* OS >3yr with No Next Line * * * * *

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* OS >3yr with No Next Line * * * * * Supplemental Figure 1. Schematic presentation of the analyzed parameters in the correlative cohort per progression survival (PFS). TMB: total mutational burden. PR: partial response. SD: stable disease. PD: progressive disease. △: mutation.

Supplemental Figure 2. Progression Free Survival (PFS) and subgroup survival analysis of the correlative cohort (N=38) by Log-rank (Mantel-Cox) test. PFS By PD-L1 categories ( 0-49% n=23 vs 50-100% n=9, p<0.001) PFS By TMB percentile (<25th percentile n=6 vs 25-50th percentile n=7 vs 50-75th percentile n=6 vs >75th percentile n=6, p=0.142) PFS By CD8 categories (0-5% n=18 vs 6-25% n=14, p=0.037) PFS By CD4 categories (0-5% n=21 vs 6-25% n=9 vs >25% n=2, p=0.123) P<0.001 P=0.142 P=0.037 P=0.123

Supplemental Figure 3. Association among the four correlative parameters.

Supplemental Table 1. Association of the four correlative parameters and with other clinical characteristics. TMB PD-L1 CD8 CD4 Smoking EGFR Squamous Spearman 1.000 0.191 0.125 0.072 .517** -0.333 -0.221 p-value 0.406 0.591 0.758 0.008 0.104 0.289 N 25 21 .660** .487** .366* -0.201 .395* <0.001 0.005 0.040 0.271 0.025 32 .396* 0.342 -0.287 0.121 0.055 0.111 0.508 -0.003 0.177 -0.031 0.985 0.334 0.865

Supplemental Table 2. Correlation of patient characteristics and ORR per irRC (PR vs SD/PD). ORR (irRC) Median (range) PR (n=16) SD/PD (n=22) p-value Test # missing TMB 189 (102-485) 55 (48-173) 0.077 Wilcx 13 PD-L1 66 (29-81) 15.3 (4-32) 0.002 6 CD8 8 (4-11) 3 (1-7) 0.017 CD4 8 (1.5-12) 2.3 (1-5) 0.168 Age 68 (61-75) 66 (59-74) 0.455 Male 9 (56.3%) 13 (59.1%) 1 Fish. EGFR Mutations 3 (21.4%) 6 (27.3%) ALK 0 (0.0%) 1 (4.5%) 5 EGFR or ALK 7 (31.8%) 0.706 2 Ever smoker 12 (54.5%) Squamous 3 (18.8%) 5 (22.7%) >=One Line Therapy 11 (68.8%) 19 (86.4%) 0.181

Supplemental Table 3. Patient characteristics (as categorical variables) in the correlative cohort per prior lines of therapy. No prev. line (n=8) >= 1 line (n=30) p-value TMB 0.785 <25 percentile 1 (14.3%) 5 (27.8%) 25-50 2 (28.6%) 50-75 3 (42.9%) 3 (16.7%) >75 percentile PD-L1 0.238 <1 1 (16.7%) 0 (0.0%) 1-49 4 (66.7%) 18 (69.2%) >49 1 (6.7%) 8 (30.8%) CD8 0.030 0-5% 17 (65.4%) 5-25% 5 (83.3%) 9 (34.6%) CD4 0.305 16 (61.5%) >25% 2 (7.7%)

Supplemental Table 4. PFS and OS of correlative characteristics (as categorical variables) by year. Median (range) All correlative cohort (N=38) PFS <= 1Yr (n=27) PFS 1yr-2yr (n=5) PFS 2-3yr (n=4) PFS >3yr (n=2) p-value TMB 0.021 <25 percentile 6 (15.8%) 5 (31.3%) 1 (25.0%) 0 (0.0%) 25-50 7 (18.4%) 1 (50.0%) 50-75 >75 percentile 1 (6.3%) 3 (100.0%) PD-L1 0.002 <1 1 (2.6%) 1 (4.0%) 1-49 22 (57.9%) 20 (80.0%) 2 (66.7%) >49 9 (23.7%) 4 (16.0%) 1 (33.3%) 1 (100.0%) CD8 0.093 0-5% 18 (47.4%) 16 (64.0%) 5-25% 14 (36.8%) 9 (36.0%) CD4 0.095 21 (55.3%) 18 (72.0%) 6 (24.0%) >25% 2 (5.3%) Median (range) All correlative cohort (N=38) OS <= 1Yr (n=16) OS 1yr-2yr (n=9) OS 2-3yr (n=6) OS >3yr (n=7) p-value TMB 0.662 <25 percentile 6 (15.8%) 1 (11.1%) 2 (40.0%) 1 (20.0%) 2 (33.3%) 25-50 7 (18.4%) 5 (55.6%) 0 (0.0%) 1 (16.7%) 50-75 2 (22.2%) >75 percentile PD-L1 0.003 <1 1 (2.6%) 1 (6.3%) 1-49 22 (57.9%) 14 (87.5%) 4 (66.7%) 1 (25.0%) 3 (50.0%) >49 9 (23.7%) 1 (33.3%) 3 (75.0%) CD8 0.048 0-5% 18 (47.4%) 12 (75.0%) 2 (50.0%) 5-25% 14 (36.8%) 4 (25.0%) CD4 0.333 21 (55.3%) 4 (35.0%) >25% 2 (5.3%)

Supplemental Table 5. Characteristics as continuous variables of long term benefiters (Overall survival > 3 years with no intervening therapies) vs all other patients in the correlative cohort. Clinical characteristics Median (range) LTB (n=5) All others (n=33) p-value TMB 173 (104-261) 83 (48.5-235) 0.530 CD8 9.5 (5.5-15) 4 (2-8.5) 0.106 PD-L1 72 (55-77) 16 (6.5-45.5) 0.029 CD4 2 (1.05-14) 3.2 (1-8) 0.763 Age 59 (59-68) 68 (60-74) 0.424 Male 4 (80.0%) 18 (54.5%) 0.374 EGFR Mutations 0 (0.0%) 9 (28.1%) 0.553 ALK Mutation/Translocation 1 (3.4%) 1.000 EGFR or ALK Mutation 10 (31.3%) 0.559 Ever smoker 3 (60.0%) Squamous 1 (20.0%) 7 (21.2%) At Least One Line Therapy 27 (81.8%) 0.279