% CI 51.8–59.9%) survived for ≥ 6 months. Specifically, 312 (66.0%), 14 (16.3%), and 8 (20.5%) patients with ECOG PS 0–1, 2, and 3–4 survived for ≥ 6 months, respectively.