Supplementary Table S1: List of actionable genes and potential matched therapy Gene Level Potential Matched Therapy AKT1 3 AKT inhibitor ALK fusion 1 ALK inhibitor ARAF 3 Sorafenib BRAF V600E 2A BRAF inhibitors BRCA1/2 loss 2B PARP Inhibitor therapy CD74-NRG 4 Anti-HER3 Monoclonal Antibody CDK4 AMP 2B CDK 4/6 inhibitors CDKN2A loss 4 CDK4/6 inhibitors c-KIT 2B Imatinib EGFR 1 EGFR Tyrosine kinase inhibitors ERBB2 mutation 3 HER2 Tyrosine kinase inhibitors ERBB2 Amplification 2B Pan-HER TKI e.g. Dacomitinib, anti-HER2 directed therapy e.g. Trastuzumab ERBB3 4 ERBB3 kinase inhibitor, anti-HER3 monoclonal antibody FGFR1 3 FGFR1 inhibitors FGFR2 3 FGFR2 Inhibitors FGFR3 3 FGFR3 inhibitors FGFR3-TACC3 fusion 3 FGFR3 inhibitors GNAS 4 MEK Inhibitors HRAS 4 MEK Inhibitors KRAS 4 MEK inhibitors MAP2K1 3 MEK Inhibitors MDM2 Amplification 4 MDM2 inhibitors MET exon 14 alteration 2B Cabozantinib, Crizotinib MET Amplification 2B Cabozantinib, Crizotinib NF1 loss 4 MEK Inhibitors NRAS 3 MEK Inhibitors PIK3CA 3 PI3K, Akt , mTOR inhibitors PTEN loss 4 PI3K, Akt , mTOR inhibitors RAF1 4 Sorafenib RET fusion 2A RET inhibitors ROS1 fusion 1 ROS1 inhibitors TSC1/TSC2 loss 2B mTOR inhibitors Supplementary Table S2: List of cooccurring Level 1-4 mutations Cooccurring Level 1 Level 2A Level 2B Level 3 Level 4 N= Level 1+2A EGFR L747_P753delinsS MET AMP CDK4 AMP CDKN2A loss 1 EGFR E746_A750del MET AMP PIK3CA E545K 1 EGFR L858R MET AMP CDKN2A loss 1 MDM2 AMP EGFR L858R MET AMP CDKN2A loss 1 EGFR L858R MET AMP BRAF D594V 1 EGFR L858R MET AMP CDKN2A loss 1 EGFR L861Q MET AMP 1 Level 1+2B EGFR E746_A750del ERBB2 AMP MDM2 AMP 1 EGFR E746_A750del ERBB2 AMP NRASQ61K CDKN2A loss 1 EGFR E746_A750del ERBB2 AMP PIK3CA E545K 1 EGFR S752_I759del ERBB2 AMP 1 EGFR S752_I759del ERBB2 AMP CDKN2A loss 1 EGFR L858R ERBB2 AMP 5 EGFR L858R ERBB2 AMP PIK3CA C420R MDM2 AMP 1 EGFR L747_A750delinsP ERBB2 AMP 1 EGFR L747_T751del ERBB2 AMP 1 EGFR ERBB2 AMP 1 EGFRL747 P753dL747_P753delinsS li S+T790M CDK4 AMP 1 EGFR E746_A750del CDK4 AMP PIK3CA H1047R MDM2 AMP 1 EGFR E746_A750 deletion CDK4 AMP MDM2 AMP 1 EGFR E746_A750del+T790M CDK4 AMP MDM2 AMP 1 EGFR E746_A750delinsP CDK4 AMP MDM2 AMP, KRAS Q61R 1 EGFR L858R CDK4 AMP PIK3CA H1047R MDM2 AMP 1 EGFR L858R CDK4 AMP 4 EGFR L858R+T790M CDK4 AMP 1 EGFR G719C+S768I CDK4 AMP MDM2 AMP 1 Level 1+3 EGFR E709_T710 del PIK3CA E545K CDKN2A loss 1 EGFR E709_T710 del PIK3CA E542K 1 EGFR E709_T710 del PIK3CA H1047R 1 EGFR E746_A750del+T790M PIK3CA E542K 2 EGFR E746_A750del+T790M PIK3CA E545K CDKN2A loss 1 EGFR E746_A750del PIK3CA H1047R 1 EGFR E746_A750del PIK3CA C420R, 1 FGFR1 AMP EGFR E746_A750del PIK3CA M1043I 1 EGFR E746_A750del PIK3CA N345K 1 EGFR E746_A750del PIK3CA E545K CDKN2A loss 1 EGFR L747_A750delinsP PIK3CA N345H 1 EGFR L858R PIK3CA H1047L 1 EGFR L858R PIK3CA H1047R 1 EGFR L858R PIK3CA E545K 2 EGFR L858R PIK3CA N345Y 1 EGFR S7681+G719C+T790M PIK3CA E545K 1 EGFR E709K+G719S PIK3CA E545K 1 Level 2A+2B MET AMP ERBB2 AMP 1 MET AMP BRCA1 loss 1 MET exon 14 TSC2 loss PIK3CA E545K 1 splice ERBB2 AMP. PIK3CA E545K 1 BRCA2 loss MET exon 14 CDK4 AMP MDM2 AMP 2 splice MET exon 14 CDK4 AMP MDM2 AMP 4 splice RET fusion, MET AMP Level 2A+3 MET exon 14 FGFR3-TACC3 fusion 1 splice BRAF-V600E IDH1 R132C 1 Level 2A+4 RET fusion CDKN2A loss 1 MET exon 14 MDM2 AMP 1 splice, MET AMP MET exon 14 NF1 loss, MDM2 AMP, 1 splice, MET AMP MET exon 14 MDM2 AMP 1 splice MET exon 14 NF1 loss, CDKN2A loss 1 splice MET exon 14 CDKN2A loss 3 splice MET AMP NF1 loss 2 MET AMP CDKN2A loss 2 MET AMP BRAFG596C 1 MET AMP KRAS G12V 1 BRAF V600E CDKN2A loss 1 BRAF V600E PTEN loss 1 Level 2B + 3 TSC1 loss KRAS G12C 2 TSC1 loss CDKN2A loss, KRAS 1 G12C TSC2 loss KRAS G12C 1 TSC2 loss PIK3CA AMP 1 TSC2 loss PIK3CA E545K 1 TSC2 loss CDKN2A loss 1 BRCA2 loss BRCA2 loss, PIK3CA E545K 1 ERBB2 AMP CDK4 AMP ERBB2 Y772_A775dup 1 CDK4 AMP ERBB2 V659E MDM2 AMP 1 PIK3CA E542K CDK4 AMP ERBB2 S310F MDM2 AMP 1 ERBB2 AMP ERBB2 Y772_A775dup CDKN2A loss 1 ERBB2 AMP ERBB2 S310F 2 ERBB2 AMP ERBB2 G776delinsVC 1 ERBB2 AMP ERBB2 Y772_A775dup CDKN2A loss 1 ERBB2 AMP PIK3CA N345K 1 Level 2B + 4 ERBB2 AMP CDKN2A loss 1 ERBB2 AMP PTEN loss, CDKN2A loss 1 TSC2 loss CDKN2A loss 1 TSC1 loss + KRAS G12C, CDKN2A 1 BRCA1 loss loss BRCA2 loss PTEN loss 1 BRCA2 loss NF1 loss 1 BRCA2 loss KRAS G12A 1 BRCA2 loss KRAS G12A, CDKN2A 1 loss, BRCA1 loss KRAS G12C 1 CDK4 AMP NF1 loss 1 CDK4 AMP BRAF D594N 1 CDK4 AMP MDM2 AMP 2 CDK4 AMP KRAS G12C 1 Level 3 + 4 AKT1 E17K KRAS G12A 1 PIK3CA M1043I KRAS G12A 1 PIK3CA E726K KRAS G12C, 1 PIK3CA E542K KRAS G12C, 2 PIK3CA E545K KRAS G12C, 2 PIK3CA N345T KRAS G12C, 1 FGFR1 AMP KRAS G12C, 1 PIK3CA G1049R KRAS G12D 1 FGFR3 AMP KRAS G12D, 1 PIK3CA E542K KRAS G12V, 1 PIK3CA E542K KRAS Q61H, 1 FGFR1 AMP NF1 loss 1 FGFR1 AMP CDKN2A loss 1 MAP2K1 K57N, CDKN2A loss 1 PIK3CA N545Y MAP2K1 E203K PTEN loss 1 NRAS Q61R BRAF K601E 1 NRAS Q61L NF1 loss 1 NRAS Q61H CDKN2A loss 1 ERBB2 Y772_A775dup MDM2 AMP 1 ERBB2 Y772_A775dup CDKN2A loss 1 ERBB2 Y772_A775dup CDKN2A loss 1 FGFR2 AMP NF1 loss 1 MAP2K1 E102_I103 CDKN2A loss 1 del PIK3CA E542K CDKN2A loss 1 PIK3CA E545K BRAF G469A 1 PIK3CA R93W PTEN loss 1 Level 1+4 EGFR L858R MDM2 AMP, CDKN2A 1 loss EGFR L858R MDM2 AMP 1 EGFR L858R CDK4, MDM2 AMP 4 EGFR L858R KRAS Q61H+ Q22K 1 EGFR L858R PTEN loss 1 EGFR L858R CDKN2A loss 1 EGFR L858R+S768I CDKN2A loss 1 EGFR L858R+T790M CDKN2A loss 2 EGFR L858R+T790M PTEN loss 1 EGFR L858R+T790M PTEN, CDKN2A loss, 1 EGFR L858R+T790M CDKN2A loss 1 EGFR L858R +E709K +T790M CDKN2A loss 1 EGFR E746_A750 deletion PTEN loss 1 EGFR E746_A750 deletion CDKN2A loss 5 EGFR E746_A750 deletion PTEN loss 2 EGFR E746_A750del +T790M CDKN2A loss 2 EGFR E746_S752delinsV CDKN2A loss 1 EGFR E746_T751delinsA CDK4 AMP 1 EGFR L747_A750delinsP CDKN2A loss, MDM2 1 AMP EGFR L747_T751 CKN2A loss 1 EGFR L861Q + G719A CDKN2A loss 1 EGFR G719A + T790M CDKN2A loss 1 EGFR E709_T710 delinsD CDKN2A loss 2 EGFR K745_E746insVPVAIK CDKN2A loss 1 EGFR L861Q CDKN2A loss 1 ROS1 fusion CDKN2A loss 2 ROS1 fusion CDKN2A loss 1 ALK fusion CDKN2A loss, NF1 loss 1 ALK fusion CDKN2A loss 5 ALK fusion MDM2 AMP 1 Level 2A + 4 RET fusion MDM2 AMP 1 RET fusion CDKN2A loss 1 RET fusion mTOR S2215F 1 Level 4+4 CDKN2A loss, MDM2 1 AMP CDKN2A loss MDM2 1 AMP KRAS G12A, PTEN loss 1 KRAS G12A, MDM2 AMP 1 KRAS G12A, CDKN2A 2 loss KRAS G12C, MDM2 AMP 1 KRAS G12C,CDKN2A loss 5 KRAS G12C, mTOR 1 S2215F KRAS G12C NF1 loss 1 KRAS G12D, BRAF 1 G469A KRAS G12D,CDKN2A loss 1 KRAS G12D, MDM2 AMP 2 KRAS G12D GNAS R201H 1 KRAS G12R, CDKN2A 1 loss KRAS G12V, NF1 loss 2 KRAS G12V, MDM2 AMP 1 KRAS G12V,CDKN2A loss 2 KRAS G12V, BRAF 1 D594Y, CDKN2A loss KRAS G13C, NF1 loss 1 KRAS G13C, BRAF 1 G469A KRAS G13D,CDKN2A loss 2 KRAS G13D, NF1 loss 1 KRAS Q61H,CDKN2A loss 2 NF1 loss, CDKN2A loss 2 NF1 loss, PTEN loss 1 NF1 loss, BRAF G466V 1 NF1 loss, HRAS G13V 1 BRAF T599 duplication 1 CDKN2A loss EGFR exon 20 insertion, 3 CDKN2A loss EGFR exon 20 insertion, 1 MDM2 AMP GNAS Q227H, CDKN2A 1 loss RAF1 S257L, NF1 loss 1 RAF1 S257L, MDM2 AMP 1 PTEN Loss, NF1 loss 1 PTEN loss, CDKN2A loss 1 PTEN loss, EGFR Exon 20 1 insertion mTOR S2215F, CDKN2A 1 loss Supplementary Table S3: EGFR mutations identified and associated therapy EGFR Mutations No. of pts EGFR Clinical Chemotherapy Immunotherapy TKI Benefit Exon 21 L858R 48 44 34^ 30 4 L861Q 5 5 2 3 3 Exon 19 deletion E746_A750del 56 53 48** 29 3 E746_S752delinsV 7 7 7 2 0 E746_T751delinsP 1 1 1 1 0 E746_T751delinsVA 1 1 1 0 0 L747_P753delinsS 7 7 6* 3 1 L747_E749del 1 4 1 1 0 L747_T751del 4 3 3 1 0 L747P 3 5 2 3 1 L747_A750delinsP 5 2 5 3 2 S752_I759del 2 1 1 1 0 L747_S752del 1 1 1 0 0 Exon 19 Insertion K745_E746insVPAIK 1 1 1 1 T790M Mutated T790M+E746_A750del 23 23 23 12 4 T790M+E746_T751delinsA 2 2 2 1 0 T790M+L858R 11 11 9 6 0 T790M+L861Q 1 1 1 1 0 T790M+L747_P753delinsS 1 1 1 1 1 T790M+L858R+D761Y 1 1 1 1 0 T790M+L858R+E709K+G5A 1 1 1 1 1 T790M+L858R+T854S 1 1 1 1 0 T790M+L747_A750delinsP 2 2 2 2 0 T790M+S752_I759del+A750P 1 1 1 1 1 T790M+G719C+S768I+C775Y 1 1 1 1 0 T790M+G719A+L707W 1 1 1 1 1 T790M+E746_T751delinsVP 1 1 1 0 0 Total Co-occurring Mutations: L858R+E709K 3 3 3 3 0 L858R+S768I 1 1 0 0 0 L858R+L833V 1 1 1 1 0 L858R+MD277IY 1 1 1 1 0 L858R+G221V 1 1 0 1 0 L858R+H870R+S306L 1 1 1 1 1 L858R+V689M 1 1 0 1 0 L858R+D761Y 1 1 1 1 0 L858R+T854S 1 1 1 1 0 L858R+D1014V 1 1 1 1 0 L858R+K860I+K867T 1 1 1 0 0 L858R+L62R 1 1 1 1 0 L858R+V834L 1 1 1 1 0 E709K+G719S 2 1 1 2 0 E709K+G719A 1 1 0 1 0 E709A+G719S 1 1 1 1 0 G719C+S7681 1 1 1 1 0 G719S+S7681 1 1 1 0 0 G719A+L861Q 1 1 1 1 0 T751_A755del+L747P 1 1 1 1 0 L747_P753delinsS+A755G 1 1 0 1 0 L861Q+S720F 1 1 0 1 0 Exon 18 E709_T710delinsD 6 5 2 4 2 G719A 3 3 1 0 0 L858R+E746_A750del 1 1 1 1 0 EGFR-KDD 2 2 2 2 1 Unknown significance 2 0 0 2 2 V765L 1 0 0 1 1 G779F 1 0 0 1 0 Exon 20 Insertions K766delinsNGQR 1 0 0 0 0 N771_H773dup 2 0 0 2 0 H773_V774insH 1 0 0 1 0 P772_H773dup 1 0 0 1 1 H773dup 1 0 0 1 1 N771delinSTH 1 0 0 1 0 V769_D770insGGTR 1 0 0 1 1 N771_P772insV 2 0 0 2 0 A767_V769dup 2 0 0 2 1 S7678_D770dup 1 0 0 1 1 K766_N771insQPP 1 1 0 1 0 D770_N771insQPP 1 0 0 1 1 D770_N771insG 1 0 0 1 0 N771_P772insH 1 0 0 1 0 Exon 20 Missense H773R 1 1 1 1 0 L858R: ^ 3 patients await imaging Exon 19 deletion: ** 3 patients await imaging L747_P753delinsS ^ 1 patient awaits imaging Supplementary Table S4: List of 410 genes in MSK-IMPACT assay Approved Approved Name Symbol ABL1 c-abl oncogene 1, non-receptor tyrosine kinase ACVR1 activin A receptor, type I AKT1 v-akt murine thymoma viral oncogene homolog 1 AKT2 v-akt murine thymoma viral oncogene homolog 2 AKT3 v-akt murine thymoma viral