BREAKWATER Trial

[Slide 1] Overview of Response by BICR Confirmed ORR by BICR Confirmed Best Overall Response, TTR, and DOR by BICR 100% Odds ratio (95% CI): 2.443 (1.403-4.253) EC + mFOLFOX6 SOC n=110 n=110 One-sided P-value=0.0008 Confirmed best overall response, n (%) 80% 60.9% CR 3 (2.7) 2 (1.8) (51.6%-69.5%) PR 64 (58.2) 42 (38.2) Percentage of patients 40.0% SD 60% 31 (28.2) 34 (30.9) (31.3%-49.3%) Non-CR/non-PD 3 (2.7) 4 (3.6) PD 3 (2.7) 9 (8.2) 40% NE 6 (5.5) 19 (17.3) n=67 n=44 TTR, median (range), weeks 7.1 (5.7-53.7) 7.3 (5.4-48.0) 20% Estimated DOR, median (range), months 13.9 (8.5-NE) 11.1 (6.7-12.7) Patients with a DOR of ≥6 months, n (%) 46 (68.7) 15 (34.1) Patients with a DOR of â¥12 months, n (%) 15 (22.4) 5 (11.4) 0% EC + mFOLFOX6 SOC n=110 n=110 CR PR CR PR Data cutoff: December 22, 2023. BICR, blinded independent central review, CR, complete response; DOR, duration of response; EC, encorafenib plus cetuximab; mFOLFOX6, modified fluorouracil/leucovorin/oxaliplatin; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease; SOC, standard of care; TTR, time to response ASCO Gastrointestinal #GI25 PRESENTED BY: Scott Kopetz, MD, PhD ASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGY Cancers Symposium Presentation is property of the author and ASCO Permission required for reuse, contact permissions@asco.org KNOWLEDGE CONQUERS CANCER --- [Slide 2] Interim Overall Survivalᵃ 6-month 12-month 1.0 92.3% 0.9 0.8 87.1% 79.5% 0.7 Probability of Survival 66.1% EC+mFOLFOX6 0.6 0.5 0.4 SOC 0.3 Number of Median Overall Survival, Events, n (%) months (95% CI) 0.2 EC+mFOLFOX6 40 (16.9) NE (19.8-NE) 0.1 SOC 72 (29.6) 14.6 (13.4-NE) Hazard ratio, 0.47 (95% CI, 0.318-0.691) P=0.0000454 0.0 0 6 12 18 24 30 Time (months) No. at risk EC+mFOLFOX6 236 156 81 20 1 0 SOC 243 138 64 14 0 0 Data cutoff: December 22, 2023. OS was tested following the prespecified plan with one-sided alpha of 0.000000083, calculated as a portion of the nominal one-sided alpha of 0.001. Statistical significance was not achieved at this time. EC, encorafenib plus cetuximab; mFOLFOX6, modified fluorouraci/leucovorin/oxaliplatin; NE, not estimable; SOC, standard of care. ASCO Gastrointestinal #GI25 ASCO AMERICAN SOCIETY OF PRESENTED BY: Scott Kopetz, MD, PhD CLINICAL ONCOLOGY Cancers Symposium Presentation is property of the author and ASCO Permission required for reuse, contact permissions@asco.org KNOWLEDGE CONQUERS CANCER

[Slide 1] The NEW ENGLAND OF JOURNA JOURNAL of MEDICINE Q ORIGINAL ARTICLE f X in x Encorafenib, Cetuximab, and mFOLFOX6 in BRAF- Mutated Colorectal Cancer Authors: Elena Elez, M.D., Ph.D., Takayuki Yoshino, M.D., Ph.D., Lin Shen, M.D., Sara Lonardi, M.D., Eric Van Cutsem, M.D., Ph.D., Cathy Eng, M.D., Tae Won Kim, M.D., Ph.D., +13 , for the BREAKWATER Trial Investigators* Author Info & Affiliations Published May 30, 2025 DOI: 10.1056/NEJMoa2501912 Copyright © 2025 --- [Slide 2] A Progression-free Survival Hazard Ratio for Hazard Ratio for Median Disease Progression Disease Progression Progression-free or Death vs. or Death vs. Survival Standard Care EC+mFOLFOX6 (95% CI) (95% CI) (95% CI) mo EC+mFOLFOX6 12.8 (11.2-15.9) 0.53 (0.41-0.68) — P<0.001 Standard Care 7.1 (6.8-8.5) — — EC 100 6.8 (5.7-8.3) 1.09 (0.84-1.42) 2.05 (1.56-2.68) 90 80 Estimated Percentage of Patients 70 Free from Event 60 50 40 EC+mFOLFOX6 30 20 Standard Care 10 EC 0 0 6 12 18 24 30 36 42 Months No. at Risk EC+mFOLFOX6 236 156 96 39 16 4 1 Standard care 243 100 34 11 3 1 0 EC 158 60 24 12 6 3 0 B Subgroup Analysis Standard Hazard Ratio for Disease Progression Subgroup EC+mFOLFOX6 Care or Death (95% CI) no. of events/no. of patients All patients (stratified analysis) 122/236 132/243 0.53 (0.41-0.68) All patients (unstratified analysis) 122/236 132/243 0.51 (0.40-0.65) Age <65 yr 78/150 71/139 0.51 (0.37-0.71) >65 yr 44/86 61/104 0.51 (0.34-0.75) Sex Male 59/123 63/119 0.50 (0.35-0.72) Female 63/113 69/124 0.53 (0.37-0.75) ECOG performance-status score 0 60/131 74/136 0.43 (0.30-0.61) 1 62/105 58/107 0.63 (0.44-0.90) No. of organs involved <2 52/119 66/127 0.40 (0.28-0.58) >3 70/117 66/116 0.64 (0.45-0.90) Location of tumor Left side of colon 51/90 53/98 0.49 (0.33-0.73) Right side of colon 71/146 79/145 0.52 (0.37-0.72) Liver metastases Yes 87/147 86/160 0.60 (0.44-0.81) No 35/89 46/83 0.36 (0.23-0.57) 0.2 1.0 2.0 EC+mFOLFOX6 Standard Care Better Better --- [Slide 3] A Overall Survival Median Hazard Ratio Hazard Ratio Overall for Death vs. for Death vs. Survival Standard Care EC+mFOLFOX6 (95% CI) (95% CI) (95% CI) mo EC+mFOLFOX6 30.3 (21.7-NE) 0.49 (0.38-0.63) — P<0.001 Standard Care 15.1 (13.7-17.7) — — 100 EC 19.5 (17.6-22.5) 0.69 (0.53-0.90) 1.45 (1.08-1.93) 90 80 Estimated Percentage of Patients Alive 70 60 50 EC+mFOLFOX6 40 30 EC 20 Standard Care 10 0 0 6 12 18 24 30 36 42 Months No. at Risk EC+mFOLFOX6 236 216 182 121 48 17 2 0 Standard care 243 202 147 64 27 9 0 0 EC 158 137 107 78 44 16 1 0 B Subgroup Analysis Standard Hazard Ratio for Death Subgroup EC+mFOLFOX6 Care (95% CI) no. of deaths/no. of patients All patients (stratified analysis) 94/236 148/243 0.49 (0.38-0.63) All patients (unstratified analysis) 94/236 148/243 0.48 (0.37-0.62) Age <65 yr 56/150 85/139 0.44 (0.31-0.62) >65 yr 38/86 63/104 0.54 (0.36-0.82) Sex Male 54/123 71/119 0.59 (0.42-0.85) Female 40/113 77/124 0.38 (0.26-0.56) ECOG performance-status score 0 42/131 76/136 0.42 (0.29-0.62) 1 52/105 72/107 0.54 (0.38-0.77) No. of organs involved <2 32/119 66/127 0.39 (0.25-0.59) >3 62/117 82/116 0.52 (0.38-0.73) Location of tumor Left side of colon 38/90 62/98 0.48 (0.32-0.72) Right side of colon 56/146 86/145 0.49 (0.35-0.68) Liver metastases Yes 73/147 104/160 0.58 (0.43-0.78) No 21/89 44/83 0.31 (0.18-0.52) 0.2 1.0 2.0 EC+mFOLFOX6 Standard Care Better Better

[Slide 1] 2025 ASCO ANNUAL MEETING May 30 — June 3, 2025 McCormick Place | Chicago, IL & Online am.asco.org #ASCO25

[Slide 1] 2 Key Takeaway Points Precision oncology has now fully entered the first-line setting of mCRC, with early combinations tailored to molecular subtypes delivering clinically transformative outcomes: encorafenib + cetuximab + mFOLFOX based on BREAKWATER in BRAF V600E is to be considered practice changing Pause nivolumab + ipilimumab based on Checkmate 8HW in MSI-H is to be considered practice changing Oral Multikinase inhibitors including antiangiogenic properties remain anchored in broader applicability, but the ANCHOR trial of anlotinib + chemotherapy does not shift current standards in 1L RAS/BRAF WT disease 2025 ASCO #ASCO25 PRESENTED BY: Andrea Sartore-Bianchi, MD ASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING Presentation is property of the author and ASCO Permission required for reuse contact permissions@@asco.org KNOWLEDGE CONQUERS CANCER --- [Slide 2] 12 The evolution of BRAF targeting in mCRC 2L+ 1L 70 14 O 60 12 50 10 ORR 40 8 PFS 30 O 6 20 4 10 2 vemurafenib EC PI3Kai BEACON ANCHOR BREAKWATER Study Phase/Line Regimen ORR PFS OS Prahallad et al (2012) Preclinical Discovery of EGFR feedback activation - - - Kopetz et al (2015) l/advanced Vemurafenib monotherapy 5% 2.1 mo - Van Geel et al (2017) I/II/advanced Encorafenib + Cetuximab + Alpelisib 18% 4.2 mo - BEACON CRC (2020) III/2L+ Encorafenib + Cetuximab 20% 4.2 mo 8.4 mo ANCHOR CRC (2021) II/1L Encorafenib + Binimetinib + Cetuximab 47.4% 5.8 mo 18.3 mo BREAKWATER (2025) III/1L Encorafenib + Cetuximab + mFOLFOX6 65.7% 12.8 mo 30.3 mo 2025 ASCO #ASCO25 PRE SENTED BY: Andrea Sartore-Bianchi, MD ASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING Presentation is property of the author and ASCO Permission required for reuse, contact permissions@asco.org KNOWLEDGE CONQUERS CANCER --- [Slide 3] 22 3501: CheckMate 8HW expanded results Clinical interpretation framework BUT YES, NIVO IPI NIVO (n 352) (n 351) Checkmate All treated patients, n (%) Any grade Grade 3/4 Any grade Grade 3/4 Progression-free survival: NIVO + IPI vs NIVO (all lines) TRAEs* Any TRAEs 285 (81) 78 (22) 249 (71) 50 (14) Centrally confirmed NIVO 100 MSI-M/diam (n = 296) ( - 286) Serious TRAEs 65 (18) 55 (16) 29 (8) 24 (7) Median PFS,' mo NR 19.3 90 12-mo rate 24-mo rate 95% CI 53.8-NE 22.1-NE TRAEs leading to discontinuation 48 (14) 33(9) 21 (6) 14 (4) 36-mo rate 60 76% 71% MR (95% o) elated deaths 2 1)* 1 1)* 67% Progression-free survival (%) 70 rted in 2 10% of patients 60 62% 91 (26) 0 63 (18) 0 50 55% 51% 71 (20) 3 (< 1) 59 (17) 2 (< 1) 40 idism 61 (17) 2 (< 1) 31(9) 0 10 20 58 (16) 2 (< 1) 44 (13) 2 (< 1) 10 42 (12) 1(<1) 35 (10) 1 (< 1) 0 Hyperthyroidism 40 (11) 0 16(5) 0 0 1 5 9 12 15 18 21 24 27 30 13 36 39 42 45 48 51 54 57 60 No. risk Months Arthralgia 38 (11) 1 (<1) 23 (7) 0 NIVO 296 248 234 225 214 207 200 180 164 146 136 134 121 102 100 61 54 29 23 0 0 Rash 34 (10) 3 (< 1) 29(8) 1 1) HIVO 286 210 E 179 169 184 158 141 124 109 " = = 72 19 19 " 15 12 1 0 Adrenal insufficiency 34(10) 8(2) 12(3) 3 (< 1) The long-term benefit of upfront dual ICI justifies the up-front immune-related risk when patients are well selected I ( clinical scores?) and toxicities managed proactively NIVO + IPI should be considered a standard of care option in 1L MSI-H mCRC 2025 ASCO #ASCO25 PRE SENTED BY: Andrea Sartore-Bianchi, MD ASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING Presentation is property of the author and ASCO Permission required for reuse, contact permissions@asco.org KNOWLEDGE CONQUERS CANCER --- [Slide 4] 5 The evolution of precision oncology in 1L mCRC Treatment of mCRC slowly progressed from primarily relying on chemotherapy to incorporating targeted therapies and immunotherapy The key advancements that catalyzed the transition of precision oncology into the 1L therapeutic landscape have been RAS selection for anti-EGFR, MMR selection, and histology-specific BRAF, KRAS G12C and HER2 targeting Bevacizumab Panitumumab chemo-sensitive Cetuximab FOLFOX Histology (CRC) - Encorafenib + 5FU 5FU/LV FOLFIRI Capecitabine RAS selection specific targeting cetuximab + CT 1960 1980 2000 2004 2006 2012 2014 2015 2020 2023 2025 Cetuximab Encorafenib + Sotorasib + Regorafenib chemo-refractory Ramucirumab cetuximab Tucatinib + Panitumumab panitumumab trastuzumab Ziv-aflibercept 2025 ASCO #ASCO25 PRESENTED BY: Andrea Sartore-Bianchi, MD ASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING Presentation is property of the author and ASCO Permission required for reuse, contact permissions@asco.org KNOWLEDGE CONQUERS CANCER

[Slide 1] The NEW ENGLAND 10 JOURNAL of MEDICINE Progression-free Survival 100 90 80 Estimated Percentage of Patients 70 Free from Event 60 50 40 EC+mFOLFOX6 30 20 Standard Care 10 EC 0 0 6 12 18 24 30 36 42 Months ORIGINAL ARTICLE MAY 30, 2025 MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY Targeted Therapy in BRAF V600E Metastatic Colorectal Cancer E. Elez and Others