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Monica Miele
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1 Sulementary aendix This aendix formed art of the original submission and has been eer reviewed. We ost it as sulied by the authors. Sulement to: Cremolini C, Louakis F, Antoniotti C, et al. FOLFOXIRI lus bevacizumab versus FOLFIRI lus bevacizumab as first-line treatment of atients with metastatic colorectal cancer: udated overall survival and molecular subgrou analyses of the oen-label, hase 3 TRIBE study. Lancet Oncol 2015; ublished online Set 1. htt://dx.doi.org/ /s (15)

FOLFOXIRI lus bevacizumab versus FOLFIRI lus bevacizumab as first-line treatment of atients with metastatic colorectal

2 Sulementary aendix 1

3 Particiating Centers and Princial Investigators Princial Investigator Site Name City Alfredo Falcone Polo Oncologico Osedale Santa Chiara Pisa Sara Lonardi Istituto Oncologico Veneto IRCCS Padova Enrico Cortesi Policlinico Umberto I Roma Rodolfo Passalacqua Azienda Istituti Ositalieri Cremona Eugenio Villa / Luca Gianni Osedale San Raffaele IRCCS Milano Libero Ciuffreda Azienda Osedaliero Universita- ria Città della Salute e della Scienza Torino Alberto Zaniboni Fondazione Poliambulanza Brescia Giusee Tonini Università Camus Biomedico Roma Sergio Frustaci Centro di Riferimento Oncologico IRCCS Aviano Domenico Amoroso Osedale Versilia Lido di Camaiore Silvana Chiara Osedale San Martino IRCCS Genova Chiara Carlomagno Azienda Osedaliera Università Federico II Naoli Corrado Boni Arcisedale Santa Maria Nuova IRCSS Reggio Emilia Giacomo Allegrini Osedale Felice Lotti Pontedera Andrea Ardizzoni Azienda Osedaliero-Universitaria di Parma Parma Carlo Barone Università Cattolica del Sacro Cuore Roma Stefano Vitello Osedale Sant Elia Caltanissetta Paolo Bidoli Osedale San Gerardo Monza Andrea Bonetti Osedale Mater Salutis Legnago Andrea Decensi Osedale Galliera Genova Federico Cauzzo Sedali Riuniti Livorno Francesco Dargenio Day Hosital Oncologico di Piombino ASL6 Piombino Angelo Di Leo Osedale Sandro Pitigliani Prato Editta Baldini Osedale San Luca Lucca Marco Merlano Osedale Santa Croce e Carle Cuneo Angela Ribecco Osedale San Giovanni di Dio Firenze Salvatore Siena Niguarda Cancer Center Milano Vito Lorusso Osedale Vito Fazzi Lecce Sergio Bracarda Osedale San Donato Arezzo Stefano Cascinu Osedali Riuniti di Ancona e Università Politecnica delle Marche Ancona Barbara Silvestri Osedale di Mirano Mirano Alessandro Bertolini Osedale di Sondrio Sondrio Marco Di Lieto Osedale San Jacoo Pistoia Gianmarco Numico Osedale Regionale della Valle d Aosta Umberto Parini Aosta 2

Universita- ria Città della Salute e della Scienza Torino Alberto Zaniboni Fondazione Poliambulanza Brescia Giusee Tonini Università Camus Biomedico Roma Sergio Frustaci Centro di Riferimento

4 - HR for death HR for rogression ECOG Performance Status [ ] < [ ] Primary tumor site Left colon or rectum Right colon 1.43 [ ] [ ] Prior adjuvant No Yes 0.59 [ ] [ ] Time to metastases Metachronous Synchronous 1.83 [ ] < [ ] Liver-only disease No Yes 0.72 [ ] [ ] Surgery on rimary No Yes 0.63 [ ] < [ ] Kohne Score Low Intermediate 1.27 [ ] [ ] High 2.86 [ ] < [ ] < Table S1. Effect of baseline characteristics on overall and rogression-free survival in the intention-to-treat oulation 3

001 Liver-only disease No 1-1 - Yes 0.72 [0.56-0.94] 0.011 0.71 [0.57-0.89] 0.002 Surgery on rimary No 1-1 - Yes 0.63 [0.51-0.78] <0.0001 0.69 [0.57-0.84] 0.001 Kohne Score Low 1-1 - Intermediate 1.

5 Characteristic HR for death HR for rogression Arm FOLFIRI lus bev FOLFOXIRI lus bev 0.77 [ ] [ ] ECOG Performance Status [ ] < [ ] Primary tumor site Left colon or rectum Right colon 1.46 [ ] [ ] 0.12 Prior adjuvant No Yes 1.18 [ ] [ ] 0.71 Time to metastases Metachronous Synchronous 1.54 [ ] [ ] 0.21 Liver-only disease No Yes 1.05 [ ] [ ] 0.51 Surgery on rimary No Yes 0.76 [ ] [ ] 0.19 Kohne Score Low Intermediate 1.25 [ ] [ ] 0.22 High 2.56 [ ] < [ ] < Table S2. Multivariable models of overall and rogression-free survival including rognostic covariates and treatment arm in the intention-to-treat oulation 4

71 Time to metastases Metachronous 1 - - Synchronous 1.54 [0.98-2.43] 0.049 1.29 [0.86-1.95] 0.21 Liver-only disease No 1-1 - Yes 1.05 [0.72-1.53] 0.81 0.90 [0.65-1.24] 0.

6 Figure S1. Kalan-Meier estimates of rogression-free survival. FOLFIRI=fluoruracil, folinic acid, and irinotecan; FOLFOXIRI=fluoruracil, folinic acid, oxalilatin, and irinotecan; bev=bevacizumab 5

7 Gene Exon N (%) N=236 KRAS Codon (67.8) Codon (15.3) Codon 12 and 13 1 (0.4) Codon 59 0 Codon 61 9 (3.8) Codon (0.8) Codon (2.2) NRAS Codon 12 8 (3.4) Codon 13 2 (0.8) Codon 59 0 Codon (5.5) Codon Codon Table S3. Incidence of RAS mutations 6

8) Codon 146 5 (2.2) NRAS Codon 12 8 (3.4) Codon 13 2 (0.

8 Characteristic HR for death HR for rogression Arm FOLFIRI lus bev FOLFOXIRI lus bev 0.79 [ ] [ ] Mutational status RAS and BRAF wt RAS mutant 1.30 [ ] [ ] 0.30 BRAF mutant 2.24 [ ] [ ] ECOG Performance Status [ ] [ ] 0.10 Primary tumor site Left colon or rectum Right colon 1.29 [ ] [ ] 0.56 Prior adjuvant No Yes 1.34 [ ] [ ] 0.29 Time to metastases Metachronous Synchronous 1.66 [ ] [ ] Liver-only disease No Yes 1.40 [ ] [ ] 0.57 Surgery on rimary No Yes 0.67 [ ] [ ] 0.10 Kohne Score Low Intermediate 1.50 [ ] [ ] High 2.73 [ ] < [ ] Table S4. Multivariable models of overall and rogression-free survival including rognostic covariates and RAS and BRAF mutational status 7

10 Primary tumor site Left colon or rectum 1-1 - Right colon 1.29 [0.97-1.71] 0.086 1.08 [0.83-1.41] 0.56 Prior adjuvant No 1-1 - Yes 1.34 [0.70-2.59] 0.38 1.36 [0.77-2.43] 0.

9 FOLFIRI+bev (N=254) Safety oulation RAS and BRAF wild-tye RAS mutant BRAF mutant FOLFOXIRI+b ev (N=250) FOLFIRI+be v (N=45) FOLFOXIRI+b ev (N=48) FOLFIRI+be v (N=119) FOLFOXIRI+b ev (N=116) FOLFIRI+bev (N=12) FOLFOXIRI+b ev (N=16) Neutroenia 52 (20.5) 125 (50.0) 9 (20.0) 24 (50.0) 21 (17.6) 55 (47.4) 4 (33.3) 8 (50.0) Febrile neutroenia 16 (6.3) 22 (8.8) 2 (4.4) 5 (10.4) 6 (5.0) 10 (8.6) 3 (25.0) 2 (12.5) Diarrhea 27 (10.6) 47 (18.8) 3 (6.7) 5 (10.4) 18 (15.1) 25 (21.6) 2 (16.7) 3 (18.8) Stomatitis 11 (4.3) 22 (8.8) 1 (2.2) 1 (2.1) 7 (5.9) 8 (6.9) 1 (8.3) 3 (18.8) Nausea 8 (3.2) 7 (2.8) 4 (8.9) 1 (2.1) 3 (2.5) 3 (2.6) 0 (0.0) 0 (0.0) Vomiting 8 (3.2) 11 (4.4) 2 (4.4) 4 (8.3) 2 (1.7) 2 (1.7) 1 (8.3) 0 (0.0) Asthenia 23 (9.1) 30 (12.0) 1 (2.2) 6 (12.5) 15 (12.6) 15 (12.9) 1 (8.3) 3 (18.8) Periheral neuroathy 0 (0.0) 13 (5.2) 0 (0.0) 0 (0.0) 0 (0.0) 6 (5.2) 0 (0.0) 1 (6.3) Hyertension 6 (2.4) 13 (5.2) 0 (0.0) 4 (8.3) 6 (5.0) 4 (3.4) 0 (0.0) 0 (0.0) Venous thromboembolism 15 (5.9) 18 (7.2) 3 (6.7) 0 (0.0) 7 (5.9) 12 (10.3) 1 (8.3) 2 (12.5) Table S5. Most common (at least 3%) grade 3 or 4 adverse events in RAS and BRAF subgrous 8

6) 3 (25.0) 2 (12.5) Diarrhea 27 (10.6) 47 (18.8) 3 (6.7) 5 (10.4) 18 (15.1) 25 (21.6) 2 (16.7) 3 (18.8) Stomatitis 11 (4.3) 22 (8.8) 1 (2.2) 1 (2.1) 7 (5.9) 8 (6.9) 1 (8.3) 3 (18.8) Nausea 8 (3.

10 RAS and BRAF wild-tye RAS mutant BRAF mutant Median overall relative dose intensity* FOLFIRI+bev (N=45) FOLFOXIRI+bev (N=48) FOLFIRI+be v (N=119) FOLFOXIRI+bev (N=116) FOLFIRI+bev (N=12) FOLFOXIRI+bev (N=16) 88% 81% 91% 75% 88% 88% Table S6. Relative dose intensity in RAS and BRAF molecular subgrous. *Based on 5-fluoruracil, irinotecan and oxalilatin data 9

FOLFIRI+bev (N=12) FOLFOXIRI+bev (N=16) 88% 81% 91% 75% 88% 88% Table S6.

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