BREAKWATER Trial

[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 1] BREAKWATER: Study Design BREAKWATER (NCT04607421) is an open-label, multicenter, phase 3 study in first line BRAF V600E-mutant mCRC Inclusion criteria Age >16 years (or >18 years based on country) No prior systemic treatment for metastatic disease (n=158) Dual primary endpoints: Measurable disease (RECIST 1.1) BRAF V600E-mutant mCRC by local or central PFS and ORR by BICR laboratory testing R (EC + mFOLFOX6 vs SOC) ECOG PS 0 or 1 1:1:1a Adequate bone marrow hepatic, and renal function + mFOLFOX6 (n=236) N=637 Exclusion criteria Key secondary endpoint: Prior BRAF or EGFR inhibitors os (EC + mFOLFOX6 vs SOC) Symptomatic brain metastases MSI-H/dMMR tumors (unless patients were SOC (n=243)c ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition) Presence of a RAS mutation Stratified by regions (US/Canada vs Europe vs Rest of World) and ECOG PS (0 vs 1) Here we present the primary analysis of ORR by BICR (one of the dual primary endpoints), an interim analysis of os, and safety in the EC + mFOLFOX6 and SOC arms Following a protocol amendment enrollment to the EC arm was stopped and patients were randomized 1:1 to the EC+mFOLFOX6 or SOC arms; data in the EC arm will be reported at a later date. Patients were enrolled between November 16. 2021. and December 22. 2023. FmFOLFOX6/FOLFOXIRICAPOX * bevacizumab. In the first 110 patients in each of the EC+mFOLFOX6 and SOC arms. CAPOX BICR binded independent central review dMMR deficient mismatch repair EC encoratenic plus cetuximate ECOG PS Eastern Cooperative Oncology Group performance status EGFR epidermal growth receptor modified FOLFOXIRI mCRC metastatic colorectal cancer MSI-H microsabolito instability high cancer RECIST Response Evaluation Criteria . Solid Tumors ASCO Gastrointestinal #GI25 PRESENTED BY Scott Kopetz MD. PhD ASCO Cancers Symposium Presentation ASCO KNOWLEDGE CONQUERS CANCER --- [Slide 2] BREAKWATER: Study Design BREAKWATER (NCT04607421) is an open-label, multicenter, phase 3 study in first line BRAF V600E-mutant mCRC Inclusion criteria Age >16 years (or >18 years based on country) No prior systemic treatment for metastatic disease (n=158) Dual primary endpoints: Measurable disease (RECIST 1.1) BRAF V600E-mutant mCRC by local or central PFS and ORR by BICR laboratory testing R (EC + mFOLFOX6 vs SOC) ECOG PS 0 or 1 1:1:1a Adequate bone marrow hepatic, and renal function + mFOLFOX6 (n=236) N=637 Exclusion criteria Key secondary endpoint: Prior BRAF or EGFR inhibitors os (EC + mFOLFOX6 vs SOC) Symptomatic brain metastases MSI-H/dMMR tumors (unless patients were SOC (n=243)c ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition) Presence of a RAS mutation Stratified by regions (US/Canada vs Europe vs Rest of World) and ECOG PS (0 vs 1) Here we present the primary analysis of ORR by BICR (one of the dual primary endpoints), an interim analysis of os, and safety in the EC + mFOLFOX6 and SOC arms Following a protocol amendment enrollment to the EC arm was stopped and patients were randomized 1:1 to the EC+mFOLFOX6 or SOC arms; data in the EC arm will be reported at a later date. Patients were enrolled between November 16. 2021. and December 22. 2023. FmFOLFOX6/FOLFOXIRICAPOX * bevacizumab. In the first 110 patients in each of the EC+mFOLFOX6 and SOC arms. CAPOX BICR binded independent central review dMMR deficient mismatch repair EC encoratenic plus cetuximate ECOG PS Eastern Cooperative Oncology Group performance status EGFR epidermal growth receptor modified FOLFOXIRI mCRC metastatic colorectal cancer MSI-H microsabolito instability high cancer RECIST Response Evaluation Criteria . Solid Tumors ASCO Gastrointestinal #GI25 PRESENTED BY Scott Kopetz MD. PhD ASCO Cancers Symposium Presentation ASCO KNOWLEDGE CONQUERS CANCER --- [Slide 3] 11 Interim Overall Survival 6-month 12-month 1.0 92.3% 0.9 0.8 87.1% 79.5% 0.7 20 ASCO Gastrointestinal 0.6 66.1% EC+mFOLFOX6 0.5 0.4 SOC 0.3 Number of Median Overall Survival Events, (%) 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 o SOC 243 138 64 14 0 o 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 encorateno plus cetuximab mFOLFOX6 modified NE not estimable SOC standard of care ASCO Gastrointestinal Cancers Symposium #GI25 PRESENTED BY Scott Kopetz MD. PhD ASCO AMERICAN SOCIETY OF CLINICAL CUNICAL ONCOLOGY INCOUNTY property the address and ASCO Permasism KNOWLEDGE CONQUERS CANCER ASCO Gastrointestinal Cancers Symposium --- [Slide 4] Key Demographic and Baseline Disease Characteristics EC + mFOLFOX6 SOC Total n=236 n=243 N=479 Age, median (range), years 60.0 (24-81) 62.0 (28-84) 61.0 (24-84) Sex n (%) Male 123 (52.1) 119 (49.0) 242 (50.5) Female 113 (47.9) 124 (51.0) 237 (49.5) ECOG PS. n (%) 0 129 (54.7) 131 (53.9) 260 (54.3) 1 103 (43.6) 98 (40.3) 201 (42.0) Side of tumor. n (%) Left 89 (37.7) 98 (40.3) 187 (39.0) Right 147 (62.3) 145 (59.7) 292 (61.0) No. of organs involved n (%)* s2 122 (51.7) 129 (53.1) 251 (52.4) 23 114 (48.3) 114 (46.9) 228(47.6) Liver metastases, n (%)* 144 (61.0) 156 (64.2) 300 (62.6) CEA at baseline, n (%) 55 ug/L 65 (27.5) 63 (25.9) 128 (26.7) >5 ug/L 166 (70.3) 163 (67.1) 329 (68.7) CRP at baseline n (%) s10 mg/L 125 (53.0) 119 (49.0) 244 (50.9) >10 mg/L 105 (44.5) 107 (44.0) 212 (44.3) Data cutoff: December 22. 2023. *Based on BICR RICR blinded independent central review CEA carcinoembryonic antigen CRP Creactive protein EC encoratonic plus cetuximab ECOC PS Eastern Cooperative Oncology Group performance status OLFOX8 modified SOC standard of care ASCO Gastrointestinal #GI25 PRESENTED BY Scott Kopetz MD. 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[Slide 1] Background: Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study (NCT02928224). Historically, first-line (1L) treatment of BRAF V600E-mutant mCRC with chemotherapy (chemo) regimens has had limited efficacy. BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating 1L EC with or without chemo vs standard of care (SOC; chemo with or without bevacizumab). Reported here are the primary analysis of objective response rate by blinded independent central review (ORR by BICR; dual primary endpoint [EP]), the first interim analysis of overall survival (OS; key secondary EP), other secondary EPs, and safety for the EC+FOLFOX (oxaliplatin, leucovorin, and 5-FU) vs SOC arms. Methods: Eligible patients (pts) had untreated BRAF V600E-mutant mCRC, measurable disease (RECIST 1.1), and ECOG PS 0-1. Pts were randomized 1:1:1 to receive EC, EC+FOLFOX, or SOC; EC arm enrollment was closed after a protocol amendment Dual primary EPs were ORR (assessed in the first 110 pts randomized to each of the EC+FOLFOX and SOC arms) and progression-free survival by BICR (EC+FOLFOX vs SOC); os was a key secondary EP (EC+FOLFOX vs SOC), other secondary EPs included response duration and time to response (TTR). Results: Four hundred seventy-nine pts were randomized to the EC+FOLFOX and SOC arms (EC+FOLFOX: n=236; SOC: n=243). Baseline demographics and disease characteristics were similar across arms (median age: 61.0 years; male: 50.5% ECOG PS 0: 54.3%). At data cutoff (Dec 22, 2023), the EC+FOLFOX arm demonstrated a clinically meaningful and statistically significant improvement in confirmed ORR vs the SOC arm, 60.9% vs 40.0% odds ratio=2.443, one-sided P-value=0.0008, meeting this dual primary EP. The response observed with EC+FOLFOX was rapid and durable. os data were immature but indicated a sustained survival benefit with EC+FOLFOX vs SOC arm. Serious treatment- emergent adverse events (EC+FOLFOX: n=231; SOC: n=228) occurred in 37.7% vs 34.6% of pts in the respective arms. The safety profile was consistent with that known for each agent. Conclusions: BREAKWATER demonstrated a substantially improved response rate that was rapid and durable with EC+FOLFOX in BRAF V600E-mutant mCRC with manageable toxicities and no new safety signals. --- [Slide 2] EC+FOLFOX SOC n=110 n=110 ORR by BICR % (95% CI) 60.9 (51.6, 69.5) 40.0 (31.3,49.3) Odds ratio (95% CI) 2.443 (1.348,4.380) P-value 0.0008 n=67 n=44 Estimated median response duration by BICR (95% CI), 13.9 (8.5, NE) 11.1 (6.7, 12.7) mo Pts with a response duration 46 (68.7) 15 (34.1) of >6 mo, n (%) Pts with a response duration of >12 mo, n (%) 15 (22.4) 5 (11.4) Median TTR by BICR (range), 7.1 (5.7-53.7) 7.3 (5.4-48.0) weeks n=236 n=243 os (95% CI), mo NE (19.8, NE) 14.6 (13.4, NE) Hazard ratio (95% CI) 0.47 (0.318, 0.691) "One-sided a=0.001. NE, not estimable.

[Slide 1] 26 Key Takeaway Points/Conclusions Practice-changing BRAF-directed therapy for mCRC: can be moved to the first-line setting FDA-approved for BRAFV600E MT mCRC based on RR and survival trend Question: Does it matter which line (1L/2L/3L) it is given? Immunotherapy for dMMR/MSI-H mCRC: combination checkpoint blockade (PD- 1/CTLA-4) has response/survival benefit over single agent PD-1 Nivo/ipi already received FDA "accelerated approval" >2L dMMR mCRC Question: is it worth additional cost and modest toxicity in every dMMR patient? Cetuximab/chemo for 1L left-sided, RAS/RAF WT mCRC: modest benefit EGFR-targeting mAb's already on guidelines with 1L doublet chemo Question: Does it matter which line (1L/2L/3L) EGFR mAb is given? ASCO Gastrointestinal #GI25 ASCO AMERICAN SOCIETY OF PRESENTED BY: Wells Messersmith, MD. FACP, FASCO 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] 26 Key Takeaway Points/Conclusions Practice-changing BRAF-directed therapy for mCRC: can be moved to the first-line setting FDA-approved for BRAFV600E MT mCRC based on RR and survival trend Question: Does it matter which line (1L/2L/3L) it is given? Immunotherapy for dMMR/MSI-H mCRC: combination checkpoint blockade (PD- 1/CTLA-4) has response/survival benefit over single agent PD-1 Nivo/ipi already received FDA "accelerated approval" >2L dMMR mCRC Question: is it worth additional cost and modest toxicity in every dMMR patient? Cetuximab/chemo for 1L left-sided, RAS/RAF WT mCRC: modest benefit EGFR-targeting mAb's already on guidelines with 1L doublet chemo Question: Does it matter which line (1L/2L/3L) EGFR mAb is given? ASCO Gastrointestinal #GI25 ASCO AMERICAN SOCIETY OF PRESENTED BY: Wells Messersmith, MD. FACP, FASCO 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] 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