BESPOKE CRC Trial

[Slide 1] Participate at meetings.asco.org/gi ASCO Gastrointestinal Cancers Symposium Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage 11/111 colorectal cancer (CRC): Interim analysis of BESPOKE CRC study Presenting author: Pashtoon Kasi1, MD, MS Co-authors: Vasily N Aushev? Joe Ensor², Nathan Langer3, Christopher Wang*, Timothy Cannon³, yudmyla BerimA, Trevor Feinstein', Axel Grothey Joseph McCollom Sujith Kalmadi1°, Ahmed Zakari¹¹, Farshid Dayyani12, Don Gravenor13, Janelle Meyer14, Saima Sharif's Adham JurdiP, Minetta C Liv2, Alexey Aleshin?, Scott Kopetz's Richmond Department VA, Well "Alabama Corneil Oncology, Medicine, Englander institute of Precision Medicine, New York Presbylerian Hospital, New York, NY, Natura, no. Austin, X Virginia Cancer institute (OCCA), Montverde, Adianta, GA FL: West Division Cancer Center, Germantown, Birmingham, TN AL; Parkview Name Schar Cancer Cancer Institute, Institute, Fort Fairtss, Wayne, VA, IN Rulgers "fromood Cancer Cancer was Research New Centers, Jersey, New Chander, Brunswick, AZ. "AdvenPiealth NJ, Pledmont Cancer Cancer Value 20 ASCO Gastrointestinal Salem, Department of Medicine, University of California Invine, Orange CA Baptist Cancer Center, Memphis, IN, "Hematology Onoology Institute, of LLP. Salem Office, Salem OR: University of lowa lows City, A University of Texas MD Anderson Cancer Center, Houston TX 24 Cancers Symposium ASCO Gastrointestinal #GI24 - Pashtoon Kasi, MD, MS Cancers Symposium I ASCO EXPIRATE CONDUCTS CARD --- [Slide 2] gs.asco.org/gi CheckMate 8HW: first results of 1L NIVO + IPI vs chemo Progression-free survival 1L centrally confirmed NIVO IPI Chemo MSI-H/dMMR (n 171) (n 84) Median PFS,ᵃ.ᵇ mo NR 5.9 100 95% CI 38.4-NE 4.4-7.8 90 12-month rate HR (97.91% CI) 0.21 (0.13-0.35) 80 24-month rate Pvalue < 0.0001 Progression-free survival (%) 70 79% 60 72% 50 NIVO + IPI 40 30 21% 20 14% 10 BD Chemo 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 No. at risk Months NIVO IPI 171 144 132 122 108 95 92 77 64 53 42 37 22 10 9 1 0 Chemo 84 53 29 20 10 6 5 5 3 2 0 0 0 0 0 0 0 PFS benefit with NIVO + IPI vs chemo was robust and consistent across the sensitivity analyses, including PFS by BICR in 1L all randomized patients (HR, 0.32; 95% CI, 0.23-0.46) *Per BICR. Median follow-up, 24.3 months. 6 --- [Slide 3] ngs.asco.org/gi Conclusions 11 BESPOKE CRC is the first large, prospective, US-based trial (133 sites - 1792 patients) to report on the utility of tumor-informed ctDNA in patients with CRC after surgery. ctDNA detection of MRD is a powerful prognostic and predictive tool in patients with stage II and III CRC. ctDNA monitoring allowed for oligometastasis-directed therapy in 40% of patients who recurred. ctDNA status during surveillance was prognostic of outcomes regardless of whether the patients received ACT (DFS ~ 9 months). The patients' perceived utility of ctDNA testing and dimensions of well-being point towards general acceptance of ctDNA testing in patients with CRC. ASCO Gastrointestinal #GI24 PRESENTED BY: Pashtoon Kasi, MD, MS Cancers Symposium ASCO AMERICAN SOCK CLINICAL ONCO A property of the who and ASCO Permission required for - contact KNOWLEDGE CONQUERS CA

[Slide 1] 4 ctDNA-positivity at MRD time point is predictive of inferior DFS 1.0 0.9 0.8 Stages II-III MRD status MRD-negative MRD-positive 0.7 Numbers of events (%) 38/530 (7.17) 55/93 (59.14) 2-year DFS post surgery, 0.6 91.59 (88.38-93.94) 29.86 (13.26-48.54) % (95% CI) Median DFS post surgery, Not reached 15.98 (13.77-20.22) 0.5 months (95%) 0.4 ######## 0.3 0.2 HR=12.1, 95% CI: 8.0-18.3, p<0.0001 0.1 0.0 12 24 36 48 60 72 84 96 108 120 132 144 156 Weeks post surgery Number at Risk MRD-negative 530 522 513 499 482 464 429 353 101 12 5 1 0 MRD-positive 93 87 78 64 54 43 36 30 8 0 ASCO Gastrointestinal PRESENTED BY Pashtoon Kasi, MD, MS ASCO AMERICAN SOCIETY OF #GI24 CUNICAL ONCOLOGY Cancers Symposium Presentation property of the eather and ASCO KNOWLEDGE CONQUERS CANCER --- [Slide 2] ctDNA-positivity at MRD time point is predictive of inferior DFS 1.0 0.9 0.8 Stages II-III 0.7 MRD status MRD-negative MRD-positive Disease-Free Survival Numbers of events (%) 38/530 (7.17) 55/93 (59.14) 0.6 2-year DFS post surgery, % (95% CI) 91.59 (88.38-93.94) 29.86 (13.26-48.54) Median DFS post surgery, Not reached 0.5 months (95%) 15.98 (13.77-20.22) 0.4 0.3 0.2 0.1 HR=12.1, 95% CI: 8.0-18.3, p<0.0001 0.0 12 24 36 48 60 72 84 96 108 120 132 144 156 Weeks post surgery Number at Risk MRD-negative 530 522 513 499 482 464 429 353 101 12 5 1 0 MRD-positive 93 87 78 64 54 43 36 30 8 0 ASCO Gastrointestinal #GI24 PRESENTED E BY Pashtoon Kasi, MD, MS ASCO AMERICAN SOCIETY or CUNICAL ONCOLOGY Cancers Symposium Presentation property of THE without and ASCO Personsion required for - contact KNOWLEDGE CONQUERS CANCER --- [Slide 3] 5 ctDNA-positivity at MRD time point is predictive of inferior DFS Stage = 1.0 09 04 MRD-positivity rate by stage II-III 0.7 I Disease ! 14 05 04 HR-188 0% Ct. p<0.0001 Stage Total, N MRD-negative, MRD-positive, 95% CI for 0.3 n (%) n (%) positivity rate 02 01 00 II 280 262 (93.57) 18 (6.43) 4.10-9.93 12 24 36 43 60 72 54 90 106 120 132 144 156 WHILE post surgery Number Rosk III 343 268 (78.13) 75 (21.87) 17.82-26.54 MRD-negative 262 257 253 245 238 227 205 171 50 4 2 1 0 MRO-positive 18 14 10 7 / 6 6 5 1 0 Total 623 530 93 Stage III 10 09 03 07 I Disease ! 04 Benchmark for proportion (%) of patients who are 05 0.4 MRD-positive with stage II and III colorectal cancer. 03 02 HR-93 90% CI 59-567, p=0001 01 : 12 24 36 45 60 72 04 96 108 120 132 144 156 Weeks post surgery Number . - MRD-negative 268 265 200 3 244 237 224 182 $1 6 3 0 MRD positive c 73 68 57 c 37 30 DI 7 0 ASCO Gastrointestinal #GI24 PRESENTED BY Pashtoon Kasi, MD, MS ASCO AMERICAN SOCIETY OF CINICAL CACOLOGE Cancers Symposium - * property of - - and ASCO Personal regist " - - KNOWLEDGE CONQUERS CANCER --- [Slide 4] 10 Perceived utility of ctDNA testing and dimensions of well-being : p=0.010 p=0. 12 p=0.094 20 15 HADS anxiety score HADS depression score reported ctDNA results FCR4 $ 73% reduced anxiety about cancer recurrence Positive Positive (N-311) (N-312) #1DNA status efDNA status status Fear Anxiety/ 1130 responses from Depression felt they were receiving 413 patients 87% the right treatment after receiving their results Patient would continue using 92% the ctDNA test to Value/Utility Confidence monitor cancer valued the additional 96% information received from ctDNA results ..... Kasi PM, et al. Poster Session C, Abstract ID: 54 ASCO Gastrointestinal PRESENTED OF Pashtoon Kasi, MD, MS #GI24 ASCO AMERICAN SOCIETY or CLINICAL CINCOLOGY Cancers Symposium property of the and ASCO Permission I contact KNOWLEDGE CONQUERS CANCER --- [Slide 5] 11 Conclusions BESPOKE CRC is the first large, prospective, US-based trial (133 sites - 1792 patients) to report on the utility of tumor-informed ctDNA in patients with CRC after surgery. ctDNA detection of MRD is a powerful prognostic and predictive tool in patients with stage II and III CRC. ctDNA monitoring allowed for oligometastasis-directed therapy in 40% of patients who recurred. ctDNA status during surveillance was prognostic of outcomes regardless of whether the patients received ACT (DFS ~ 9 months). The patients' perceived utility of ctDNA testing and dimensions of well-being point towards general acceptance of ctDNA testing in patients with CRC. ASCO Gastrointestinal #GI24 PRESENTED BY Pashtoon Kasi, MD. MS ASCO AMERICAN SOCIETY or CLINICAL ONCOLOGY Cancers Symposium Presentation property of be withor and ASCO Personal required for - contact KNOWLEDGE CONQUERS CANCER

[Slide 1] ctDNA-positivity at MRD time point is predictive of inferior DFS 4 1.0 0.9 0.8 Stages II-III 0.7 MRD status MRD-negative MRD-positive Disease-Free Survival Numbers of events (%) 38/530 (7.17) 55/93 (59.14) 0.6 2-year DFS post surgery, % (95% CI) 91.59 (88.38-93.94) 29.86 (13.26-48.54) Median DFS post surgery, Not reached months (95%) 15.98 (13.77-20.22) 0.5 0.4 0.3 0.2 0.1 HR=12.1, 95% Cl: 8.0-18.3, p<0.0001 0.0 12 24 36 48 60 72 84 96 108 120 132 144 156 Weeks post surgery Number at Risk MRD-negative 530 522 513 499 482 464 429 353 101 12 5 1 0 MRD-positive 93 87 78 64 54 43 36 30 8 0 ASCO Gastrointestinal #GI24 PRESENTED BY BY: Pashtoon Kasi, MD, MS ASCO AMERICAN SOCIETY or CLINICAL ONCOLOGY Cancers Symposium Presentation property of DE wher and ASCO Permission required for - contact KNOWLEDGE CONQUERS CANCER --- [Slide 2] Recurrence-Free Survival Median follow-up 36 months 100% 84% 82% 80% 1 84% recurrence-free survival 74% 60% Strata 40% arm=Standard Management arm=ctDNA-informed 20% HR (95% CI): 1.38 (0.76, 2.50), P . 0.28 0% 0 6 12 18 24 30 36 months Number at risk (number censored) 75(0) 72(1) 71(1) 64(1) 56(7) 44(18) 35(27) 155(0) 150(0) 141(1) 129(3) 111(19) 80(42) 62(57) ASCO Gastrointestinal Cancers Symposium #GI24 PRESENTED BY Jeanne Tie, MBChB FRACP MD ASCO AMERICA CLINICAL CHICOLOGY - property - - ASCO Permission required - - - KNOWLEDGE CONQUERS CANCER ASCO G

[Slide 1] ctDNA testing was associated with higher oligometastasis-directed therapy 101 patients recurred Oligometastasis-directed N therapy type Surgery 30 Oligometastasis-directed No oligometastasis-directed therapy (N=40) therapy (N=61) Radiofrequency Ablation (RFA) 3 Microwave Ablation (MWA) 2 Unknown status (n=2) Stereotactic Body Radiation 2 Therapy (SBRT) Disease-free (N=21. 55%) Second recurrence (N=17, 45%) Y90 radiotherapy 2 Chemoradiation 1 ASCO Gastrointestinal Pashtoon Kasi, MD. MS ASCO #G124 PRESENTED KNOWLEDGE COMOUNAS CANCER Cancers Symposium Passion --- [Slide 2] ctDNA-positivity at MRD time point is predictive of inferior DFS 1.0 0.9 0.8 Stages II-III 0.7 MRD status MRD-negative MRD-positive Disease-Free Survival Numbers of events (%) 38/530 (7.17) 55/93 (50.14) 0.6 2-year DFS post surgery, % (95% Ci) 91.59 (88.38-93.94) 29.58 (13.26-48.54) Median DFS post surgery, Not reached 0.5 months (05%) 15.90 (13.77-20.22) 0.4 0.3 0.2 0.1 HR=12.1, 95% CI: 8.0-18.3, p<0.0001 0.0 12 24 36 48 60 72 84 96 108 120 132 144 156 Weeks post surgery Number at Risk MRD-negative 530 522 513 499 482 464 429 353 101 12 5 1 0 MRD-positive 93 87 78 64 54 43 36 30 8 0 ASCO Gastrointestinal PRESENTED BY Pashtoon Kasi, MD, MS ASCO SECUTION LIF Cancers Symposium #GI24 CINCK CHOCOLOGY - . property of the - and ANCO Person to - cashel KNOWLEDGE CONQUERS CANCER --- [Slide 3] 6 Benefit from ACT observed in MRD-positive but not MRD-negative patients MRD-positive patients MRD-negative patients 10 1.0 0.9 0.9 0.8 08 07 Disease-Free Survival 07 HR=1.47, 95% Ct: 0.78-2.78, p=0.2316 0.6 0.5 Disease-Free Survival 0.6 0.5 0.4 0.4 0.3 03 02 02 0.1 HR=3.06, 95% Cl: 1.43-6.56, p=0.0025 0.1 0.0 0.0 12 24 36 48 60 72 84 96 108 120 12 24 36 48 60 72 84 96 108 120 132 144 156 Weeks post surgery Weeks post surgery Number at Risk Number at Risk ACT 85 80 72 56 48 39 32 18 2 0 ACT 296 293 288 281 271 263 251 207 61 10 4 1 0 Observation 8 6 4 3 2 1 1 1 0 Observation 234 229 225 218 211 201 178 146 40 2 1 0 Adjuvant strategy ACT Observation Adjuvant strategy ACT Observation Numbers of events (%) 47/85 (55.29) 8/8 (100) Numbers of events (%) 18/206 (6.08) 20/234 (8.55) 2-year OFS post surgery, 2-year DFS post surgery, 42.44 (31.55-52.91) 12.50 (0.66-42.27) % (05% CI) 93.70 (90.03-96.05) 90.39 (85.38-93.75) % (95% CI) Median DFS post surgery, Median DFS post surgery, 17.78 (14.37-not reached) 7.52 (3.52-15.88) Not reached Not reached months (95%) months (95%) ASCO Gastrointestinal ASCO AMERICAN SOCIETY OF PRESENTED BY Pashtoon Kasi, MD CINICAL CHOOLOGE Cancers Symposium #GI24 - . property of the - and ASCO Personal - - contact KNOWLEDGE CONQUERS CANCER --- [Slide 4] Sustained ctDNA clearance is associated with superior DFS when compared to transient or no clearance DFS by cIDNA clearance patterns 85% of patients with transient clearance develop molecular recurrence by the 15th month 1.00 100 0.75 DFS probability Patients converted to ctDNA-positive (%) 75 0.50 50 0.25 25 0.00 0 0 5 10 15 20 6-9 9-12 12-15 21-24 27-30 Time (months) (n-3) (n=7) (tw2) (n=1) (n=1) Number at risk Sustained clearance 17 16 16 12 1 Month Intervals from surgery Translent clearance 14 11 6 5 1 No clearance 14 6 3 3 1 ASCO Gastrointestinal #GI24 PRESENTED - Pashtoon Kasi, MD, MS ASCO AMERICAN CINICAL CHOCLOGY Cancers Symposium - . - of the - will ASCO - august - - cantal KNOWLEDGE CONQUERS CANCER --- [Slide 5] ctDNA testing was associated with higher oligometastasis-directed therapy 101 patients recurred Oligometastasis-directed N therapy type Surgery 30 Oligometastasis-directed No oligometastasis-directed therapy (N=40) therapy (N=61) Radiofrequency Ablation (RFA) 3 Microwave Ablation (MWA) 2 Unknown status (n=2) Stereotactic Body Radiation 2 Therapy (SBRT) Disease-free (N=21, 55%) Second recurrence (N=17, 45%) Y90 radiotherapy 2 Chemoradiation 1 ASCO Gastrointestinal PRESENTED BY Pashtoon Kasi, MD, MS ASCO AMERICAN OR Cancers Symposium #GI24 CINICAL EXCELOGY - - property - the - and ASCO Pession agent is - - personsible KNOWLEDGE CONQUERS CANCER

[Slide 1] 5 ctDNA-positivity at MRD time point is predictive of inferior DFS Stage II 10 00 0-8 MRD-positivity rate by stage II-III 07 04 0.5 04 Total, N MRD-negative, MRD-positive, 95% CI for 03 Stage n (%) n (%) positivity rate 02 01 00 II 280 262 (93.57) 18 (6.43) 4.10-9.93 12 24 x 40 60 72 54 9d 100 120 132 144 156 Weeks post surgery Number Risk III 343 268 (78.13) 75 (21.87) 17.82-26.54 262 257 253 246 238 227 206 171 50 4 0 MRO-positive 14 10 Total 623 530 93 Stage III 10 09 03 07 0.5 05 Benchmark for proportion (%) of patients who are 0.4 MRD-positive with stage II and III colorectal cancer. 03 02 01 00 12 24 36 48 40 72 84 96 908 120 132 544 156 Weeks post surgery . Risk MRO 258 265 200 253 244 237 224 182 51 # 3 0 68 SZ at 30 ASCO Gastrointestinal Pashtoon Kasi, MD. MS #GI24 ASCO Cancers Symposium KNOWLEDGE CONQUERS CANCER --- [Slide 2] 5 ctDNA-positivity at MRD time point is predictive of inferior DFS Stage II 10 09 08 MRD-positivity rate by stage II-III 07 Disease I From 00 05 04 90% a 19305 p<0.0001 Total, N MRD-negative, MRD-positive, 95% CI for 03 Stage n (%) n (%) positivity rate 02 01 00 II 280 262 (93.57) 18 (6.43) 4.10-9.93 42 24 36 4d 8 72 54 96 108 120 132 144 156 Works post surgery Number at Risk III 343 268 (78.13) 75 (21.87) 17.82-26.54 MRD negative 262 257 253 246 238 227 205 171 50 . 2 1 0 MRD-positive 18 14 10 7 / 0 $ 5 1 0 Total 623 530 93 Stage III 10 09 0.8 I 07 04 Benchmark for proportion (%) of patients who are 0.5 0.4 MRD-positive with stage II and III colorectal cancer. 03 02 90% CI 5.9.167, p-0-0001 01 00 12 24 36 48 60 72 64 96 108 120 132 544 156 I Include Number - Risk MRO-negative 268 265 260 253 244 237 224 182 M 8 3 0 MRD-positive c 73 68 37 47 17 30 0 7 0 ASCO Gastrointestinal Cancers Symposium #GI24 PRESENTED BY Pashtoon Kasi, MD, MS ASCO AMERICAN SOCIETY OF CUNCK CHOOLOGY - - property of the - and ASCO Pession segaral to - cantact personsions@gmail.com - KNOWLEDGE CONQUERS CANCER --- [Slide 3] 6 Benefit from ACT observed in MRD-positive but not MRD-negative patients MRD-positive patients MRD-negative patients 1.0 1.0 0.9 0.9 0.8 0.8 0.7 Disease-Free Survival 0.7 HR=1.47, 95% CI: 0.78-2.78, p=0.2316 0.6 0.5 Disease-Free Survival 0.6 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 HR=3.06, 95% CI: 1.43-6.56, p=0.0025 0.1 0.0 0.0 12 24 36 48 60 72 84 96 108 120 12 24 36 48 60 72 84 96 108 120 132 144 156 Weeks post surgery Weeks post surgery Number at Risk Number at Risk ACT 85 80 72 56 48 39 32 18 2 0 ACT 296 293 288 281 271 263 251 207 61 10 4 1 0 Observation 8 6 4 3 2 1 1 1 0 Observation 234 229 225 218 211 201 178 146 40 2 1 0 Adjuvant strategy ACT Observation Adjuvant strategy ACT Observation Numbers of events (%) 47/85 (55.29) 8/8 (100) Numbers of events (%) 18/296 (6.08) 20/234 (8.55) 2-year DFS post surgery, 2-year DFS post surgery, 42.44 (31.55-52.91) 12.50 (0.66-42.27) % (95% CI) 93.70 (90.03-96.05) 90.39 (85.38-93.75) % (95% CI) Median DFS post surgery, Median DFS post surgery, 17.78 (14.37-not reached) 7.52 (3.52-15.88) Not reached Not reached months (95%) months (95%) ASCO Gastrointestinal #GI24 PRESENTED BY: Pashtoon Kasi, MD ASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGY Cancers Symposium Presentabcn 8 property of the withor and ASCO Permission required for rese, contact permissions@asco.org KNOWLEDGE CONQUERS CANCER --- [Slide 4] 8 Sustained ctDNA clearance is associated with superior DFS when compared to transient or no clearance DFS by ctDNA clearance patterns 85% of patients with transient clearance develop molecular recurrence by the 15th month 1.00 100 0.75 0.50 Patients converted to ctDNA-positive (%) 75 DFS probability 50 0.25 25 0.00 0 0 5 10 15 20 6-9 9-12 12-15 21-24 27-30 Time (months) (n=3) (n=7) (n=2) (n=1) (n=1) Number at risk Sustained clearance 17 16 16 12 1 Month Intervals from surgery Transient clearance 14 11 6 5 1 No clearance 14 6 3 3 1 ASCO Gastrointestinal #GI24 PRESENTED BY: Pashtoon Kasi, MD, MS ASCO AMERICAN SOCIETY or CLINICAL ONCOLOGY Cancers Symposium Presentation A property of the author and ASCO Personsion required for - contact permissions@asco.org KNOWLEDGE CONQUERS CANCER