Supplementary Fig. S1 Patient selection from the database

Supplementary Fig. S1 Patient selection from the database

Supplementary Fig. S2 Kaplan-Meier plots of overall survival (OS) by corticosteroid

prescription (yes/no) within 3 months before pembrolizumab initiation as (a) first-line (log-rank P=0.0133) and (b) second-line/later therapy (log-rank P=0.29).

(OS for all lines log-rank P=0.0014) a.

b.

Supplementary Fig. S3 Kaplan-Meier plot of overall survival by BRAF mutation status: mutant or wild type (log-rank P=0.90)

Supplementary Fig. S4 Kaplan-Meier plot of overall survival by presence (yes) or absence (no) of brain metastasis (log-rank P=0.22)

Supplementary Fig. S5 Kaplan-Meier plot of overall survival by presence (yes) or absence (no) of autoimmune condition within 2 years before pembrolizumab initiation (log-rank P=0.49)

Supplementary Table S1 Patients with one or more autoimmune diagnoses within 2 years before pembrolizumab initiation

Autoimmune condition, n (%) N=43 (8.1%

^a

)

ICD-9 codes ICD-10 codes

Spondyloarthropathy 11 (2.1) 721.90, 716.90 M47.819, M12.9

Rheumatoid arthritis 9 (1.7) 714, 714.0, 714.1, 714.2, 714.89, 714.9

M06.9, M05.00, M05.30, M05.60, M06.1, M06.4,

M06.9

Myositis 8 (1.5) 710.3, 710.4, 729.1 M33.90, M33.20, M60.9,

M79.1, M79.7 Ulcerative colitis 5 (0.9) 556, 556.0, 556.1, 556.2,

556.3, 556.5, 556.6, 556.8, 556.9

K51.80, K51.20, K51.30, K51.50, K51.00, K51.90

Vitiligo 2 (0.4) 709.01 L80

Polymyalgia rheumatica 2 (0.4) 725 M35.3

Multiple sclerosis 2 (0.4) 340 G35

Myasthenia gravis 2 (0.4) 358.00, 358.01, 358.02 G70.00, G70.01

Sarcoidosis 2 (0.4) 135 D86.9

Autoimmune hemolytic anemia 1 (0.2) 283.0 D59.0, D59.1

Type 1 diabetes 1 (0.2) 250.x1, 250.x3 E10.9, E10.65, E10.10,

E10.65, E10.69, E10.11, E10.641, E10.29, E10.21, E10.311, E10.319, E10.36,

E10.39, E10.40, E10.51, E10.618, E10.620, E10.621, E10.622, E10.628, E10.630, E10.638, E10.649, E10.8

Reiter’s disease 1 (0.2) 099.3 M02.30

a

Percentages represent proportion of all 532 patients in the study.

Supplementary Table S2 Timing of brain metastasis diagnosis before pembrolizumab initiation (index date)

Time from brain metastasis diagnosis to index date

Patients with brain metastasis (N=96)

<3 months, n (%) 45 (47)

^a

3–<6 months, n (%) 15 (16) 6–<9 months, n (%) 12 (13) 9–<12 months, n (%) 6 (6) 12–<18 months, n (%) 11 (11) 18–<24 months, n (%) 5 (5)

≥24 months, n (%) 2 (2)

a

18 of 45 patients (40%) had a history of corticosteroid prescription(s) <3 months before the

index date.

Supplementary Table S3 Treatment regimens for 34 patients who received pembrolizumab as part of combination therapy

Pembrolizumab treatment line

First line Second line Third line & later

Regimen (n = 18) (n = 6) (n = 10)

Pembrolizumab, dabrafenib, trametinib, n 8 2 4

Pembrolizumab, ipilimumab, n 7 0 0

Pembrolizumab, cobimetinib, vemurafenib, n 1 0 0

Pembrolizumab, imatinib, n 1 0 0

Pembrolizumab, ipilimumab, nivolumab, n 1 1 0

Pembrolizumab, cisplatin, vinblastine, n 0 1 0

Pembrolizumab, temozolomide, n 0 1 2

Pembrolizumab, vemurafenib, n 0 1 0

Pembrolizumab, bicalutamide, triptorelin, n 0 0 1

Pembrolizumab, crizotinib, n 0 0 1

Pembrolizumab, dabrafenib, n 0 0 1

Pembrolizumab, trametinib, n 0 0 1

Supplementary Table S4 Overall survival: subgroup Kaplan-Meier analyses including patients with no missing data

Pembrolizumab treatment line

First line Second line/later Overall

Age <55 years, n 56 53 109

Median OS (95% CI), mo Not reached (19.8 - NA) 10.7 (5.3 - 22.7) 19.8 (10.8 - NA) 1-year survival (95% CI) 70.33% (56.19 - 80.67%) 47.64% (33.21 - 60.74%) 59.50% (49.37 - 68.26%) 2-year survival (95% CI) 50.98% (31.94 - 67.18%) 34.28% (20.51 - 48.50%) 43.22% (31.63 - 54.27%)

Age 55–74 years, n 143 103 246

Median OS (95% CI), mo Not reached (25.1 - NA) 16.8 (10.5 - NA) 35.3 (19.4 - NA) 1-year survival (95% CI) 70.67% (62.23 - 77.57%) 57.83% (47.46 - 66.86%) 65.27% (58.80 - 70.98%) 2-year survival (95% CI) 61.92% (52.16 - 70.26%) 43.86% (33.59 - 53.66%) 54.09% (47.01 - 60.64%)

Age ≥75 years, n 116 61 177

Median OS (95% CI), mo 15.1 (10.8 - NA) 13.9 (9.1 - 25.9) 15.1 (11.9 - 21.8)

1-year survival (95% CI) 56.58% (46.54 - 65.43%) 56.72% (42.91 - 68.38%) 56.66% (48.66 - 63.88%) 2-year survival (95% CI) 41.48% (30.79 - 51.81%) 40.43% (27.19 - 53.28%) 41.39% (33.11 - 49.45%)

Log-rank p-value 0.0191 0.5279 0.0459

ECOG 0–1, n 109 59 168

Median OS (95% CI), mo 25.1 (15.9 - NA) 12.8 (9.4 - 29.1) 22.3 (13.7 - NA)

1-year survival (95% CI) 66.98% (56.97 - 75.17%) 55.64% (41.70 - 67.50%) 62.93% (54.90 - 69.93%) 2-year survival (95% CI) 51.81% (40.04 - 62.34%) 37.09% (24.08 - 50.12%) 46.23% (37.30 - 54.68%)

ECOG 2–4, n 28 23 51

Median OS (95% CI), mo 7.9 (2.3 - 13.0) 9.1 (2.3 - 19.0) 8.2 (3.6 - 12.5)

1-year survival (95% CI) 43.93% (24.95 - 61.43%) 40.13% (19.80 - 59.77%) 42.42% (28.30 - 55.85%) 2-year survival (95% CI) 25.89% (10.59 - 44.33%) 29.26% (11.68 - 49.50%) 27.58% (15.34 - 41.27%)

Log-rank p-value 0.0010 0.1719 0.0006

Normal LDH level, n 162 121 283

Median OS (95% CI), mo Not reached (22.6 - NA) 24.8 (12.9 - 30.5) 29.1 (21.9 - NA) 1-year survival (95% CI) 73.03% (65.30 - 79.31%) 61.03% (51.46 - 69.28%) 67.95% (62.02 - 73.16%) 2-year survival (95% CI) 59.06% (49.53 - 67.39%) 50.42% (40.53 - 59.51%) 55.69% (48.97 - 61.89%)

Elevated LDH level, n 36 40 76

Median OS (95% CI), mo 13.6 (3.7 - NA) 7.9 (2.9 - 12.6) 11.2 (5.1 - 16.8)

1-year survival (95% CI) 60.53% (41.78 - 74.92%) 38.70% (23.20 - 53.97%) 49.10% (36.92 - 60.18%) 2-year survival (95% CI) 26.80% (6.97 - 52.15%) 29.77% (15.88 - 45.03%) 32.43% (20.81 - 44.58%)

Log-rank p-value 0.0029 0.0210 <0.0001

BRAF wild-type, n 174 111 285

Median OS (95% CI), mo Not reached (21.2 - NA) 13.9 (10.8 - 21.6) 22.3 (16.8 - 35.3) 1-year survival (95% CI) 65.61% (57.90 - 72.25%) 57.30% (47.24 - 66.13%) 62.48% (56.44 - 67.92%) 2-year survival (95% CI) 54.96% (46.02 - 63.03%) 40.47% (30.77 - 49.95%) 49.42% (42.86 - 55.64%)

BRAF mutant, n 90 85 175

Median OS (95% CI), mo Not reached (16.8 - NA) 19.0 (8.0 - NA) 22.6 (14.6 - NA) 1-year survival (95% CI) 73.57% (62.66 - 81.75%) 55.90% (44.40 - 65.92%) 64.86% (57.01 - 71.63%) 2-year survival (95% CI) 51.88% (37.22 - 64.67%) 42.95% (31.29 - 54.09%) 47.83% (38.79 - 56.30%)

Log-rank p-value 0.7364 0.8312 0.8990

No brain metastasis, n 264 172 436

Median OS (95% CI), mo Not reached (21.8 - NA) 13.7 (11.0 - 22.7) 22.7 (16.8 - 35.3) 1-year survival (95% CI) 66.21% (59.94 - 71.73%) 55.58% (47.60 - 62.83%) 62.00% (57.11 - 66.51%) 2-year survival (95% CI) 55.16% (47.90 - 61.82%) 41.90% (33.94 - 49.66%) 49.74% (44.36 - 54.88%)

Brain metastasis, n 51 45 96

Median OS (95% CI), mo 21.9 (11.0 - NA) 13.3 (6.3 - 25.1) 18.4 (10.8 - 25.1)

1-year survival (95% CI) 62.38% (47.02 - 74.44%) 53.18% (37.17 - 66.83%) 58.06% (47.15 - 67.49%) 2-year survival (95% CI) 40.38% (22.89 - 57.25%) 36.92% (22.25 - 51.65%) 39.61% (28.34 - 50.66%)

Pembrolizumab treatment line

First line Second line/later Overall

Log-rank p-value 0.3134 0.6439 0.2171

No corticosteroid <3 months, n 281 131 412

Median OS (95% CI), mo Not reached (21.9 - NA) 14.7 (10.7 - 28.2) 25.9 (19.2 - NA) 1-year survival (95% CI) 67.45% (61.42 - 72.76%) 57.88% (48.61 - 66.07%) 64.41% (59.40 - 68.96%) 2-year survival (95% CI) 54.92% (47.71 - 61.55%) 43.01% (33.81 - 51.86%) 51.20% (45.57 - 56.54%)

Corticosteroid <3 months, n 34 86 120

Median OS (95% CI), mo 12.6 (4.3 - NA) 12.2 (7.5 - 22.3) 12.2 (8.4 - 19.4)

1-year survival (95% CI) 50.13% (31.92 - 65.87%) 50.99% (39.77 - 61.14%) 50.78% (41.29 - 59.50%) 2-year survival (95% CI) 33.66% (14.85 - 53.70%) 37.74% (26.87 - 48.55%) 36.88% (27.41 - 46.36%)

Log-rank p-value 0.0133 0.2876 0.0014

No autoimmune condition 295 194 489

Median OS (95% CI), mo Not reached (19.8 - NA) 12.9 (10.7 - 19.9) 21.6 (15.9 - 28.2) 1-year survival (95% CI) 65.64% (59.69 - 70.92%) 54.33% (46.80 - 61.26%) 61.14% (56.50 - 65.44%) 2-year survival (95% CI) 51.77% (44.63 - 58.44%) 39.91% (32.43 - 47.28%) 47.07% (41.92 - 52.05%)

Autoimmune condition ≤2 years 20 23 43

Median OS (95% CI), mo Not reached (3.9 - NA) 14.7 (5.7 - NA) Not reached (7.2 - NA) 1-year survival (95% CI) 65.00% (40.30 - 81.53%) 60.87% (38.27 - 77.37%) 62.79% (46.63 - 75.29%) 2-year survival (95% CI) 65.00% (40.30 - 81.53%) 47.43% (26.34 - 65.90%) 54.57% (38.23 - 68.28%)

Log-rank p-value 0.6123 0.4335 0.4871

ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; NA, not

available (because not reached).