A. B. C. H1975 xenografts: long-term treatment Vehicle CED 6 mg/kg Resistant Tumors B. P = 0.015 vehicle CED VAN P = 0.057 C. H1975 xenografts: short-term treatment A549 xenografts: long-term treatment Vehicle CED 6 mg/kg Resistant Tumors Cascone et al., Figure S1

A. C. B. Cascone et al., Figure S2 Common angiogenic human genes 42 43 VAN prog. vs. VAN sens. CED prog. CED sens. 42 43 14 56 57 VAN sens VAN prog Tumor genes VAN-resistant vs. sensitive tumors CED prog CED sens Tumor genes in CED-resistant vs. CED-sensitive tumors Significant human angiogenic genes in VAN-prog. vs. VAN-sens. H1975 tumors Significant human angiogenic genes in CED-prog. vs. CED-sens. tumors C. B. MARS TNFSF15 HIF3A RPS7 AGGF1 PTGS1 PGF PPIA IL6 SPTBN1 PSME2 PTN MOCS3 CASP1 Cascone et al., Figure S2

VAN vehicle progression sensitive p-MET Cascone et al., Figure S3

A. B. H1975 cells HCC827 cells vector HGF.20 HGF (pg/106 cells) vector 500 1000 1500 2000 2500 3000 3500 4000 vector HGF.20 HGF (pg/106 cells) A. HCC827 cells P < 0.0001 2000 4000 6000 8000 10000 12000 14000 16000 18000 vector HGF.24 HGF (pg/106 cells) B. H1975 cells P < 0.0001 Cascone et al., Figure S4

A. B. H1975 xenograft tumors CAIX CAIX staining score vehicle VAN sensitive progression CAIX A. sensitive progression vehicle VAN CAIX staining score B. P = 0.02 100 200 300 Cascone et al, Figure S5

Pazopanib in phase II trial of mRCC PFS Probability 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Weeks 10 20 30 40 50 60 70 80 90 100 110 120 130 Plasma HGF < Median (E/N = 108/216) Median PFS 53 weeks Plasma HGF ≥ Median (E/N = 108/216) Median PFS 28 weeks P = 0.016 Cascone, Figure S6

Cascone, Supplementary Table S1&2 Table S1. Mouse angiogenic genes modulated in VAN-resistant (progression) vs. sensitive (14 days) H1975 xenografts Gene ID SYMBOL VAN prog (log2 value) VAN sens Fold Change P value ILMN_1229161 Eng 7.98624 7.98407 6.19711 6.41261 6.90484 2.79 0.025 ILMN_2763245 Cxcl1 7.55128 9.07913 7.29075 7.28179 6.80426 2.28 0.079 ILMN_2916116 Rps7 11.54232 11.47146 9.93707 9.93815 11.41153 2.11 0.037 ILMN_1237666 Hgf 7.18368 7.30979 6.39711 6.41852 5.75835 2.08 0.020 ILMN_2729153 Nos3 6.785550 6.15684 5.55489 5.60969 5.94719 1.70 0.073 ILMN_2696977 Rpl37 13.0061 12.9586 13.6961 13.6690 13.8357 -1.68 0.002 ILMN_2946520 Npy 5.72519 5.70043 6.61058 6.54797 6.34713 -1.72 0.072 Table S2. Mouse angiogenic genes modulated in CED-resistant (progression) vs. sensitive (14 days) H1975 xenografts Gene ID SYMBOL CED sens (log2 value) CED prog CED sens (log2 value) Fold Change P value ILMN_1229161 Eng 6.35332 6.66675 8.86604 8.99963 6.25625 7.74032 2.628 0.019 ILMN_2763245 Cxcl1 6.69334 7.42467 6.80038 8.94976 6.62117 6.39420 2.227 0.058 ILMN_2788593 Nos3 6.01167 5.73389 7.63807 7.82470 5.95675 6.26566 1.983 0.01 ILMN_2729153 5.49441 5.72546 6.96693 6.66490 5.47735 6.02569 1.725 0.042 ILMN_1237666 Hgf 5.96278 6.58285 6.62600 6.70666 5.97292 5.89457 1.619 0.079 ILMN_2946520 Npy 6.83175 6.49361 5.76208 5.69766 6.72164 6.68929 -1.697 0.053 ILMN_2696977 Rpl37 13.9512 13.205 13.0442 14.0691 13.8039 -1.795 0.0003 Cascone, Supplementary Table S1&2

Cascone, Supplementary Table 3 Table S3. Human angiogenic genes modulated in VAN-resistant (progression) vs. VAN-sensitive (14 days) H1975 xenografts Gene ID SYMBOL VAN prog (log2 value) VAN sens Fold Change P value ILMN_1663015 HIF3A 11.0225 7.34189 6.33413 5.54658 5.19534 11.237 0.0001 ILMN_1661335 SPTBN1 5.45943 9.64889 5.34234 5.7439 5.119 4.446 0.015 ILMN_2287061 6.65076 7.96981 5.11436 5.3466 5.282 4.177 0.000002 ILMN_1704529 PPIA 6.33985 8.22862 5.48542 5.15785 5.0793 4.122 0.06 ILMN_1809813 PGF 7.87375 7.69306 6.84561 5.66163 4.9316 3.919 0.0005 ILMN_2070072 RPS7 9.04589 5.61294 5.57591 5.142 5.3656 3.913 0.053 ILMN_2339835 PTGS1 9.03510 5.11603 5.36211 5.3512 5.2577 3.368 0.057 ILMN_1786612 PSME2 5.16832 8.37551 5.07424 5.2269 5.2968 2.974 0.054 ILMN_1699651 IL6 6.05809 7.55604 5.25851 5.4805 2.872 0.04 ILMN_1759501 TNFSF15 7.21247 5.80915 5.53946 5.12432 5.2299 2.318 0.036 ILMN_2064917 AGGF1 6.83668 5.48671 5.20202 5.19377 5.2961 1.907 0.045 ILMN_1799819 MARS 6.27015 6.26472 5.46466 5.2913 5.2604 1.903 0.033 ILMN_1687481 6.70293 5.32624 5.21101 5.04832 5.4138 1.729 0.002 ILMN_1813753 PTN 5.22689 5.37121 8.10951 5.6002 -2.143 0.062 ILMN_2326509 CASP1 5.30414 5.36036 7.54 5.47508 6.7092 -2.366 0.042 ILMN_1766652 MOCS3 5.46727 5.68762 8.8423 6.77728 6.2088 -3.246 0.018 Cascone, Supplementary Table 3

Cascone , Supplementary Table 4 Table S4. Human angiogenic genes modulated in CED-resistant (progression) vs. CED-sensitive (14 days) H1975 xenografts Gene ID SYMBOL CED prog (log2 value) CED sens Fold Change P value ILMN_1704529 PPIA 5.46695 6.57758 11.33459 5.2315 5.33127 6.27593 4.532 0.027 ILMN_1661335 SPTBN1 8.34775 9.1293 9.09035 6.5697 6.59245 7.14435 4.249 0.009 ILMN_1663015 HIF3A 7.30113 5.34802 8.14496 5.42357 5.38024 5.1815 3.038 0.022 ILMN_1699651 IL6 7.78542 6.23285 7.39874 5.43095 5.80529 5.78031 2.764 0.028 ILMN_1766652 MOCS3 5.93404 5.48639 8.71942 5.32012 5.37955 5.54596 2.459 0.039 ILMN_1759501 TNFSF15 5.43396 5.45516 8.28331 5.36806 5.2114 5.43629 2.074 0.041 ILMN_2287061 6.02547 5.33055 6.43112 5.35508 5.23572 5.32624 1.54 0.026 ILMN_1799819 MARS 6.70418 7.50279 5.49217 7.51514 7.52591 7.12814 -1.77 0.034 ILMN_1813753 PTN 7.25936 6.14057 5.42223 7.19908 7.35526 7.52904 -2.124 ILMN_2064917 AGGF1 5.67666 7.58022 5.64414 7.23993 7.55405 7.60866 -2.246 0.007 ILMN_1809813 PGF 5.30706 5.29535 5.16309 6.68915 6.65892 6.12122 -2.353 0.008 ILMN_1786612 PSME2 8.6355 8.4577 5.50398 8.79769 8.96037 9.27728 -2.788 0.043 ILMN_2070072 RPS7 5.26228 6.66576 5.66362 7.25474 7.25408 8.0882 -3.179 0.066 ILMN_2326509 CASP1 5.23457 6.61338 5.33378 7.67912 7.9338 8.39025 -4.836 0.0003 ILMN_2339835 PTGS1 5.41582 6.83605 5.42827 8.24174 8.42815 8.50597 -5.651 0.004 Cascone , Supplementary Table 4

Cascone, Supplementary Table 5&6 Table S5. Predictive plasma HGF at baseline adjusted by gender and smoking among VAN and CP arms in the NSCLC phase II study  C/AF VAN arm Chemotherapy (CP) arm P for interaction* Median PFS (Days) HR Plasma Low HGF 121 (40, 202) 1.437 (1.038-1.988) 140 (47, 194) 0.777 (0.544-1.110) 0.0357 [HR 0.612 (0.387-0.968)] Plasma High HGF 80 (21,149) 167 (145, 228) Table S6. Predictive plasma HGF at baseline among VAN and E arms in the NSCLC phase III study Subgroup Randomized treatment N Number of events (%) Hazard Ratio 95% CI Positive Vandetanib 300 mg Erlotinib 150 mg 99 93 93 (93.9) 88 (94.6) 1.11 (0.82, 1.49) Negative 96 97 88 (91.7) 86 (88.7) 0.87 (0.63, 1.20) Unknown 428 427 371 (86.7) 371 (86.9) 0.95 (0.82, 1.10) Known 195 190 181 (92.8) 174 (91.6) 0.98 (0.79, 1.21) Cascone, Supplementary Table 5&6