CRITICS-II Trial

[Slide 1] CRITICS-II Neoadjuvant Strategies in Resectable Gastric Cancer Phase II | ASCO GI 2026 @DrRishabhOnco All treatment before surgery Arm 1 Arm 2 Arm 3 Chemotherapy Chemotherapy Chemoraditerapy Alone Chemoraditherapy Alone 1-yr EFS: 1-yr EFS: 1-yr EFS: 68% 84% 78% Failed 1-yr OS: Best efficacy 89% compliance threshold Higher toxicity 1-yr EFS: 84% 1-yr EFS: 78% 1-yr OS: 89% Best compliance pCR: 20% (highest) Lowest toxicity Key message Chemotherapy alone is insufficient. Total neoadjuvant therapy shows strongest efficacy. CRT alone remains a well-tolerated alternative.

[Slide 1] CRITICS Trial design Chemotherapy D2 surgery 4x DOC R Chemotherapy Chemoradiation D2 surgery 2x DOC 45 Gy + 5x PC Chemoradiation 45 Gy + 5x PC D2 surgery Tissue & blood banking - - HRQOL Stratified for: Center, Histological type Slagter et al. BMC Cancer 2018 ASCO Gastrointestinal #GI26 PRESENTED BY: Marcel Verheij MD PhD, Netherlands Cancer Institute/Radboud university medical center, CRITICS-II trial 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] CRITICS Results: Study Profile Underwent R Started Completed pre-operative treatment curative Completed surgery treatment surgery n=68 4x DOC Surgery n=54 100% n=55 (81%) n=62 n=60 (79%) n=65 2x DOC (n=60) CRT 5x PC (n=43); 45 Gy (n=51) Surgery n=41 n=201 100% n=42 (65%) n=60 n=58 (63%) n=68 CRT 5x PC (n=58); 45 Gy (n=64) Surgery n=53 100% n=57 (84%) n=63 n=63 (78%) ASCO Gastrointestinal Cancers Symposium #GI26 PRESENTED BY: Marcel Verheij MD PhD, Netherlands Cancer Institute/Radboud university medical center, CRITICS-II trial ASCO AMERICAN SOCIETY OF CUNICAL ONCOLOGY Presentation is property of the author and ASCO Permission required for reuse, contact permissions@asco.org KNOWLEDGE CONQUERS CANCER --- [Slide 3] 16 Results: Pathology (2) Arm 1: DOC Arm 2: DOC+CRT Arm 3: CRT Total n=62 (%) n=60 (%) n=63 (%) n=185 (%) Tumor regression grade TRG 1 (pCR) 4 (8) 10 (20) 7 (13) 21 (13) TRG 2 9 (17) 13 (25) 16 (30) 38 (24) TRG 3 11 (21) 12 (24) 18 (33) 41 (26) TRG 4 15 (28) 10 (20) 10 (19) 35 (22) TRG 5 (no response) 14 (26) 6 (12) 3 (6) 23 (15) Missing 9 9 9 27 Radicality of resection R0 53 (98) 50 (91) 56 (93) 159 (94) R1 1 (2) 5 (9) 4 (7) 10 (6) Missing 8 5 3 16 Number of lymph nodes Median (range) 31 (14 - 83) 23 (0 42) 21 (8 47) 25 (0 - 83) Central review in progress ASCO Gastrointestinal #GI26 PRESENTED BY: Marcel Verheij MD PhD, Netherlands Cancer Institute/Radboud university medical center, CRITICS-II trial ASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGY Cancers Symposium Presentation a property of the author and ASCO Permission required for reuse; contact permissions@asco.org KNOWLEDGE CONQUERS CANCER --- [Slide 4] CRITICS Results: Event-Free Survival Strata DOC surgery DOC CRT surgery CRT surgery 1.00 0.75 Survival probability 0.50 Arm 1-year EFS 95% CI (%) (%) 0.25 1: DOC 68 58 - 80 2: DOC+CRT 84 75 94 0.00 3: CRT 78 69 - 88 0 12 24 36 48 60 72 Time (months) Number at risk DOC surgery 68 45 33 23 12 6 0 Strata DOC CRT surgery 65 51 34 26 14 6 0 CRT surgery 68 52 36 24 13 5 0 0 12 24 36 48 60 72 Time (months) ASCO Gastrointestinal #GI26 PRESENTED BY: Marcel Verheij MD PhD, Netherlands Cancer Institute/Radboud university medical center, CRITICS-II trial 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 1] CRITICS Trial design Chemotherapy D2 surgery 4x DOC R Chemotherapy Chemoradiation D2 surgery 2x DOC 45 Gy + 5x PC Chemoradiation 45 Gy + 5x PC D2 surgery Tissue & blood banking - HRQOL Stratified for: Center, Histological type Slagter et al. BMC Cancer 2018 ASCO Gastrointestinal #GI26 PRESENTED BY: Marcel Verheij MD PhD, Netherlands Cancer Institute/Radboud university medical center, CRITICS-II trial 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] CRITICS Results: Study Profile Underwent R Started Completed pre-operative treatment curative Completed surgery treatment surgery n=68 4x DOC Surgery n=54 100% n=55 (81%) n=62 n=60 (79%) n=65 2x DOC (n=60) CRT 5x PC (n=43); 45 Gy (n=51) Surgery n=41 n=201 100% n=42 (65%) n=60 n=58 (63%) n=68 CRT 5x PC (n=58); 45 Gy (n=64) Surgery n=53 100% n=57 (84%) n=63 n=63 (78%) ASCO Gastrointestinal Cancers Symposium #GI26 PRESENTED BY: Marcel Verheij MD PhD, Netherlands Cancer Institute/Radboud university medical center, CRITICS-II trial ASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGY Presentation 5 property of the author and ASCO Permission required for reuse; contact permissions@asco.org KNOWLEDGE CONQUERS CANCER --- [Slide 3] CRITICS-II Outcomes Event-Free Survival Overall Survival 100 100 80 80 DOC + CRT + surgery DOC + CRT + surgery 60 60 EFS OS HHHH (%) DOC + surgery (%) 40 40 DOC + surgery CRT + surgery CRT + surgery 20 20 0 0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 Months Months No. at risk No. at risk DOC + surgery 68 45 33 23 12 6 0 DOC surgery 68 47 35 24 14 7 0 DOC * CRT + surgery 65 51 34 26 14 6 0 DOC CRT surgery 65 53 37 28 16 7 0 CRT + surgery 68 52 36 24 13 5 0 CRT surgery 68 54 37 26 15 7 0 ASCO Gastrointestinal Christopher L. Hallemeier, M.D. ASCO or PRESENTED BY CHRICAL #GI26 Cancers Symposium KNOWLIDGE CONQUES CANCER Presentation . property of be author and ASCO Permission required for reuse, contact --- [Slide 4] CRITICS Results: overview Parameter (%) Arm 1: DOC Arm 2: DOC+CRT Arm 3: CRT 1-year EFS (>75%) 68 84 78 1-year OS 74 89 84 Pre-operative compliance 81 65 84 Pre-operative toxicity grade 3-5 56 55 43 Surgery related complications 21 15 21 Pathological complete response 8 20 13 Considering survival, surgical complications and pathological response rates, "total neoadjuvant" chemotherapy plus chemoradiotherapy is identified as preferred pre-operative regimen ASCO Gastrointestinal Cancers Symposium #GI26 PRESENTED BY: Marcel Verheij MD PhD, Netherlands Canoer Institute/Radboud university modical center, CRITICS-II trial ASCO SOCIETY - COMPAE - Presentation is property of the any and ASCO Purchase required for result, contact CHOWLEDGE CONQUERS CANCER

[Slide 1] TPS Abstract 464: An open label phase 2 study of Total Neoadjuvant Therapy (TNT) consisting of FLOT with pembrolizumab and short radiation for patients with locally advanced gastroesophageal junction adenocarcinoma (EPOC2301) Kazuma Sato Izuma Nakayama Masahiro Yurs Akihiro Sato Mitsuko Suzuki Tomohiro Kadota Masaki Nakamura Nacya Sakamoto", Tadayoshi Hashimoton, Shingo Sakashita Masashi Wakabayash Hirokazu Shojint, EPOC Tsutomu Hayashi Hroyuki Dalko Ken Kato Takayuki Yoshino Tomonon Yano", alleo Fujta", Takahiro Kinoshita Kohei Shitara Division of sophageal Surgery National Cancer Center Hospital East (NOCE) Japan Dept of Gastroenterology and Gastrointestinal Oncology NOCE, Japan Dept. of Gastric Surgery NOCE Japan 4) Clinical Research Support office NCCE Japan Dept. Gastroenterslogy and Endoscopy NCCE Japan, 4) Dept of Radiation Onoology NCCE Japan Dept. of Pathology and Cinical Laboratories, NOCE, Japan #) Dept. for the Promotion of Drug and Diagnostic Development NCCE, Japan Dept. of Gastrointestinal Medical Oneslogy NCC, Japan, 10) Dept of Gastric Surgery NCC, Japan, 11), Dept of Eaophageal Surgery NCC Japan (2) Dept of read and Neck, Esophages Medical Oneology NCC Hospital, Japan EPOC2301 (ClinicalTrials.gov (NCT07018570)/jRCT 2031250089) A multicenter, open-label, phase II study investigating TNT with FLOT plus pembrolizumab and Background 25Gy of SRT in patients with resectable GEJA. This figure was created using BioRender materials and customized Perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) has been established as the standard of care for Immuno- Immuno- resectable upper gastrointestinal adenocarcinoma based on the FLOT4 and ESOPEC trials 1.2. chemotherapy Radiation chemotherapy 2 Key eligible criteria The phase III MATTERHORN trial demonstrated that the addition of durvalumab to FLOT (D-FLOT) significantly improved Gastroesophageal junction adenocarcinoma event-free survival (EFS) and overall survival (OS) in patients with resectable gastric and gastroesophageal junction Pembrolizumab (Siewert Type I-III) adenocarcinoma (GEJA). leading to FDA approval of D-FLOT3. cT2-4:1 any, MO Aged 18 years or older FLOT Despite these advances, surgical resection remains required for all patients and is associated with considerable ECOG postoperative morbidity and reduced QOL 4.5. FLOT Cocetaint mg/ml, Primary endpoint: 3-year EFS Osaliptatin mg/ml D-FLOT achieved a pathological complete response (pCR) in approximately 20% of patients, suggesting that a subset of Levololinate 200 Secondary endpoints SFU mg/ml (v) 01 15 22 01 15 individuals may achieve cure without surgery. organ-sparing survival, 05. clinical response rate, (CR rate, MPR rate pCR rate, radical resection rate, 200 regidose (v) 25Gy/5tr Increasing the clinical complete response (cCR) rate through intensified TNT with short-course radiation (SRT) could TNT completion rate, treatment completion rate, AE. allow non-operative management (NOM) in carefully selected patients with resectable locally advanced GEJA. dona clearance EORTC QLO C30, and Q-0G25 Response evaluation 2 Yes Immunochemotherapy.as NOM CT scan Serial CIDNA monitoring Endoscopy (bite-on-bite) Methods PET-CT cCR/near CR Response evaluation 1 Blood test (Tumor markers) " CIDNA The major inclusion criteria CT scan Pembrolizumab No (i) histologically confirmed adenocarcinoma of the GEJ (Siewert type I-III), (ii) cT22 and/or N+, MO according to the 8th PETCT Yes edition of the UICC-TNM classification, (iii) age 2 18 years, (iv) Eastern Cooperative Oncology Group Performance Status FLOT of 0 or 1, (vi) no prior systemic chemotherapy, (vii) adequate organ functions. Surgery 6 15 22 29 43 17 Endoscopy cCR/near CR Treatment details (bite biopsy) <Immunochemotherapy 1 and 2> Blood (fumor markers (IDNA) No Postoperative immunochemotherapy Two cycles of FLOT (docetaxel 50 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, 5-FU 2600 mg/m2, administer 4 doses at 14-day intervals starting from day 1) and two dose of pembrolizumab (200 mg/dose, administer at 21-day intervals Serial CIDNA monitoring starting from day1), followed by RT, then an additional two cycles of FLOT and one dose of pembrolizumab. <Short course radiation therapy (SRT)> A total dose of 25 Gy in 5 fractions was delivered to the tumor and involved lymph nodes, without elective nodal irradiation. References and Acknowledgements A 3.0-cm margin for the primary lesion and 0.5-1.0 cm for lymph nodes were added to the gross tumor volume to define the clinical target volume (CTV). An additional margin of 0.5-1.0 cm was applied to both primary and nodal CTVs to account for internal motion and setup uncertainties. Radiotherapy was delivered with IMRT and daily image guidance. 1. Al-Batran SE. Homann N. Pauligk C. Goetze TO. Meiler J. Kasper S. et at Lancet 2019;393(10184):1948-57. 2. Hoeppner J. Brunner T. Schmoor C. Bronsert P. Kulemann B. Claus R, et al. N Engl Med 2025,392(4) 323-35 <immunochemotherapy as NOM or post-operative immunochemotherapy> 3. Janjigian YY, Al-Batran SE, Wainberg 2A Muro K, Molena D. Van Cutsem E. et at N Engl Med 2025,393(3) 217-30 4. Mine S. Kurokawa Y. Takeuchi H, Terashima M. Yasuda T. Yoshida K. et at Gastric Cancer 2022;25(2) 430-7. Four cycles of FLOT and 3 doses of pembrolizumab followed by 10 doses of pembrolizumab. 5. Fuchs H, Holscher AH, Leers J. Bludau M. Brinkmann S. Schröder W, et al. Gastric Cancer 2016;19(1)312-7. Sample size and statistical analysis Acknowledgments We are grateful to all participating patients, their families, all investigators involved in the EPOC2301, and Merck & Co., Inc. When calculated using the exact method based on a binomial distribution with a threshold 3-year EFS of 46%, expected Funding value of 70%, one-sided alpha of 10%, and power of 80%, the number of patients required would be 24. The target number MSD K.K., Tokyo. Japan provided financial support and drug. of patients was set at 26, considering a few ineligible patients.

[Slide 1] CRITICS Results: Event-Free Survival Strata DOC surgery DOC CRT surgery CRT surgery 1.00 0.75 Survival probability 0.50 Arm 1-year EFS 95% CI (%) (%) 0.25 1: DOC 68 58 80 2: DOC+CRT 84 75 - 94 0.00 3: CRT 78 69 88 0 12 24 36 48 60 72 Time (months) Number at risk DOC . surgery 68 45 33 23 12 6 0 Strata DOC CRT surgery 65 51 34 26 14 6 0 CRT surgery 68 52 36 24 13 5 0 0 12 24 36 48 60 72 Time (months) ASCO Gastrointestinal #GI26 PRESENTED BY Marcel Verheij MD PhD, Netherlands Cancer Institute/Radboud university medical center, CRITICS-II trial ASCO AMERICAN 30C ETY OF CLINICAL GRODUCT Cancers Symposium Presentation property of the euthor and ASCO Permission required for reuse, contact CHOWLEDGE CONQUERS CANCER ASCO Gastrointestinal Cancers Symposium --- [Slide 2] CRITICS Results: Study Profile Underwent R Started Completed pre-operative treatment curative Completed surgery treatment surgery n=68 4x DOC Surgery n=54 100% n=55 (81%) n=62 n=60 (79%) n=65 n=201 2x DOC (n=60) CRT 5x PC (n=43); 45 Gy (n=51) Surgery n=41 100% n=42 (65%) n=60 n=58 (63%) n=68 CRT 5x PC (n=58); 45 Gy (n=64) Surgery n=53 100% n=57 (84%) n=63 n=63 (78%) ASCO Gastrointestinal Cancers Symposium #GI26 PRESENTED BY: Marcel Verheij MD PhD, Netherlands Cancer Institute/Radboud university medical center, CRITICS-II trial ASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGY Presentation property of the - and ASCO Permission required or - contact permissions@ase.org KNOWLEDGE CONQUERS CANCER ASCO Gastrointestinal Cancers Symposium --- [Slide 3] Gastric Cancer When to consider nCRT, usually after initial FLOT +- 10* Anatomic Biological Conditional Risk for R1 Equivocal M1 PS decline with chemo cT4 Poor response to Age/comorbidities chemo ? surgical candidate *Based on oncological principles, not phase 3 RCTs Patients should be discussed in multi-D manner Clinical trials when appropriate ASCO Gastrointestinal #GI26 PRESENTED BY Christopher L. Hallemeier, M.D. ASCO CONTRAL GNODLOGY Cancers Symposium Presentation is property of the author and ASCO Person required for reuse contact permissions@asco.com KNOWLEDGE CONQUERS CANCER ASCO Gastrointestinal Cancers Symposium --- [Slide 4] CRITICS Summary (1) CRITICS-II compares 3 pre-operative regimens without adjuvant treatment Pre-operative compliance rate was high (77%), and most favorable after chemotherapy alone and after chemoradiotherapy alone Pre-operative toxicity was lowest after chemoradiotherapy alone Surgical quality was excellent with 91% undergoing ≥ D1+ dissection and removal of a median of 25 lymph nodes Surgery related complications were acceptable, being lowest after chemotherapy plus chemoradiotherapy (15%) ASCO Gastrointestinal #GI26 PRESENTED BY Marcel Verheij MD PhD, Netherlands Cancer Institute/Radboud university medical center, CRITICS-II trial ASCO AMERICAN SOCIETY OF CLINICAL CANCOLOGY Cancers Symposium Presentation property two author and ASCO Permission required for reuse, contact permissions@gue.co.org KNOWLEDGE CONQUERS CANCER ASCO Gastrointestinal Cancers Symposium