Reference Slide Deck. Abstract 553 Abstract 554 Abstract 560

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1 Clinicl Spotlight Immunotherpy Advnces for Colorectl Crcinom in 2018: Newly Relesed Dt From the Gstrointestinl Cncers Symposium in Sn Frncisco Reference Slide Deck Abstrct 553 Abstrct 554 Abstrct 560

2 Mismtch Repir Deficient Colorectl Cncer Genetic nd epigenetic defects in mismtch repir led to microstellite instbility (MSI-H) Germline (Lynch syndrome) nd/or spordic muttions (MLH1, MSH2, MSH6, PMS2, EpCAM) Epigenetic silencing (MLH1 hypermethyltion) Associted with hereditry nonpolyposis colorectl crcinom (HNPCC) 15% of colorectl crcinoms cross ll stges MSI Frequency, % Colon Cncer Stge

3 Immune Relted Adverse Events (iraes) With Immune Check Point Blockde: Any Orgn Cn Be Affected Inflmmtory nture of iraes Cn rise every time, even fter end of therpy Erly recognition of signs nd symptoms is essentil Educte ptients nd ll helthcre tem Tretment guidelines estblished for iraes Key therpy Systemic steroids Hormone replcement therpy in cse of endocrinopthies Postow MA, et l. N Engl J Med. 2018;378(2):158-68

4 Nivolumb in Ptients With DNA Mismtch Repir-Deficient/Microstellite Instbility-High Metsttic Colorectl Cncer: Long-Term Survivl According to Prior Line of Tretment From CheckMte-142 Abstrct 554 Overmn MJ, Bergmo F, McDermott R, Agliett M, Chen F, Fbio Gelsomino,Yeung K, Wong M, Morse M, Vn Cutsem E, Hendlisz A, Neyns B, Moss RA, Zho H, Co ZA, Kmble S, Kopetz S, André T

5 Introduction Approximtely 4% of ptients with mcrc hve deficiency in the DNA mismtch repir system (dmmr) tht leds to high microstellite instbility (MSI-H) 1-4 Nivolumb demonstrted meningful clinicl benefit in ptients with dmmr/msi-h mcrc 5 With 13 months of follow-up, ORR ws 32% per blinded independent centrl review (BICR); 73% of ptients were live t 1 yer FDA grnted ccelerted pprovl bsed on notble clinicl benefit (ORR per BICR 28%; medin DOR not reched) in subset of ptients tht hs progressed following chemotherpy with fluoropyrimidine, oxlipltin, nd irinotecn 6 Here we present BICR-ssessed efficcy nd sfety results with 21 months of follow-up for the nivolumb monotherpy cohort s well s subnlyses by prior chemotherpy with fluoropyrimidine, oxlipltin, nd irinotecn DOR, durtion of response; mcrc, metsttic colorectl cncer 1. Koopmn M, et l. Br J Cncer. 2009;100(2): Venderbosch S, et l. Clin Cncer Res. 2014;20(20): Le DT, et l. Science. 2017;357(6349): Tougeron D, et l. Ann Oncol. 2017;28(suppl 5) Abstrct 533P. 5. Overmn MJ, et l. Lncet Oncol 2017;18(9): Nivolumb [pckge insert]. Princeton, NJ: Bristol-Myers Squibb; Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

6 CheckMte-142 Monotherpy Cohort Study Design Histologiclly confirmed metsttic or recurrent CRC dmmr/msi-h per locl lbortory 1 prior line of therpy Monotherpy cohort Nivolumb 3 mg/kg q2w Primry endpoint: ORR per investigtor ssessment Other key endpoints: ORR per BICR, DCR, b DOR, PFS, OS, nd sfety Primry nlysis (N = 74): efficcy per BICR nd sfety; medin follow-up, 21 months (rnge, 17 40) c Subset nlysis: Group A (n = 53): received 3 prior chemotherpies, including fluoropyrimidine, oxlipltin, nd irinotecn Group B (n = 21): did not receive prior tretment with ll 3 of these chemotherpies (fluoropyrimidine, oxlipltin, nd irinotecn) DCR, disese-control rte Enrollment ws stggered with dditionl ptients being enrolled if 7 of the first 19 centrlly confirmed MSI-H ptients hd confirmed response (CR or PR). b Ptients with CR, PR, or SD for 12 weeks. c Time from first dose to dt cutoff Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

7 Presented by: Dr. Michel J. Overmn Bseline Chrcteristics All Ptients N = 74 Medin ge (rnge), yers 52.5 (26-79) Mle, n (%) 44 (59) ECOG performnce sttus, n (%) c 0 1 Disese stge t dignosis, n (%) I-III IV Muttion sttus, n (%) BRAF/KRAS wildtype BRAF mutted KRAS mutted Unknown Clinicl history of Lynch syndrome, n (%) d Yes No Unknown 32 (43) 41 (55) 41 (55) 33 (45) 29 (39) 12 (16) 27 (36) 6 (8) 28 (38) 27 (36) 19 (26) Group A n = 53 Group B b n = (26-79) 52.0 (27-77) 30 (57) 14 (67) 21 (40) 31 (58) 31 (58) 22 (42) 21 (40) 6 (11) 22 (42) 4 (8) 20 (38) 15 (28) 18 (34) 11 (52) 10 (48) 10 (48) 11 (52) 8 (38) 6 (29) 5 (24) 2 (10) 8 (38) 12 (57) 1 (5) Group A ptients received 3 prior chemotherpies, including fluoropyrimidine, oxlipltin, nd irinotecn. b Group B ptients did not receive prior tretment with ll 3 of these chemotherpies (fluoropyrimidine, oxlipltin, nd irinotecn). c One ptient hd ECOG performnce sttus of 3 t bseline. d Bsed on the clinicl records of the ptients t sites in countries where this reporting ws permitted (excluded Itly). Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

8 Prior Therpies All Ptients N = 74 Group A n = 53 Group B b n = 21 Prior lines of therpy, n (%) Prior therpies received, n (%) Fluoropyrimidines (5FU/cpecitbine) Oxlipltin Irinotecn VEGF inhibitors d EGFR inhibitors e Regorfenib Other 1 (1) 11 (15) 22 (30) 40 (54) 0 1 (2) 15 (28) 37 (70) 1 (5) c 10 (48) 7 (33) 3 (14) 73 (99) 71 (96) 55 (74) 57 (77) 31 (42) 12 (16) 11 (15) 53 (100) 53 (100) 53 (100) 45 (85) 27 (51) 12 (23) 9 (17) 20 (95) 18 (86) 2 (10) 12 (57) 4 (19) 0 (0) 2 (10) 5FU, fluorourcil; EGFR, epiderml growth fctor receptor; VEGF, vsculr endothelil growth fctor Group A ptients received 3 prior chemotherpies, including fluoropyrimidine, oxlipltin, nd irinotecn. b Group B ptients did not receive prior tretment with ll 3 of these chemotherpies (fluoropyrimidine, oxlipltin, nd irinotecn). c One ptient refused ll tretment. d Included bevcizumb, flibercept, nd rmucirumb. e Included cetuximb nd pnitumumb. Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

9 ORR, n (%) [95% CI] Response, Disese Control, nd Durbility Best overll response, n (%) CR PR SD PD Unble to determine Disese control, n (%) d [95% CI] All Ptients N = (34) [23.2, 45.7] 7 (9) 18 (24) 23 (31) 22 (30) 4 (5) 46 (62) [50.1, 73.2] Medin DOR (rnge), months NR (1.4+ to 31.6+) Group A,b n = (26) [15.3, 40.3] 4 (8) 10 (19) 16 (30) 19 (36) 4 (8) 29 (55) [40.4, 68.4] Group B,c n = (52) [29.8, 74.3] 3 (14) 8 (38) 7 (33) 3 (14) 0 17 (81) [58.1, 94.6] NR (4.6+ to 27.2+) NR (1.4+ to 31.6+) Medin durtion of SD (rnge), months 8.3 (4.2, NE) 8.5 (4.1, NE) 5.3 (2.6, NE) Medin time to response ws pproximtely 2.8 months cross ll groups Clinicl benefit ws observed cross ll groups NE, not estimble; NR, not reched. BICR dt with medin follow-up of 21 months (rnge, 17-40). b Group A ptients received 3 prior chemotherpies including fluoropyrimidine, oxlipltin, nd irinotecn. c Group B ptients did not receive prior tretment with ll 3 of these chemotherpies (fluoropyrimidine, oxlipltin nd irinotecn). d Ptients with CR, PR, or SD for 12 weeks. Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

10 Best Reduction From Bseline in Trget Lesion Size, % Best Reduction in Trget Lesion: All Ptients % of ptients hd reduction in tumor burden from bseline with nivolumb monotherpy *Confirmed response per BICR ssessment; % Chnge truncted to 100%. Ptient from Group A with 0% best reduction in trget lesion Group A: ptients received 3 prior chemotherpies including fluoropyrimidine, oxlipltin, nd irinotecn Group B: ptients did not receive prior tretment with ll 3 of these chemotherpies (fluoropyrimidine, oxlipltin nd irinotecn) BICR dt with medin follow-up of 21 months (rnge, 17-40) Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 554.

11 Deepening of Response With Longer Follow-Up ORR, n (%) [95% CI] Best overll response, n (%) CR PR SD PD Not determined 13-Month Follow-Up b,1 24 (32) [22.0, 44.3] 2 (3) 22 (30) 25 (34) 21 (28) 4 (5) All Ptients n = Month Follow-Up b 25 (34) [23.2, 45.7] 7 (9) 18 (24) 23 (31) 22 (30) 4 (5) Disese control, n (%) c 47 (64) 46 (62) CR rtes incresed in ll ptients with longer follow-up Similr trends in CR were observed in groups A nd B d BICR dt; b Defined here s the time from first dose to dt cutoff; c Ptients with CR, PR, or SD for 12 weeks; d Group A ptients received 3 prior chemotherpies, including fluoropyrimidine, oxlipltin, nd irinotecn. Group B ptients did not receive tretment with ll 3 of these chemotherpies (fluoropyrimidine, oxlipltin, nd irinotecn). 1. Overmn MJ, et l. Lncet Oncol. 2017;18(9): Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

12 Chrcteriztion of Response: All Ptients Responders With Nivolumb Ptients (n = 25) On tretment Off tretment Ongoing response Nivolumb continued to provide cliniclly meningful nd durble responses 80% of responders hd ongoing responses t dt cutoff 64% hd responses lsting 12 months Censored First response BICR dt with medin follow-up of 21 months (rnge, 17-40) Weeks Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 554.

13 Progression-Free Survivl, % Progression-Free Survivl: All Ptients Months Medin PFS (95% CI), months PFS rte (95% CI), % 12 months 18 months All Ptients n = (3.0, NE) 44 (32.6, 55.3) 44 (32.6, 55.3) Medin PFS ws 4.2 months nd not reched in groups A nd B, respectively b 12-months nd 18-month PFS rtes were 41% (group A) nd 52% (group B) b No. t Risk NE, not estimble. BICR dt with medin follow-up of 21 months. b Group A ptients received 3 prior chemotherpies, including fluoropyrimidine, oxlipltin, nd irinotecn. Group B ptients did not receive prior tretment with ll 3 of these chemotherpies (fluoropyrimidine, oxlipltin, nd irinotecn). Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

14 Overll Survivl: All Ptients Overll Survivl, % Medin OS (95% CI), months OS rte (95% CI), % 12 months 18 months All Ptients n = 74 NR (19.6, NE) 72 (60.0, 80.9) 67 (54.9, 76.9) Medin OS ws not reched in groups A or B 12-month OS rte ws 68% (group A) nd 81% (group B) 18-month OS rte ws 66% (group A) nd 70% (group B) Months No. t Risk NR, not reched Group A ptients received 3 prior chemotherpies, including fluoropyrimidine, oxlipltin, nd irinotecn. Group B ptients did not receive prior tretment with ll 3 of these chemotherpies (fluoropyrimidine, oxlipltin nd irinotecn). Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

15 Overll Survivl, % No. t Risk Overll Survivl by Best Overll Response Presented by: Dr. Michel J. Overmn CR + PR Months CR + PR SD PD Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 554. PD SD Medin OS (95%CI), months CR + PR n = 25 NR (NE) SD n = 23 NR (14.3, NE) Best overll response to nivolumb tretment correlted with overll survivl PD n = (3.0, NE)

16 Chnge From Bseline in Sum of Trget Lesions, % b Antitumor Activity After Initil Progression in Ptients With Best Overll Response of PD (n = 20) First occurrence of new lesion Off tretment % chnge truncted to 100% Progression Ptient with OS < 12 months Ptient with OS 12 months Weeks Ptients with best overll response of PD who hd reduction in or stbiliztion of trget lesions were more likely to survive 12 months Ptients (n = 22) who hd best overll response of PD per BICR; 2 ptients were not included due to no bseline nd 1 postbseline tumor ssessment; b BICR dt with medin follow-up of 21 months (rnge 17-40) Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 554.

17 Sfety Summry All Ptients (n = 74) Ptients, n (%) Any Grde Grde 3-4 Any TRAE 54 (73) 15 (20) Any serious TRAE 10 (14) 9 (12) Any TRAE leding to discontinution b 6 (8) 5 (7) TRAEs reported in >10% of ptients c Ftigue Dirrhe Pruritus Lipse incresed Rsh 17 (23) 16 (22) 12 (16) 9 (12) 8 (11) 1 (1) 1 (1) 0 6 (8) 0 No new sfety signls were reported with long-term follow-up Sfety ws consistent cross subgroups evluted TRAE, tretment-relted dverse event One ptient hd grde 5 event of sudden deth; b Resons for discontinution included cute kidney injury (n = 1), lnine minotrnsferse incresed (n = 1), utoimmune disese (n = 1), colitis (n = 1), duodenl ulcer (n = 1), nd stomtitis (n = 1); c Hypothyroidism (grde 1-2) ws reported in 7 (9%) ptients nd no grde 3-4 events were observed. Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

18 Conclusions Nivolumb continued to provide durble clinicl benefit with long-term follow-up (21 months) in previously treted ptients with dmmr/msi-h mcrc PFS nd OS rtes demonstrted continued stbility CR rte incresed with longer follow-up Medin DOR nd OS were not reched Durble clinicl benefit with deepening of response ws observed regrdless of prior chemotherpy with fluoropyrimidine, oxlipltin, nd irinotecn No new sfety signls were reported with long-term follow-up Results support ongoing evlution of nivolumb-bsed therpy in the first-line setting Presented by: Dr. Michel J. Overmn Overmn MJ, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

19 Nivolumb + Ipilimumb Combintion in Ptients With DNA Mismtch Repir-Deficient/Microstellite Instbility-High Metsttic Colorectl Cncer: First Report of the Full Cohort From CheckMte-142 Abstrct 553 André T, Lonrdi S, Wong M, Lenz H-J, Gelsomino F, Agliett M, Morse M, Vn Cutsem E, McDermott R, Hill AG, Swyer MB, Hendlisz A, Neyns B, Svrcek M, Moss RA, Ledeine J-M, Co ZA, Kmble S, Kopetz S, Overmn MJ

20 Introduction Approximtely 4% of ptients with mcrc hve deficiency in the DNA mismtch repir system (dmmr) tht leds to high microstellite instbility (MSI-H) 1,2 These ptients benefit less from conventionl chemotherpy thn ptients identified s MMR proficient or microstellite stble 3-5 Nivolumb demonstrted durble responses, sustined disese control, nd encourging survivl in ptients with dmmr/msi-h mcrc in the monotherpy cohort of CheckMte Nivolumb nd ipilimumb ct synergisticlly to promote T-cell ntitumor ctivity; therefore, combintion therpy could further improve results 7-9 Presented here re nlyses from the nivolumb + ipilimumb combintion therpy cohort of CheckMte-142, which is the lrgest single-study report of combintion immune checkpoint inhibitors in ptients with dmmr/msi-h mcrc mcrc, metsttic colorectl cncer 1. Le DT, et l. Science 2017;357(6349(: Koopmn M, et l. Br J Cncer 2009;100(2): Venderbosch S, et l. Clin Cncer Res 2014;20(20: Tougeron D, et l. Ann Oncol 2017;28(suppl 5). Abstrct 533P. 5. Lenz H, et l. J Clin Oncol 2017;35(suppl): Abstrct Overmn MJ, et l. Lncet Oncol 2017;18(9): Diz LA, et l. Ann Oncol. 2017;28(suppl 5). Abstrct 386P. 8. Antoni SJ, et l. Lncet Oncol 2016;17(7): Lrkin J, et l. N Engl J Med 2015;373(1): Presented by: Prof Thierry André André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct

21 Histologiclly confirmed metsttic or recurrent CRC dmmr/msi-h per locl lbortory 1 prior line of therpy CheckMte-142 Study Design Combintion cohort Monotherpy cohort Phse II Nonrndomized Study Nivolumb 3 mg/kg + ipilimumb 1 mg/kg Q3W (4 doses nd then nivolumb 3 mg/kg Q2W) Nivolumb 3 mg/kg Q2W Primry endpoint: ORR per investigtor ssessment (RECIST v1.1) Other key endpoints: ORR per BICR, DCR, b DOR, PFS, OS, nd sfety Medin follow-up in the combintion therpy cohort (N = 119) ws 13.4 months (rnge, 9-25) c Results of the monotherpy cohort (N = 74) with similr medin follow-up of 13.4 months (rnge, 10-32) re lso presented 1,c Enrollment ws stggered with dditionl ptients being enrolled if 7 of the first 19 centrlly confirmed MSI-H ptients hd confirmed response (CR or PR). CheckMte-142 monotherpy nd combintion therpy cohorts were not rndomized or designed for forml comprison. b Ptients with CR, PR, or SD for 12 weeks. c Defined here s the time from first dose to dt cutoff. BICR, blinded independed centrl review; CR, complete response; DCR, disese control rte; DOR, durtion of response; ORR, overll response rte; OS, overll survivl; PFS, progression-free survivl 1. Overmn MJ, et l. Lncet Oncol. 2017;18(9): André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 553. Overmn MJ, et l. J Clin Oncol Jn 20. [Epub hed of print]. 21

22 Bseline Chrcteristics Nivolumb + Ipilimumb N = 119 Medin ge (rnge), yers 58.0 (21-88) Mle, n (%) 70 (59) ECOG performnce sttus, n (%) 0 54 (45) 1 65 (55) Disese stge t dignosis, n (%) I-III IV Tumor PD-L1 expression t bseline, n (%) 1% <1% Unknown Muttion sttus, n (%) BRAF/KRAS wildtype BRAF muttion KRAS muttion Unknown Clinicl history of Lynch syndrome, n (%) b Yes No Unknown 66 (55) 53 (45) 26 (22) 65 (55) 28 (24) 31 (26) 29 (24) 44 (37) 15 (13) 35 (29) 31 (26) 53 (45) All ptients hd stge IV disese t study entry. b Bsed on the clinicl records of the ptients t sites in countries where this reporting ws permitted (excluded Itly). Presented by: Prof Thierry André André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 553. Overmn MJ, et l. J Clin Oncol Jn 20. [Epub hed of print]. 22

23 Prior Therpies Nivolumb + Ipilimumb N = 119 Prior lines of therpy, n (%) (23) 43 (36) 48 (40) Prior therpies received, n (%) Fluoropyrimidine b Oxlipltin Irinotecn VEGF inhibitors c EGFR inhibitors d Regorfenib Trifluridine/tipircil Other chemotherpy Other experimentl drugs 76% of ptients received 2 prior lines of therpy 69% received 3 prior chemotherpies including fluoropyrimidine, oxlipltin, nd irinotecn Presented by: Prof Thierry André 118 (99) 111 (93) 87 (73) 68 (57) 35 (29) 11 (9) 2 (2) 8 (7) 3 (3) EGFR, epiderml growth fctor receptor; VEGF, vsculr endothelil growth fctor One ptient hd received no prior lines of therpy. b Included fluorourcil nd cpecitbine. c Included bevcizumb, flibercept, nd rmucirumb. d Included cetuximb nd pnitumumb. André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 553. Overmn MJ, et l. J Clin Oncol Jn 20. [Epub hed of print]. 23

24 Investigtor-Assessed Response nd Disese Control Nivolumb + Ipilimumb N = Nivolumb N = 74 1,c Ptients, % ORR (95% CI): 55% (45.2, 63.8) ORR (95% CI): 31% (20.8, 42.9) CR PR SD PD Unknown DCR b ws 80% (95% CI: 71.5, 86.6) with combintion therpy nd 69% (57.1, 79.2) with monotherpy 1,d Combintion therpy provided numericlly higher ORR, including CRs, nd DCR reltive to monotherpy during similr follow-up period d Medin follow-up ws 13.4 months (rnge, 9-25). b Disese control ws defined s ptients with CR, PR, or SD for 12 weeks. c Medin follow-up ws 13.4 months (rnge, 10 32). d CheckMte-142 monotherpy nd combintion therpy cohorts were not rndomized or designed for forml comprison. 1. Overmn MJ et l. Lncet Oncol. 2017;18(9): Presented by: Prof Thierry André André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 553. Overmn MJ, et l. J Clin Oncol Jn 20. [Epub hed of print]. 24

25 Chrcteriztion of Response Nivolumb + Ipilimumb Medin time to response ws 2.8 months (rnge, 1-14) Responses were durble: Responders (n = 65) On tretment Off tretment First response Ongoing response Censored Deth Medin DOR ws not reched 94% of responders hd ongoing responses t dt cutoff 83% of responders hd responses lsting 6 months Response per investigtor ssessment. Weeks André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 553. Overmn MJ, et l. J Clin Oncol Jn 20. [Epub hed of print]. 25

26 Response nd Disese Control in Ptient Subsets Nivolumb + Ipilimumb (N = 119) n ORR DCR b Tumor PD-L1 expression, n (%) 1% (54) 20 (77) <1% (52) 51 (78) BRAF/KRAS muttion sttus, n (%) Wildtype (55) 24 (77) BRAF mutnt (55) 23 (79) KRAS mutnt (57) 37 (84) Clinicl history of Lynch syndrome, n (%) c Yes (71) 30 (86) No (48) 25 (81) Responses were observed irrespective of tumor PD-L1 expression, BRAF or KRAS muttionl sttus, or clinicl history of Lynch syndrome Per investigtor ssessment. b Ptients with CR, PR, or SD for 12 weeks. c Bsed on the clinicl records of the ptients t sites in countries where this reporting ws permitted (excluded Itly). Presented by: Prof Thierry André André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 553. Overmn MJ, et l. J Clin Oncol Jn 20. [Epub hed of print]. 26

27 No. t Risk Progression-Free Survivl, % c Progression-Free nd Overll Survivl Nivolumb + ipilimumb Nivolumb Nivolumb + ipilimumb,b Months Nivolumb 1,e,f 9-month rte (95% CI), % 76 (67.0, 82.7) 54 (41.5, 64.5) 12-month rte (95% CI), % 71 (61.4, 78.7) 50 (38.1, 61.4) Nivolumb + ipilimumb Nivolumb With similr follow-up, combintion therpy provided improved PFS nd OS reltive to monotherpy,e,f Overll Survivl, % Nivolumb + ipilimumb Nivolumb Nivolumb + ipilimumb,d Months Nivolumb 1,e,f 9-month rte (95% CI), % 87 (80.0, 92.2) 78 (66.2, 85.7) 12-month rte (95% CI), % 85 (77.0, 90.2) 73 (61.5, 82.1) Medin follow-up ws 13.4 months (rnge, 9-25). b Medin PFS ws not reched (95% CI, not estimble). c PFS per investigtor ssessment. d Medin OS ws not reched (95% CI, 18.0, not estimble). e Medin follow-up ws 13.4 months (rnge, 10-32). f CheckMte-142 monotherpy nd combintion therpy cohorts were not rndomized or designed for forml comprison. 1. Overmn MJ, et l. Lncet Oncol. 2017;18(9): André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 553. Overmn MJ, et l. J Clin Oncol Jn 20. [Epub hed of print]. 27

28 40 Ptient-Reported Outcomes EORTC QLQ-C30 globl helth sttus/qol Nivolumb + Ipilimumb 30 EQ-5D VAS Lest Squres Men Chnge From Bseline (95% CI) Better Worse ** ** ** ** ** ** ** ** Weeks ** ** ** ** ** * * P<.05; ** P< Ptient no ** Sttisticlly significnt nd cliniclly meningful improvements were chieved in key ptientreported outcomes, with improvements mintined for extended periods while on tretment Better Worse ** ** ** ** Weeks ** ** ** ** * P<.05; ** P<.01 ** ** EORTC, Europen Orgnistion for Reserch nd Tretment of Cncer; QoL, qulity of life; VAS, visul nlogue scle Chnges in men scores over time were nlyzed using liner mixed models djusted for bseline score. Chnges from bseline of 10 points (EORTC QLQ-C30) nd 7 points (EQ-5D VAS) were regrded s cliniclly meningful. 1,2 1. Osob D, et l. J Clin Oncol 1998;16(1): Pickrd AS, et l. Helth Qul Life Outcomes 2007;5:70. André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 553. Overmn MJ, et l. J Clin Oncol Jn 20. [Epub hed of print]. 28

29 Sfety Summry Ptients, n (%) Nivolumb + Ipilimumb N = 119 Any Grde Grde 3-4 Any TRAE 87 (73) 38 (32) Any serious TRAE 27 (23) 24 (20) Any TRAE leding to discontinution 15 (13) 12 (10) TRAEs reported in >10% of ptients Dirrhe 26 (22) 2 (2) Ftigue 21 (18) 2 (2) Pruritus 20 (17) 2 (2) Pyrexi 18 (15) 0 Incresed AST 17 (14) 9 (8) Hypothyroidism 16 (13) 1 (1) Nuse 15 (13) 1 (1) Incresed ALT 14 (12) 8 (7) Rsh 13 (11) 2 (2) Hyperthyroidism 13 (11) 0 No new sfety signls or tretmentrelted deths were reported Ptients who discontinued tretment due to study drug-relted AE (n = 16) hd n ORR (63%) consistent with the overll popultion For combintion therpy reltive to monotherpy: 1,b,c,d Any-grde TRAEs (73%; 70%) were comprble Grde 3-4 TRAEs (32%; 20%) were cceptble TRAEs leding to discontinution (13%; 7%) were modest ALT, lnine minotrnsferse; AST, sprtte minotrnsferse; TRAE, tretment-relted dverse event. Autoimmune heptitis nd cute kidney injury were the only TRAEs tht led to discontinution in >1 ptient (2% ech). b Combintion: medin follow-up, 13.4 months (rnge, 9-25). c Monotherpy: medin follow-up, 13.4 months (rnge, 10-32). d CheckMte-142 monotherpy nd combintion therpy cohorts were not rndomized or designed for forml comprison. 1. Overmn MJ et l. Lncet Oncol. 2017;18(9): André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 553. Overmn MJ, et l. J Clin Oncol Jn 20. [Epub hed of print]. 29

30 Conclusions Nivolumb + ipilimumb provided durble clinicl benefit in previously treted ptients with dmmr/msi-h mcrc, of whom 76% hd received 2 prior lines of therpy High ORR (55%) nd durble responses (medin DOR not reched) High rte of disese control (80%) for 12 weeks Encourging survivl (medin PFS nd OS not reched; 85% of ptients live t 1 yer) Sfety ws mngeble with low (13%) rte of discontinution due to TRAEs Meningful improvements were observed in key ptient-reported outcomes Indirect comprisons in this nonrndomized phse II study (CheckMte-142) suggest tht nivolumb + ipilimumb provides numericlly higher ORR, PFS, nd OS rtes t 1 yer reltive to nivolumb monotherpy with fvorble benefit-risk profile Nivolumb + ipilimumb represents promising new tretment option for ptients with previously treted dmmr/msi-h mcrc André T, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 553. Overmn MJ, et l. J Clin Oncol Jn 20. [Epub hed of print]. 30

31 A Phse Ib Study of Sfety nd Clinicl Activity of Atezolizumb nd Cobimetinib in Ptients With Metsttic Colorectl Cncer Abstrct 560 Bendell J, Bng Y-J, Chee CE, Ryn DP, McRee AJ, Chow LQ, Desi J, Wongchenko M, Yn Y, Pitcher B, Foster P, Ch E, Grossmn W, Kim TW

32 Colorectl Cncer Ptients with chemo-refrctory, loclly dvnced or metsttic CRC hve poor survivl prognosis of 6-7 months with SOC, highlighting unmet medicl needs 1,2 Single-gent PD-L1/PD-1 inhibitors hve shown miniml ctivity in MSS mcrc, suggesting need for combintion therpy 3 95% of ptients with mcrc re mismtch-repir proficient nd MSS 3 MSS mcrc is chrcterized by lower TMB tht results in fewer neontigens compred with MSI-high tumors 4 Preclinicl evidence suggests tht combining tezolizumb nd cobimetinib cn result in synergistic effect tht genertes ntitumor T-cell responses 5 Atezolizumb (nti PD-L1) is n engineered mab tht inhibits the binding of PD-L1 to its receptors PD-1 nd B7.1, thus restoring tumor-specific immunity 6,7 Cobimetinib is potent MEK1/2 inhibitor tht my improve tumor immune recognition, promotes T-cell ccumultion in tumors nd limits T-cell exhustion 5 CRC, colorectl cncer; DCR, disese control rte; mab, monoclonl ntibody; mcrc, metsttic CRC; MEK1/2, mitogen ctivted protein kinse kinse 1 nd 2; MSI, microstellite instbility; MSS, microstellite stble; ORR, objective response rte; SOC, stndrd-of-cre; TMB, tumor muttionl burden. 1. Grothey A, et l. Lncet. 2013;381(9863): Myer RJ, et l. N Engl J Med. 2015;372(20): Le DT, et l. N Engl J Med. 2015;372(26): George TJ, et l. J Clin Oncol. 2016;34(suppl):Abstrct Ebert PJ, et l. Immunity. 2016;44(3): Herbst RS, et l. Nture. 2014;515(7528): Chen DS, et l. Clin Cncer Res. 2012;18(24): Bendell J, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 560.

33 Phse Ib Dose Escltion nd Cohort Expnsion Study (NCT ) Stge 1: Dose Escltion Atezo 800 mg IV q2w + cobi 20 mg PO 21/7 n = 4 (mcrc: n = 2) Atezo 800 mg IV q2w + cobi 40 mg PO 21/7 n = 4 Atezo 800 mg IV q2w + cobi 60 mg PO 21/7 n = 6 (mcrc: n = 1) N = 150 Atezo 800 mg + cobi 60 mg Stge 2: Expnsion Solid tumors seril biopsy mcrc n = 16 mcrc: n = 1 n = 59 Cobi 21 d on/7 d off NSCLC n = 20 mcrc seril biopsy n = 21 Cobi 14 d on/14 d off Endpoints: Primry Sfety nd tolerbility Secondry Investigtor-ssessed ORR nd PFS by RECIST v1.1, nd OS Ptients: PD-L1 unselected MSI sttus ws loclly reported nd centrlly confirmed by NGS-bsed scoring Metsttic melnom n = 20 Atezo, tezolizumb; cobi, cobimetinib; NGS, next-genertion sequencing; NSCLC, non-smll cell lung cncer; ORR, overll response rte; OS, overll survivl; PFS, progression-free survivl Sfety-evluble popultion consisting of ptients who received t lest 1 dose of tezolizumb Bendell J, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 560.

34 Bseline Demogrphic nd Clinicl Chrcteristics Chrcteristic n = 84 Medin ge (rnge), yers 56.5 (23-81) Mle femle, % ECOG PS, % Prior systemic therpies, n (%) b (1) 2 4 (5%) 3 5 (6) 4 8 (10) (79) Chrcteristic n = 84 KRAS muttion, % c Wildtype mutnt, % PD-L1 expression, n (%) IC0/1 48 (57) IC2/3 7 (8) Unknown d 29 (35) MSI sttus, n (%) e MSS 42 (50) MSI-low 9 (11) MSI-high 1 (1) Unknown 32 (38) ECOG, Estern Coopertive Oncology Group; IC, tumor-infiltrting immune cells; IC0/1, <5% PD-L1+; IC2/3, 5% PD-L1+ As of September 4, 2017, the medin follow-up ws 17.0 months (rnge, months). b Refers to totl number of prior systemic therpies dministered rther thn lines of therpy dministered. c 2 ptients (2.4%) hd unknown KRAS muttion sttus. d Due to insufficient or unevluble tumor smples. e Bsed on locl or centrlized testing results. Bendell J, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 560.

35 Sfety Summry Ptients With mcrc (n = 84) n (%) All-cuse AEs: All grdes 82 (98) Tretment-relted AEs: All grdes 81 (96) Grde (38) Grde 5 0 SAEs 38 (45) Tretment-relted SAEs 10 (12) AEs leding to withdrwl of ny study drug 20 (24) AEs leding to withdrwl of tezolizumb 11 (13) AEs leding to withdrwl of cobimetinib 20 (24) The mjority of AEs were mngeble Rsh, dirrhe, ftigue, nd incresed blood cretine phosphokinse were the most frequent tretment-relted grde 3-4 AEs (5% incidence ech) AE, dverse events; SAE, serious dverse events. Dt cutoff: September 4, 2017 Bendell J, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 560.

36 Best Overll Response b, c BOR (n = 84) n (%) ORR 7 (8) CR 0 PR 7 (8) SD 19 (23) DCR 26 (31) PD 51 (61) Mximum SLD Reduction From Bseline, % 7 ptients (8% [95% CI: 3, 16]) experienced PR (confirmed per RECIST v1.1) 4 ptients hd MSS nd 1 ptient hd MSI-low mcrc; the remining 2 hd unknown MSI sttus b The DCR ws 31% (DCR defined s PR + SD 6 weeks) BOR, best overll response; CI, confidence intervl; CR, complete response; DCR, disese control rte; PD, progressive disese; PR, prtil response; RECIST v1.1, Response Evlution Criteri In Solid Tumors version 1.1; SD, stble disese; SLD, sum of longest dimeters Dt cutoff: September 4, Cobimetinib dose nd schedule vried bsed on cohort nd phse of the study 7 ptients (8%) hd missing or unevluble BOR. b Bsed on combined locl or centrlized testing results. c Unlbeled brs represent ptients with unknown MSI sttus. Bendell J, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 560.

37 Durtion of Response KRAS Wildtype,b (n = 23) KRAS Mutnt,b (n = 52) Chnge in Sum of Lrgest Dimeters From Bseline, % ORR b 8% (95% CI: 1, 26) DCR c 32% Chnge in Sum of Lrgest Dimeters From Bseline, % ORR b 9% (95% CI: 3, 19) DCR c 30% Time on Study, Months Time on Study, Months The medin durtion of response ws 14.3 months (95% CI: 6.0, NE) NE, not estimble. Dt cutoff: September 4, ptients hd unknown KRAS muttion sttus nd re not included in these grphs. b BOR ws missing or unevluble for 2 ptients with KRAS wildtype disese nd 5 ptients with KRAS-mutnt disese. c DCR defined s PR or SD 6 weeks. Bendell J, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 560.

38 Progression-Free Survivl nd Overll Survivl PFS OS PFS, % OS, % Time, Months Time, Months Ptients PFS Medin (95% CI) 6-Month Medin (95% CI) 6-Month 12-Month OS All (n = 84) 1.9 months (1.8, 2.3) 18% 9.8 months (6.2, 14.1) 65% 43% MSS (n = 42) 2.5 months (1.8, 3.7) 27% 13.0 months (6.0, 25.8) 71% 51% KRAS mutnt (n = 57) b 2.0 months (1.8, 2.3) 22% 9.5 months (6.0, 17.6) 67% 44% KRAS wildtype (n = 25) b 1.8 months (1.8, 2.6) 9% 10.0 months (4.9, 17.1) 65% 43% Dt cutoff: September 4, Of the remining 42 non-mss ptients, 32 ptients hd unknown MSI sttus, 9 ptients were MSI-low nd 1 ptient ws MSI-high. b 2 ptients hd unknown KRAS muttion sttus. Bendell J, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 560.

39 Conclusions The combintion of tezolizumb + cobimetinib ws tolerted in hevily pretreted ptients with loclly dvnced or metsttic CRC With medin follow-up of 17.0 months, the medin OS ws 9.8 months nd the 12-month OS rte ws 43% in mcrc The 12-month OS compred fvorbly with the 12-month OS of 24% with regorfenib Durble responses were observed regrdless of KRAS sttus nd in ptients with MSS tumors, popultions with high unmet medicl need The tezolizumb + cobimetinib combintion represents the first potentil immunemodifying combintion for ptients with MSS mcrc Dt from the confirmtory phse III study IMblze370 (NCT ) re nticipted in 2018 For more detils, plese visit poster #560 (Poster session C, Jnury 20, PM 2.00 PM) Bendell J, et l. J Clin Oncol. 2018;36(suppl 4S): Abstrct 560.

40 IMblze-370: Ongoing Phse III Study Unresectble mcrc ptients Received t lest 2 regimens in metsttic setting (not including mintennce) 2:1:1 N = 360 Primry Endpoint: Overll survivl (OS) Cobimetinib + Atezolizumb Atezolizumb Regorfenib Secondry Endpoints: PFS, investigtor-ssessed objective response, DOR, qulity of life (EORTC QLQ-C30), sfety Strtified by tumor extended RAS sttus nd time since dignosis of first metstsis MSI-H cpped t pproximtely 5%; 95% MSS At lest 180 ptients with extended RAS-mutnt tumors to be enrolled Ntionl Institutes of Helth. Accessed: Jnury 12, 2018.

41 CEA-TCB: The First T-Cell Bispecific Antibody With Novel 2 to 1 Formt, Optimized for Efficcy nd Sfety Binds simultneously with 1 rm to CD3 on T cells nd with 2 rms to CEA on tumor cells Flexible 2-to-1 formt enbles high-vidity binding nd selective killing of high CEAexpressing tumor cells Longer hlf-life compred with other TCB formts Silent Fc results in reduced risk of FcyR-relted cytokine relese/irrs Simultneously binging of TCB to tumor (CEA) nd T cells (CD3) Killing of tumor cells independent of preexisting immunity T-cell prolifertion t site of ctivtion Fb, frgment ntigen-binding region; IRR, infusion-relted rection 1. Bcc M, et l. Clin Cncer Res. 2016;22(13): Bcc M, et l. Oncoimmunology. 2016;5(8):e Green J, et l. The Scientist. 2014;28(4). 1. Argilés G, et l. Ann Oncol. 2017;28(suppl_3): Abstrct LBA-004.

42 CEA-TCB t Doses 60 mg + Atezolizumb Demonstrted Enhnced Clinicl Activity vs Monotherpy in mcrc Confirmed Best Overll Response (RECIST v1.1), n (%) Study 1: CEA-TCB Monotherpy n = 31, 60 mg-600 mg MSS, n = 28 (90%) b Study 2: CEA-TCB + Atezolizumb n = 25, 5 mg-160 mg MSS, n = 23 (92%) c n = 11, 80 mg or 160 mg MSS, n = 11 (100%) Prtil response 2 (6) 3 (12) d 2 (18) d Stble disese 12 (39) 10 (40) 7 (64) Disese control 14 (45) 13 (52) 9 (82) Progressive disese 16 (52) 12 (48) 2 (18) Nonevluble 1 (3) Tbernero J, et l. J Clin Oncol. 2017;35(suppl): Abstrct 3002.