Patients

A total of 7724 patients were registered and CRFs were completed for 7444 patients. After excluding 23 patients for the reasons listed in Fig. 1, the overall population comprised 7421 patients (safety analysis set). The general characteristics, including the type of cancer and medical histories, of the overall population are summarized in Table 2. Males and females comprised 67.1% and 32.9% of patients, respectively. The median age was 67.0 (range 14–98) years, and 21.8% were ≥ 75 years old. MM, NSCLC, RCC, HNC, and GC accounted for 26.7%, 48.5%, 7.5%, 8.2%, and 8.8% of the patients, respectively. Twenty-five patients received nivolumab for off-label purposes (23 in the MM PMS [9] and 2 in the NSCLC PMS [10]) and were included in the safety analyses here. Overall, 2.9% of patients had a history of autoimmune disease, 3.9% had a history of ILD, 1.1% had a history of tuberculosis, 1.2% had a history of hepatitis B, and 0.9% had a history of hepatitis C. Eighty-nine patients (1.2%) were vaccinated during the PMS, 77 for influenza, and 12 for Streptococcus pneumoniae. The distribution of nivolumab doses by indication is shown in ESM Table 1.

Fig. 1

Patient disposition. CRF case-report form

Table 2 Characteristics of the overall population of patientsTRAEs in the overall population

TRAEs were reported in 49.1% of patients, with grade ≥ 3 TRAEs in 16.7% (ESM Table 2). This table also shows the frequencies of TRAEs by system organ class (SOC) in the overall population.

The frequencies of TRAESI (any grade and grade ≥ 3) are listed in Table 3. Endocrine disorders (14.4%), hepatobiliary disorders (10.9%), ILD (7.0%), gastrointestinal disorders (5.5%), and infusion reaction within 24 h (5.3%) were the five most common categories of TRAESI (any grade). The five most common grade ≥ 3 TRAESI were hepatobiliary disorders (3.1%), ILD (2.9%), gastrointestinal disorders (1.5%), endocrine disorders (1.4%), and type 1 diabetes mellitus (T1DM) (0.5%). Rare TRAESI that have a high risk of becoming serious (e.g. myasthenia gravis, myocarditis, rhabdomyolysis, T1DM, encephalitis, venous thromboembolism) are also listed in Table 3. These TRAE categories occurred in < 1% of patients, but most of the events were grade ≥ 3, including life-threatening and fatal events.

Table 3 TRAESI in the overall population (N = 7421)

The median time to the onset of TRAESI was mostly within 90 days (ESM Fig. 1). However, the median time to onset exceeded 90 days for severe skin disorders (median [range]: 93.5 [4–350] days), hemophagocytic syndrome (94.5 [28–258] days), serious blood disorders (119.0 [4–323] days), T1DM (146.0 [13–341] days), and tuberculosis (173.0 [148–198] days).

The five most common TRAEs were hypothyroidism (8.1%), ILD (5.0%), aspartate aminotransferase increased (4.3%), diarrhea (4.3%), and alanine aminotransferase increased (3.5%). The five most common grade ≥ 3 TRAEs were ILD (2.1%), hepatic function abnormal (1.0%), diarrhea (0.8%), aspartate aminotransferase increased (0.7%), and alanine aminotransferase increased (0.6%).

TRAEs in prespecified subgroups of patientsAutoimmune disease

TRAEs occurred in 61.2% of patients with a medical history of autoimmune disease, with grade ≥ 3 TRAEs in 20.6% (ESM Table 3). This table also shows the frequencies of TRAE SOCs in these patients.

The TRAESI are listed in Table 4; the three most common were endocrine disorders (19.6%), hepatobiliary disorders (15.0%), and ILD (12.6%). ILD (5.1%) and hepatobiliary disorders (3.7%) were the two most common grade ≥ 3 TRAESI.

Table 4 TRAESI in patients with a history of autoimmune disease, ILD, tuberculosis, hepatitis B, or hepatitis C

Exacerbation/recurrence of autoimmune diseases is listed in Table 5. Overall, 16 patients (7.5%) experienced exacerbation/recurrence of their autoimmune disease, which was classified as resolved/resolving in 11 (68.8%). ESM Table 4 shows the frequencies of TRAEs (any) and TRAESI according to the type of preexisting autoimmune disease. The frequencies of TRAEs varied among the types of autoimmune disease.

Table 5 Exacerbation/recurrence of autoimmune diseasesHistory of ILD

Of 290 patients with a history of ILD, 64.5% experienced any TRAE and 24.5% experienced a grade ≥ 3 TRAE (ESM Table 3). The table also shows the frequency of TRAE SOCs in this patient population. As shown in Table 4, the most common TRAESI were ILD (24.1%), endocrine disorders (15.2%), and hepatobiliary disorders (12.1%). The most common grade ≥ 3 TRAESI were ILD (11.0%), hepatobiliary disorders (3.8%), and endocrine disorders (3.4%). The proportions of patients with resolved/remission ILD, by grade, were similar between those with history of ILD and those without history of ILD (ESM Table 5).

History of tuberculosis

Overall, 56.0% of patients with a medical history of tuberculosis experienced any TRAE and 19.0% experienced a grade ≥ 3 TRAE (ESM Table 3). The table also shows the frequency of TRAE SOCs in this patient population.

As shown in Table 4, the most common TRAESI were endocrine disorders (14.3%), gastrointestinal disorders (10.7%), and hepatobiliary disorders (8.3%). Grade ≥ 3 TRAESI were ILD (3.6%), gastrointestinal disorders (3.6%), myasthenia gravis (1.2%), and hepatobiliary disorders (1.2%). No exacerbation/recurrence of tuberculosis was reported. Tuberculosis was reported as a TRAE in 2 patients (< 0.1%) without a medical history of tuberculosis. Both of these TRAEs were classified as grade ≤ 2.

Hepatitis B/C

TRAEs occurred in 55.1% of patients with a medical history of hepatitis B and in 45.6% of patients with a medical history of hepatitis C (ESM Table 3). Grade ≥ 3 TRAEs occurred in 23.6% and 14.7% of patients, respectively. This table also shows the frequencies of TRAE SOCs in patients with hepatitis B or C.

In patients with a medical history of hepatitis B, the three most common TRAESI were hepatobiliary disorders (16.9%), endocrine disorders (9.0%), and ILD (7.9%) (Table 4). The most common grade ≥ 3 TRAESI were hepatobiliary disorders (5.6%). In patients with a medical history of hepatitis C, the three most common TRAESI were hepatobiliary disorders (10.3%), endocrine disorders (8.8%), and infusion reaction within 24 h (8.8%). Grade ≥ 3 TRAESI were hepatobiliary disorders (2.9%), ILD (1.5%), and severe skin disorders (1.5%) (Table 4).

Patients vaccinated during the PMS

Among patients vaccinated during the PMS, 62.9% experienced any TRAE and 11.2% experienced a grade ≥ 3 TRAE (ESM Table 6). The TRAE SOCs in this patient population are shown in this table.

As shown in Table 6, the three most common TRAESI were endocrine disorders (19.1%), hepatobiliary disorders (13.5%), and gastrointestinal disorders (7.9%). Myositis, gastrointestinal disorders, hepatobiliary disorders, T1DM, renal and urinary disorders, and severe skin disorders were reported as grade ≥ 3 TRAEs in 1 patient (1.1%) each (Table 6).

Table 6 TRAESI in patients with a history of vaccination (N = 89)By age: < 75 and ≥ 75 years old

Among patients aged < 75 years, 48.4% experienced any grade TRAEs and 16.5% experienced grade ≥ 3 TRAEs. Among patients aged ≥ 75 years, 51.7% experienced any grade TRAEs and 17.1% experienced grade ≥ 3 TRAEs (ESM Table 7). This table also shows the TRAE SOCs in both age-groups.

Table 7 shows the TRAESI in both age-groups. The three most common TRAESI were the same in patients aged < 75 and those aged ≥ 75 years, comprising endocrine disorders (14.1% and 15.5%, respectively), hepatobiliary disorders (10.9% and 11.1%, respectively), and ILD (6.9% and 7.5%, respectively). The three most frequent grade ≥ 3 TRAESI among patients aged < 75 years were hepatobiliary disorders (3.3%), ILD (2.7%), and gastrointestinal disorders (1.6%). The three most common grade ≥ 3 TRAESI in patients aged ≥ 75 years were ILD (3.3%), hepatobiliary disorders (2.3%), and endocrine disorders (1.5%).

Table 7 TRAESI in patients aged < 75 or ≥ 75 years