Highlights of Posters on Colorectal Cancer (CRC)

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1 ESMO 2 th World Congress on Gastrointestinal Cancer, Barcelona Highlights of Posters on Colorectal Cancer (CRC) Highlights No-lights as well! June 22 nd, 218 Takayuki YOSHINO, M.D. Director, Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East (NCCE), Japan

2 Disclosure of Conflict of Interests Research Funding: Chugai, MSD, Sanofi, Sumitomo Dainippon, GlaxoSmithKline and Boehringer Ingelheim Lecture Fee: Sanofi, Chugai, Eli Lilly, and Merck Serono

3 Presentations on ESMO-GI 218 Colorectal Cancer (CRC) Track Selected Abstract (Oral): 23 Poster Discussion (PD): 15 Poster (P): 136 I would like to Highlight ONLY PD & P!

4 However, NO enough time for preparation Oh My God! Posters are presented today, and there are only few hours left for preparing for my presentation slide deck!!!

5 Selection from 15 Poster Discussions Poster Discussions Highlights Posters # Brief Title Author PD-6 DNA CNV for CRLM M Marques PD-7 Network analysis S Choi PD-8 Molecular character of immune M Giordano PD-9 Acquired resistance for EGFR blockade T Yamada PD-1 REVERCE QoL T Yoshino PD-11 SAPHIRE M Takahashi PD-12 ETS and tr-symtoms: 3 Pani studies J Taieb PD-13 Usefulness of ICG J Park PD-14 Brain meta: Danish population-bd A Boysen PD-15 1L in mcrc with mucinous V Catalano PD-16 Safety of SEMS(Stents) for GiP V P-Barcia PD-17 Extrahepatic PD in CRLM E Ongaro PD-18 Left vs. Right: Belgium population-bd K Janssens PD-19 RENCA Macrobead therapy A Nazarian PD-2 XELAVIRI RAS status and Age D Modest

6 Selection from 15 Poster Discussions Focusing on 4 chemo abstracts Poster Discussions Highlights Posters # Brief Title Author PD-6 DNA CNV for CRLM M Marques PD-7 Network analysis S Choi PD-8 Molecular character of immune M Giordano PD-9 Acquired resistance for EGFR blockade T Yamada PD-1 REVERCE QoL T Yoshino PD-11 SAPHIRE M Takahashi PD-12 ETS and tr-symtoms: 3 Pani studies J Taieb PD-13 Usefulness of ICG J Park PD-14 Brain meta: Danish population-bd A Boysen PD-15 1L in mcrc with mucinous V Catalano PD-16 Safety of SEMS(Stents) for GiP V P-Barcia PD-17 Extrahepatic PD in CRLM E Ongaro PD-18 Left vs. Right: Belgium population-bd K Janssens PD-19 RENCA Macrobead therapy A Nazarian PD-2 XELAVIRI RAS status and Age D Modest

7 #PD-1 REVERCE QoL N=18 Metastatic CRC Treatment failure with R-C arm Regorafenib Cetuximab FP, oxaliplatin, and 16 mg PD PD (+ irinotecan).75 3 wks on, 1 wk off irinotecan or or Anti-EGFR naive unaccept unaccept KRAS exon 2 WT able Pts. with minor RAS Cetuximab Regorafenib able.5 toxicities toxicities mutations are excluded C-R arm (+ irinotecan) 16 mg 3 wks on, 1 wk off since March QOL evaluation by EQ-5D Primary endpoint: OS Secondary endpoint: TTF, PFS, ORR, DCR, toxicities, and QOL by EQ-5D (pre, at week 4, and 8 in Tx1 and 2). QoL score by EQ5D Mean EQ-5D index Before Tx1 R-C C-R 1:1 Cetuximab Regorafenib Error bars represent 95% CI Tx1 4 weeks Treatment 1 (Tx1) Tx1 8 weeks Cetuximab Regorafenib Before Tx2 Tx2 4 weeks Treatment 2 (Tx2) Tx2 8 weeks Adverse event Anorexia Fatigue HFSR Rash OS Proportion Grade 1. Event/N % Median (months) R-C 37/51 73% 17.4 ( ) C-R 44/5 88% 11.6 ( ) HR* =.61 (95%CI: ) Stratified log rank p =.29 *adjusted by intent to use irinotecan Median follow-up: 29. months Time (months) Estimate (95% CI) G1 vs G.1 (-.52,.55).958 G2 vs G-.61 (-.121, -.2).43 G1 vs G-.3 (-.67,.6).16 G2 vs G-.16 (-.173, -.39).2 G1 vs G-.4 (-.4,.32).832 G2 vs G-.25 (-.71,.22).3 G1 vs G.8 (-.31,.47).686 G2 vs G.11 (-.43,.65).695 P Estimate T Yoshino et al. ESMO-GI 218 #PD-1.

8 #PD-1 REVERCE QoL N=18 Metastatic CRC Treatment failure with R-C arm Regorafenib Cetuximab FP, oxaliplatin, and 16 mg PD PD (+ irinotecan).75 3 wks on, 1 wk off irinotecan or or Anti-EGFR naive unaccept unaccept KRAS exon 2 WT able Pts. with minor RAS Cetuximab Regorafenib able.5 toxicities toxicities mutations are excluded C-R arm (+ irinotecan) 16 mg 3 wks on, 1 wk off since March QOL evaluation by EQ-5D Primary endpoint: OS Secondary endpoint: TTF, PFS, ORR, DCR, toxicities, and QOL by EQ-5D (pre, at week 4, and 8 in Tx1 and 2). QoL score by EQ5D Mean EQ-5D index Before Tx1 R-C C-R 1:1 Cetuximab Regorafenib Error bars represent 95% CI Tx1 4 weeks Treatment 1 (Tx1) Tx1 8 weeks Cetuximab Regorafenib Before Tx2 Tx2 4 weeks Treatment 2 (Tx2) QoL score was comparable in two arms with lower score during regorafenib. Tx2 8 weeks Adverse event Anorexia Fatigue HFSR Rash OS Proportion Grade 1. Event/N % Median (months) R-C 37/51 73% 17.4 ( ) C-R 44/5 88% 11.6 ( ) HR* =.61 (95%CI: ) Stratified log rank p =.29 *adjusted by intent to use irinotecan Median follow-up: 29. months Time (months) Estimate (95% CI) G1 vs G.1 (-.52,.55).958 G2 vs G-.61 (-.121, -.2).43 G1 vs G-.3 (-.67,.6).16 G2 vs G-.16 (-.173, -.39).2 G1 vs G-.4 (-.4,.32).832 G2 vs G-.25 (-.71,.22).3 G1 vs G.8 (-.31,.47).686 G2 vs G.11 (-.43,.65).695 Fatigue had the largest negative impact on QoL in patients among the four adverse events. P Estimate T Yoshino et al. ESMO-GI 218 #PD-1.

9 #PD-11 SAPHIRE (rp2): maintenance with FU + panitumumab Enrollment* 1 2 PFS rate (8% Cl), % H: PFS rate 3% RR, % (95% Cl) 3 4 Randomization 1 st -line mfolfox6 + panitumumab 6 cycles Statistical analysis Primary endpoint: PFS rate at 9 months after randomization Secondary endpoints: PFS, OS, RR, TTF and safety Sub-group: ETS, DpR, Primary tumor location Stratification factor Study site, age, number of metastasized organs, response per RECIST v1.1 (CR, PR, or SD at randomization) Group A Group A (N=56) 46.4 ( ) P=.37 Group A (N=56) 8.4 ( ) Discontinuation of protocol treatment Key Eligibility Criteria Aged 2 years, RAS wild type Measurable lesion(s) No previous chemotherapy ECOG PS or 1 No signs of PD within 14 days after the 6th cycle of treatment. Group B (N=57) 47.4 ( ) P=.21 Group B (N=57) 87.7 ( ) This study met primary endpoint with a PFS rate at 9 months significantly above 3% threshold. Continue mfolfox6 + panitumumab Group B Switch to 5-FU/LV + panitumumab Primary endpoint: PFS rate at 9months RR (%) PFS mfolfox6 + panitumumab (Group A; n=56) 5-FU/LV + panitumumab (Group B; n=57) Median PFS Group A 9.1 ( ) Group B 9.3 (6.-13.) HR=.93, 95% Cl: Time from randomization (months) : 1 month=28 days PN-related Aes* (%) 1 *PN related AEs; Peripheral motor and sensory neuropathy % 35.7% Group A (N=56) (%) OS Time from randomization (months) : 1 month=28 days 71.4% mfolfox6 + panitumumab (Group A; n=56) 5-FU/LV + panitumumab (Group B; n=57) *Median OS was not reached in both group. HR=1.41, 95% Cl: G1 G2 57.4% 9.3% Group B (N=54) 66.7% 5-FU/LV plus panitumumab maintenance is better in terms of incidence of peripheral neuropathy. M Takahashi et al. ESMO-GI 218 #PD-11.

10 Lessons from SAPHIRE and VALENTINO (O-16) studies Maintenance with panitumumab alone is likely inferior than 5-FU/LV plus panitumumab in terms of PFS. 5-FU/LV plus panitumumab may be a preferred option. F Pietrantonio et al. ASCO 218 #355, ESMO-GI 218#O-16

11 #PD-12 ETS and Tumor-Related Symptoms: 3 Pani Studies Kaplan-Meier estimate Impact of ETS on Time to New Symptomatic Event 3 Panitumumab Studies: PRIME + PEAK Events Median months (95% CI) HR P value ETS 3% (3.9, 7.).8 (.66.97).21 ETS <3% (2.8, 4.6) Time to first symptom event on study (months) Impact of DpR on Time to New Symptomatic Event Impact of ETS on Composite Endpoint, New Symptomatic Events and Time to ECOG Decline Adjusted HR (95% CI) Composite endpoint.8 (.66.97) New opiate use First weight-loss event New anaemia-type event New asthenia-type event.71 (.55.92).64 (.48.85).6 (.41.88).77 (.6 1.) ECOG PS decline.87 ( ).5 1 HR Favours ETS 3% (95% CI) Favours ETS <3% p value Kaplan-Meier estimate Events Median months (95% CI) HR (95% CI) p value DpR 73 1% (4.1, 8.).49 (.33,.73).4 DpR 53 72% (3.7, 7.5).49 (.33,.73).4 DpR 31 52% (3., 6.6).55 (.37,.82).37 DpR 3% (1.4, 3.2).83 (.56, 1.25).3745 DpR <% (.9, 2.9) J Taieb et al. ESMO-GI 218 #PD-12.

12 #PD-12 ETS and Tumor-Related Symptoms: 3 Pani Studies Kaplan-Meier estimate Impact of ETS on Time to New Symptomatic Event 3 Panitumumab Studies: PRIME + PEAK Events Median months (95% CI) HR P value ETS 3% (3.9, 7.).8 (.66.97).21 ETS <3% (2.8, 4.6) Time to first symptom event on study (months) Impact of DpR on Time to New Symptomatic Event Impact of ETS on Composite Endpoint, New Symptomatic Events and Time to ECOG Decline Adjusted HR (95% CI) Composite endpoint.8 (.66.97) New opiate use First weight-loss event New anaemia-type event New asthenia-type event.71 (.55.92).64 (.48.85).6 (.41.88).77 (.6 1.) ECOG PS decline.87 ( ).5 1 HR Favours ETS 3% (95% CI) Favours ETS <3% p value Kaplan-Meier estimate Events Median months (95% CI) HR (95% CI) p value DpR 73 1% (4.1, 8.).49 (.33,.73).4 DpR 53 72% (3.7, 7.5).49 (.33,.73).4 DpR 31 52% (3., 6.6).55 (.37,.82).37 DpR 3% (1.4, 3.2).83 (.56, 1.25).3745 The onset of new tumour-related symptoms was delayed in patients DpR <% (.9, 2.9) with RAS WT mcrc who achieved ETS 3% versus ETS <3%. Greater DpR was associated with a longer delay until the onset of new tumour-related symptoms. Retrospective and the symptomatic endpoints were not pre-defined; prospective trials are needed. J Taieb et al. ESMO-GI 218 #PD-12.

13 #PD-2 RAS status and Age : XELAVIRI (P3, AIO-KRK11) N=434 mcrc untreated, ECOG -1 unresectable lesions R 1:1 A FP* + Bevacizumab PD FP* + Irinotecan + Bevacizumab *5-FU/LV(q2w), Capecitabine(q3w) <Presented as ESMO-GI 217 #O-26/ESMO 217#486O> OS Arm OS (95% CI), months FP + BEV 21.9 ( ) FP+ IRI+ BEV 23.5 ( ) HR=.84 (95% CI ) p (log rank)=.14 Group OS, months RAS/BRAF WT (Arm A) 25.2 RAS/BRAF WT (Arm B) 32.2 RAS MT (Arm A) 21.3 RAS MT (Arm B) 23.2 BRAF MT (Arm A) 12.4 BRAF MT (Arm B) 7.8 Stratification Leucocytes, alkaline phosphatase, prior adjuvant therapy B FP* + Irinotecan + Bevacizumab =TFS (Time to failure of strategy) D Modest et al. ESMO-GI 217 #O-26, ESMO 217#486O. Time to failure of strategy- molecular groups.3 Initial FP+IRI+BEV better Initial FP+BEV better non-inferiority.3 3. Cox model interaction-test for study arm *RAS status: p=.3 Group HR (9% CI) FAS.86 ( ) NI not shown RAS/BRAF WT.61 ( ) superiority of FP+IRI+BEV RAS MT 1.9 ( ) NI of FP+BEV BRAF MT 1.62 ( ) NI not shown 6-day mortality according to age All pts arm A 8.7 All pts arm B <65 yrs 65<75 yrs 75+ yrs D Modest et al. ESMO-GI 218 #PD-2.

14 #PD-2 RAS status and Age : XELAVIRI (P3, AIO-KRK11) N=434 mcrc untreated, ECOG -1 unresectable lesions R 1:1 Stratification Leucocytes, alkaline phosphatase, prior adjuvant therapy A B FP* + Bevacizumab PD FP* + Irinotecan + Bevacizumab =TFS (Time to failure of strategy) <Presented as ESMO-GI 217 #O-26/ESMO 217#486O> OS Arm OS (95% CI), months FP + BEV 21.9 ( ) recommended in FP+ pts IRI+ BEV with 23.5 RAS( ) WT mcrc. Group OS, months RAS/BRAF WT (Arm A) 25.2 Initial FP+BEV in pts fit for intensive combination regimens cannot be RAS/BRAF WT (Arm B) 32.2 RAS MT (Arm A) 21.3 RAS MT (Arm B) 23.2 *5-FU/LV(q2w), Capecitabine(q3w) Intensive 1st-lineHR=.84 chemotherapy (95% CI ) was not associated with a substantial p (log rank)=.14 BRAF MT (Arm A) 12.4 improvement of outcome in pts with RAS MT mcrc. BRAF MT (Arm B) 7.8 Overall, age subgroups did not influence TFS nor OS to a great extent FP* + Irinotecan + Bevacizumab (moderate prognostic impact). However, risk of early mortality (@6 days) appeared to rise with age. D Modest et al. ESMO-GI 217 #O-26, ESMO 217#486O. Time to failure of strategy- molecular groups.3 Initial FP+IRI+BEV better Initial FP+BEV better non-inferiority.3 3. Cox model interaction-test for study arm *RAS status: p=.3 Group HR (9% CI) FAS.86 ( ) NI not shown RAS/BRAF WT.61 ( ) superiority of FP+IRI+BEV RAS MT 1.9 ( ) NI of FP+BEV BRAF MT 1.62 ( ) NI not shown 6-day mortality according to age All pts arm A 8.7 All pts arm B <65 yrs 65<75 yrs 75+ yrs D Modest et al. ESMO-GI 218 #PD-2.

15 Congratulations for your PD presentations!

16 Selection from 136 Posters Poster Discussions Highlights Posters

17 Selection from 136 Posters Poster Discussions Highlights Posters Posters No-Light Posters!?

18 Selection from 136 Posters Poster Discussions Highlights Posters Posters Highlights of No-Light posters

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20 #P-228 VOLTAGE #P-253 APOLLON #P-295 DS-821a

21 #P-228 VOLTAGE: Nivo for LARC Resectable primary rectal cancer (ct3 4 Nany M, Inferior margin < 12 cm from the anal verge) or Resectable recurrent rectal cancer confined to the pelvis Protocol treatment Within 14 days More than 14 days Nivolumab monotherapy Nivolumab 3 cycles Imaging/Endoscopy Preoperative chemoradiotherapy (capecitabine + 5.4Gy) Diagnostic imaging Informed consent Enrollment Imaging/Endoscopy Imaging/Endoscopy Without distant metastasis Without progression Nivolumab 2 cycles Imaging/Endoscopy Resectabl e Radical Surgery Postoperative adjuvant chemotherapy (e.g., FOLFOX and XELOX) Serial sample collections at 4 times No.1: before CRT Biopsy, blood and stool collection No.2 post CRT, before nivolumab Biopsy, blood and stool collection No.3 after 3cycles of nivolumab Biopsy, blood and stool collection No. 4 after 5cycles of nivolumab Biopsy, blood and stool collection Surgical sample collection ID Age/ Sex 49/ F 59/ F 53/ F 48/ F 48/ F 59/ M 44/ M P S Primary/ Recurrent Clinical diagnosis Primary T3NM Stage II Primary T3NM Stage II Primary T3NM StageII Primary T3N1M Stage III Primary T3NM Stage II Primary T3NM Stage II Primary T3NM Stage II MMR status pmm R pmm R pmm R pmm R pmm R pmm R pmm R + By a local pathological assessment, *Only single cells were observed. Local pathologist diagnosed as near pcr (AJCC grade 1) Case report: 44 year-old male (ID No. 7) From 4/Sep/217 to 13/Oct/217, CRT was performed (RT 5.4Gy/28Fr, Capecitabine 3mg/day). From 24/Oct/217 to 22/Dec/217, 5 doses of nivolumab were administered. On 16/Jan/218, radical surgical resection was performed. Before CRT After 3 cycles of Nivo After CRT, before NivoAfter 5 cycles of Nivo AJCC Adverse events TRG pcr+ Nivolumab period Perioperative period Phase Ib part Grade Pruritus: Gr1 No AE Yes Grade No AE Nausea: Gr1 Yes Grade No AE No* 1* Grade 3 Grade 2 Grade Grade Phase II part Gastritis: Gr2 Pain: Gr1 Extrapyramidal disorder : Gr1 No Pruritus: Gr1 Back pain: Gr1 No Yes Yes Hyperthyroidism: Gr1 Sore throat: Gr1 Pruritus: Gr1 Allergic rhinitis: Gr1 Hypothyroidism: Gr1 AST elevation: Gr2 ALT elevation: Gr3 No AE Dry skin: Gr1 Pelvic infection: Gr3, Gastrointestinal anastomotic leak: Gr3 SAE Upper respiratory infection: Gr3 Stoma site erosion: Gr2 Large intestine: No residual carcinoma, consistent with pcr status post-chemoradiotherapy lymph node: Negative for metastatic tumor (/31) AJCC tumor regression: grade by local pathologists. H Bando et al. ESMO-GI 218 #P-228.

22 #P-253 APOLLON (P1/2): TAS-12 + Panitumumab Dosage and Schedules Pmab TAS-12 (N=54) 6 mg/kg 35 mg/m² BID Day Endpoints Primary PFS rate at 6 months Secondary Safety: Adverse events. Efficacy: OS, PFS, RR, DoR, DCR, TTF Best Overall Response Rate Course 1 All, n (%) L, n (%) R, n (%) CR (.) (.) (.) PR 2 (37.) 18(38.3) 2(28.6) SD 24 (44.4) 22(46.8) 3(28.6) PD 11 (18.5) 7(14.9) 3(42.9) RR 2 (37.) 18(38.3) 2(28.6) DCR 44 (81.5) 4 (85.1) 4 (57.1) L: Left-sided tumors (N=47), R: Right-sided tumors (N=7) Course 2 PFS rate (%) 1 At risk PFS in over all Events Median PFS 95% CI months % reduction PFS by primary tumor location (Left, N=47; Right, N=7) Maximum % Change in Target Lesion Size in overall PD SD PR Maximum % Change in Target Lesion Size by TL (Left, N=47; Right, N=7) K Yamazaki et al. ESMO-GI 218 #P-253.

23 #P-295 DS-821a for mcrc Trial in progress DS-821a Structure and Mechanism of Action (MoA) Cys Conjugation chemistry The linker is connected to the cysteine residue of the antibody Propriety drug-linker and payload Cysteine residue Drug-Linker Payload (Dxd) Exatecan derivative Efficacy Outcomes with DS-821a in HER2-expressing Solid Tumors in the Ongoing Phase 1 Trial (April, 218 cutoff) 5 Confirmed ORR a Confirmed DCR a (95% CI) a PFS Median (95% CI), mo HER2+ breast cancer b 54.5% (54/99) 93.9% (93/99) NR HER2+ gastric cancer b 43.2% (19/44) 79.5% (35/44) 5.6 (3., 8.3) Other HER2- expressing/mutated % (12/31) 83.9% (26/31) 12.1 (2.7, 14.1) a Subjects who had 2 postbaseline scans, had progressive disease, or discontinued treatment for progressive disease or any other reason prior to second postbaseline scan. b IHC 3+ or IHC2+ and ISH+. Doi T, et al. Lancet Oncol. 217, Iwata H, et al ASCO 218 Payload with a different MoA High potency of payload Payload with short systemic half-life Bystander effect Tumor-selective cleavable linker Stable linker-payload High drug-to-antibody ratio Change from baseline (%) Change from baseline (%) Colorectal NSCLC O the r Colorectal NSCLC O the r Other Cancers N = Weeks Study Design HER2-status centrally confirmed Cohort A HER2-positive mcrc (IHC 3+ or IHC 2+/ISH+) DS-821a 6.4 mg/kg q3wk n=5 Cohort B HER2-expressing mcrc (IHC 2+/ISH-) DS-821a 6.4 mg/kg q3wk n =2 Cohort C HER2-expressing mcrc (IHC 1+) DS mg/kg q3wk n=2 Cohorts B and C will open for enrollment depending on the risk/benefit assessment in cohort A Primary Endpoint ORR (proportion who achieved a best overall response of CR or PR) assessed by the independent radiologic facility review based on RECIST version 1.1 in Cohort A. Secondary Efficacy Endpoints OS PFS DCR DoR ORR based on RECIST version 1.1 in Cohorts B and C ORR assessed by the investigator based on RECIST version 1.1 T Yoshino et al. ESMO-GI 218 #P-295.

24 Thank you for your kind attention!!!