ASCO 2017 updates in Colorectal and Gastric Cancers. May Cho, M.D.

Transcription

1 ASCO 2017 updates in Colorectal and Gastric Cancers May Cho, M.D.

2 Relevant financial relationships in the past twelve months by presenter or spouse/partner: None The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.

3 Outline Colorectal Cancer IDEA trial (adjuvant therapy) CALGB/SWOG Prognostic Factors SWOG S1406 (VIC vs IC in BRAF mcrc) Gastric Cancer FLOT KEYNOTE-059

4 IDEA: Pooled Analysis of Adjuvant Oxaliplatin for 3 vs 6 Months in Stage III Colon Cancer

5 IDEA: Trials, Treatment Prospectively pooled analysis of data from 6 concurrent randomized phase III trials in pts with stage III CC (mitt population: N 12,834) Trial Pts randomized 1:1 to 3 vs 6 mos tx with oxaliplatin-based tx (investigator s choice of FOLFOX or CAPOX) Stage III CC Pts, N Treatment Country Median F/u, Mos Pts on CAPOX, % TOSCA 2402 CAPOX or FOLFOX4 Italy SCOT 3983 CAPOX or mfolfox6 Australia, Denmark, New Zealand, Spain, Sweden, UK IDEA France 2010 CAPOX or mfolfox6 France C mfolfox6 Canada, US 35 0 HORG 708 CAPOX or FOLFOX4 Greece ACHIEVE 1291 CAPOX or mfolfox6 Japan Shi Q, et al. ASCO Abstract LBA1.

6 IDEA: Statistical Plan Primary endpoint: DFS in mitt population* DFS: time from randomization to earliest date of relapse, secondary colorectal primary tumor, or death Preplanned subgroup analyses by regimen, risk groups Statistical analyses DFS HR for 3 vs 6 mos (2-sided 95% CI) estimated with Cox model stratified by trial Predefined noninferiority margin for HR < 1.12 (12% increase in relative risk) Requires 3390 DFS events for 90% power with 1-sided α = Predefined noninferiority margin for 3-yr DFS rate difference (3 vs 6 mos): -2.7% Additional endpoints: treatment compliance, safety *Received 1 dose of study drug. Shi Q, et al. ASCO Abstract LBA1.

7 IDEA: Pt Characteristics by Tx Duration, Regimen Characteristic 3 Mos (n = 3870) FOLFOX 6 Mos (n = 3893) 3 Mos (n = 2554) CAPOX 6 Mos (n = 2517) Median age, yrs ECOG PS 0/1,* % 77/22 77/22 82/18 81/19 T stage, % T1-2 T3 T4 N stage, % N1 N Reached final planned cycle, % *1% of FOLFOX-treated pts had ECOG PS Shi Q, et al. ASCO Abstract LBA1.

8 IDEA: DFS in mitt Population, Risk Subgroups Noninferiority of oxaliplatin-based tx for 3 vs 6 mos not proven DFS HR: 1.07 (95% CI: ) Difference in 3-yr DFS rates: -0.9% (95% CI: -2.4% to 0.6%) 3-yr DFS rate difference of 20% between low risk (T1-3, N1) vs high risk (T4 or N2) subgroups Risk Group HR Favors 3 mos Favors 6 mos Interaction P Value T1-3, N1 T4 or N Shi Q, et al. ASCO Abstract LBA1. Reproduced with permission HR

9 IDEA: DFS by Risk Subgroups and Regimen Risk Group Regimen Favors 3 mos Favors 6 mos HR (95% CI) T1-3, N1 FOLFOX CAPOX Not proven Noninferior 1.10 ( ) 0.85 ( ) T4 or N2 FOLFOX CAPOX Inferior Not proven 1.20 ( ) 1.02 ( ) HR Noninferiority margin Shi Q, et al. ASCO Abstract LBA1. Reproduced with permission.

10 IDEA: Safety AE, % Any event Grade 2 Grade 3/4 Neurotoxicity Grade 2 Grade ¾ Diarrhea Grade 2 Grade 3/4 *For Chi-squared test for trend. 19 grade 5 events reported. FOLFOX CAPOX 3 Mos 6 Mos P Value* 3 Mos 6 Mos P Value* < < < <.0001 < Shi Q, et al. ASCO Abstract LBA1.

11 IDEA: Investigator Conclusions DFS noninferiority of adjuvant oxaliplatin-based tx for 3 vs 6 mos not established in overall pts with stage III CC Shorter tx associated with greater treatment compliance, much less grade 2 neuropathy Investigators recommend risk-vs-benefit approach when selecting duration of adjuvant oxaliplatin-based tx Low-risk pts (T1-3, N1): 3 mos High-risk pts (T4, N2, or other high-risk variables): 3-6 mos depending on tolerability, pt preferences, recurrence risk, regimen (FOLFOX vs CAPOX) Shi Q, et al. ASCO Abstract LBA1.

12 Prognostic Factors for First-line Chemotherapy + Bevacizumab or Cetuximab in Metastatic Colorectal Cancer

13 CALGB/SWOG 80405: Study Design and Survival Randomized, open-label phase III trial Pts with KRAS wildtype (Codons 12, 13) metastatic/advanced CRC and no previous therapy for advanced disease (N = 1137) Cetuximab + Chemotherapy* (n = 578) Bevacizumab + Chemotherapy* (n = 559) *Physician choice of FOLFIRI or FOLFOX. OS, Mos PFS, Mos No difference between cetuximab and bevacizumab when combined with FOLFIRI or FOLFOX with respect to OS or PFS [1] 1. Venook A, et al. JAMA (in press). 2. Venook A, et al. ASCO Abstract Innocenti F, et al. ASCO Abstract 3504.

14 CALGB/SWOG Prognostic Factors: OS by Side of Tumor and Biologic Treatment Pts with right-sided tumor, n = 293 (27%); left-sided, n = 732 (68%) OS (%) Pts with transverse colon tumors excluded from analysis (n = 66) Side Left Right OS by Sidedness N (Events) 732 (550) 293 (242) Left mos (95% CI) 33.3 ( ) 19.4 ( ) HR (95% CI) 1.55 ( ) P Value <.0001 OS (%) OS by Side and Treatment Left/Bevacizumab mos 31.4 (95% CI: ) Left/Cetuximab mos 36.0 (95% CI: ) Right/Bevacizumab mos 24.2 (95% CI: ) Right/Cetuximab mos 16.7 (95% CI: ) 20 Right Mos Venook A, et al. ASCO Abstract Reproduced with permission Mos

15 CALGB/SWOG Prognostic Factors: Current Analyses Multivariate analysis of prognostic utility of tumor sidedness (independent of other molecular features) [1] Evaluated in subset of pts with left-/ right-sided tumors (no transverse) and available molecular data (n = 728) Used Cox proportional hazard models* Evaluated potential biomarkers of sidedness/tumor burden Analysis of mutational profile and prognostic, clinical value of DNA alterations [2] DNA from 504 tumor specimens Mutation profile determined by PCR genotyping in 12 genes, MSI-high status by microsatellite mutation analysis, mutational load in 395 genes by NGS Primary endpoint: OS *Models stratified by adjuvant CT, prior RT. Models adjusted for age, race, sex, synchronous vs metachronous, BRAF. Sidedness analysis also adjusted for consensus molecular subtypes, MSI, NRAS, KRAS, HRAS; mutational analysis for liver metastases only, sidedness. No adjustment for multiple comparisons. 1. Venook AP, et al. ASCO Abstract Innocenti F, et al. ASCO Abstract Used Cox proportional hazard models* to test association with molecular alterations

16 CALGB/SWOG Prognostic Factors: Sidedness Independent of Molecular Features Multivariate analysis found that sidedness a significant prognostic factor independent of other molecular features HR: (95% CI: ; P =.031*) Clinical characteristics compared between pts with right- vs left-sided tumors to determine whether sidedness potentially a surrogate for tumor burden Pattern of metastases significantly differed by side (Chi-squared P =.0136) No significant differences with other tumor burden indicators *Per stratified, adjusted Cox proportional hazard model. Venook AP, et al. ASCO Abstract Tumor Burden Indicator, % Right-Sided Tumors (n = 167) Left-Sided Tumors (n = 330) Median LDH, IU/L Metastatic sites, n Prior adjuvant tx ⁰ in place at tx initiation Intent, palliative/curative 86.4/ /16.9 Pattern of metastases Liver only Liver + extrahepatic Extrahepatic only

17 CALGB/SWOG Prognostic Factors: OS by BRAF Genotype Patient Genotype Group Median OS, Mos (95% CI) HR adj (95% CI) P for Interaction, BRAF/biologics BRAF genotype Wild type (n = 432) Mutant (n = 72) 34.2 ( ) 12.9 ( ) 1.82 ( ) P =.0001* BRAF wild type Treated with cetuximab (n = 225) Treated with bevacizumab (n = 207) BRAF mutant Treated with cetuximab (n = 31) Treated with bevacizumab (n = 41) 33.4 ( ) 34.4 ( ) 11.7 ( ) 15.0 ( ) 0.97 ( ) P = ( ) P = *If further adjusted for sidedness of tumor, HR: 1.67 (95% CI: ; P =.0035). Innocenti F, et al. ASCO Abstract 3504.

18 CALGB/SWOG Prognostic Factors: OS by MSI Status Patient Subgroup Median OS, Mos (95% CI) HR adj (95% CI) Microsatellite instability High level of instability (n = 29; 52% BRAF mutant) Stable (n = 389; 11% BRAF mutant) Microsatellite stable Treated with cetuximab (n = 224) Treated with bevacizumab (n = 220) Microsatellite instability-high Treated with cetuximab (n = 13, 46% BRAF mutant) Treated with bevacizumab (n = 18, 61% BRAF mutant) 30.3 (22.6-NE) 31.8 ( ) 33.4 ( ) 32.8 ( ) 11.5 (10.3-NE) 30.3 (23.6-NE) 0.84 ( ) P = ( ) P = ( ) P =.002 P for Interaction, MSI/biologics.0002 Innocenti F, et al. ASCO Abstract 3504.

19 CALGB/SWOG Prognostic Factors: OS by Mutational Load Patient Subgroup Median OS, Mos (95% CI) HR adj (95% CI) P for Interaction, Mutational Load/Biologics Mutational Load in MSS mcrc 8 (n = 228) > 8 (n = 65) 30.1 ( ) 35.7 ( ) 0.67 ( ) P =.02 Mutational Load 8 in MSS mcrc Treated with cetuximab (n = 103) Treated with bevacizumab (n = 125) Mutational Load > 8 in MSS mcrc Treated with cetuximab (n = 27) Treated with bevacizumab (n = 38) 29.1 ( ) 30.3 ( ) 35.8 ( ) 35.1 ( ) 1.00 ( ) P = ( ) P = Innocenti F, et al. ASCO Abstract 3504.

20 CALGB/SWOG Prognostic Factors: Investigator Conclusions In pts with mcrc and no previous therapy for advanced disease: Left-sided tumors significantly associated with improved OS, regardless of biologic tx [1] Sidedness a prognostic factor independent of other molecular features (HR: 1.392; P =.031) Investigators concluded that tumor sidedness differences not due to tumor burden; further study warranted to identify mechanisms behind sidedness as independent prognostic factor BRAF status strong prognostic marker, even when adjusted for tumor sidedness, but has no predictive interaction with biologic therapy [2] MSI status not prognostic but may be predictive for biologic therapy [2] Mutational load in pts with MSS CRC has prognostic potential but does not seem to be predictive for biologic therapy [2] According to investigators, these data indicate that pt and tumor characteristics may help predict response to biologic therapy but larger numbers of pts and more markers need to be explored [1,2] 1. Venook AP, et al. ASCO Abstract Innocenti F, et al. ASCO Abstract 3504.

21 SWOG S1406: Vemurafenib in Combination With Irinotecan and Cetuximab in BRAF V600E Metastatic CRC

22 SWOG S1406: Background BRAF V600E: mutation leading to constitutive activation of BRAF kinase and MAPK pathway [1] BRAF mutated in ~ 8% of mcrc cases Associated with aggressive disease, poor prognosis, minimal benefit from standard chemotherapy [2] Vemurafenib: kinase inhibitor selective for mutated BRAF protein [3] Vemurafenib monotherapy associated with limited activity in mcrc Phase I study suggested improved survival and response in combination with irinotecan + cetuximab in refractory mcrc with BRAF V600E [4] Current study evaluated efficacy and safety of vemurafenib addition to irinotecan + cetuximab in pts with BRAF V600E mcrc [5] References in slidenotes.

23 SWOG S1406: Study Design Randomized, multicenter, open-label phase II trial Stratified by prior irinotecan treatment (yes vs no) Randomized 1:1 Pts with mcrc, extended RAS WT and BRAF V600E, previously treated with 1-2 systemic CT lines for metastatic or advanced unresectable disease, no prior panitumumab or cetuximab, no prior BRAF or MEK inhibitors, ECOG PS 0-1 (N = 106)* *Only 99 pts eligible to receive treatment after randomization. Vemurafenib 960 mg PO BID + Cetuximab 500 mg/m 2 IV Q2W + Irinotecan 180 mg/m 2 IV Q2W (n = 49) Cetuximab 500 mg/m 2 IV Q2W + Irinotecan 180 mg/m 2 IV Q2W (n = 50) Until PD Until PD; crossover allowed to vemurafenib arm after PD Primary endpoint: PFS Secondary endpoints: OS, ORR, treatment-related AEs Kopetz S, et al. ASCO Abstract ClinicalTrials.gov. NCT

24 SWOG S1406: Baseline Characteristics Characteristic, n (%) VIC (n = 49) IC (n = 50) Median age, yrs (range) 60 (34-83) 62 (31-83) Female 21 (43) 37 (74) Race White Black Asian 43 (88) 1 (2) 4 (8) 49 (98) 0 (0) 1 (2) Hispanic ethnicity 2 (4) 2 (4) ECOG PS 1 25 (51) 27 (54) Prior irinotecan 20 (41) 19 (38) Prior regimens for mcrc 1 2 Failed adjuvant within 6 mos 27 (55) 19 (39) 3 (6) 26 (52) 17 (34) 7 (14) Kopetz S, et al. ASCO Abstract 3505.

25 SWOG S1406: PFS (Primary Endpoint) PFS (%) Events, n mpfs (95% CI) VIC ( ) IC ( ) HR: 0.48 (95% CI: ; P =.001) Median follow-up: 7.3 mos Among 48% of pts who crossed over to VIC after PD on IC, mpfs was 5.8 mos PFS significantly prolonged with vemurafenib in most subgroups Mos Significant benefit in pts with tumors on right vs left/rectum, no prior irinotecan, MSS, or mutated PIK3CA Kopetz S, et al. ASCO Abstract Reproduced with permission.

26 SWOG S1406: OS, Response OS (%) mos, Mos 95% CI VIC 9.6 ( ) IC 5.9 ( ) HR: 0.73 (95% CI: ; P =.19) Mos In crossover pts, mos: 12.1 mos (95% CI: ) Distribution of responses significantly different with addition of vemurafenib vs IC alone (Chi-squared P =.001) Endpoint, % VIC (n = 44)* IC (n = 47)* Crossover (n = 24) PR SD PD NR DCR *Measurable disease in 93 pts overall. Excludes 6 pts (2 pts without PD before crossover, 4 pts without measurable disease). Includes confirmed and unconfirmed. Includes symptomatic deterioration. Kopetz S, et al. ASCO Abstract Reproduced with permission.

27 SWOG S1406: Safety Grade 3/4 AE, n (%) VIC (n = 46) IC (n = 46) Anemia 6 (13) 0 (0) Dehydration 5 (11) 3 (7) Diarrhea 11 (24) 6 (13) Febrile neutropenia 5 (11) 2 (4) Fatigue 7 (15) 7 (15) Neutropenia 15 (33) 3 (7) Rash 2 (4) 3 (7) Hypomagnesemia 0 (0) 2 (4) Nausea 9 (20) 1 (2) Arthralgia 3 (7) 0 (0) AE-related discontinuations more common with vemurafenib combination (16%) vs cetuximab + irinotecan alone (6%) Median duration of treatment imbalanced between arms 88 days for VIC 47 days for IC Kopetz S, et al. ASCO Abstract 3505.

28 SWOG S1406: Investigator Conclusions Addition of vemurafenib to cetuximab + irinotecan associated with significantly prolonged PFS in mcrc pts with BRAF V600E mpfs: 4.3 vs 2.0 mos, respectively (HR: 0.48; P =.001) PFS benefit observed across most subgroups Addition of vemurafenib associated with benefit in pts crossing over after PD on IC alone mpfs: 5.8 mos; mos: 12.1 mos mos numerically higher with VIC (9.6 mos) vs IC alone (5.9 mos), but did not reach statistical significance (HR: 0.73; P =.19) Analysis limited by 48% crossover to VIC after PD on IC alone Investigators concluded that VIC is a new treatment for BRAF V600E mcrc Kopetz S, et al. ASCO Abstract 3505.

29 Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin(flot) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4): A multi center, randomized phase III trial

30 FLOT4 Study Design Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

31 Endpoints and Populations Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

32 Baseline 1 Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

33 Surgery 1 Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

34 Histopathology (yptn) Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

35 FLOT4: Progression-Free Survival Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

36 FLOT4: Overall Survival Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

37 Chemo Related Toxicity 1 < > > > < < Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

38 Discussion Strengths Well designed and executed prospective randomized phase III study Clear benefit to FLOT over ECF Limitations Overlap with patients treated in CROSS trial similar mos (48.6m) Does not answer the question do patients need adjuvant therapy? Increased rates of curative surgery, PFS and OS Practice Changing? Yes, for perioperative chemotherapy approach

39 KEYNOTE-059 (Cohort 1): Pembrolizumab Monotherapy in Previously Treated Advanced Gastric or GEJ Adenocarcinoma

40 Pembrolizumab for Pretreated Advanced Gastric or GEJ Adenocarcinoma: Background PD-L1 overexpression a feature of gastric cancers [1-3] Pembrolizumab: humanized anti PD-1 IgG4-κ mab; blocks PD-1 interaction with its ligands PD-L1/2 [4] Phase Ib KEYNOTE-012: manageable toxicity, 22% ORR in pts with advanced PD-L1+ gastric cancer [5] Current analysis reports data from phase II KEYNOTE-059 of pembrolizumab with focus on cohort 1 (pts with advanced gastric/gej cancer and 2 prior lines of therapy who received pembrolizumab monotherapy) [6] 1. Kim JW, et al. Gastric Cancer. 2016;19: Qing Y, et al. Drug Des Devel Ther. 2015;9: Dong M, et al. Hum Pathol. 2016;53: Pembrolizumab [package insert]. 5. Muro K, et al. Lancet Oncol. 2016;17: Fuchs CS, et al. ASCO Abstract 4003.

41 KEYNOTE-059: Study Design Open-label, multicohort phase II study Pts with recurrent or metastatic gastric or GEJ adenocarcinoma; ECOG PS 0/1; HER2/neu negative*; no prior PD-1/PD-L1 tx, systemic steroids, autoimmune disease, ascites, or CNS mets (N = 259) Cohort 1 2 prior lines of CT Cohort 2 No prior tx Cohort 3 No prior tx, PD-L1+ Pembrolizumab 200 mg Q3W Pembrolizumab 200 mg Q3W + Cisplatin 80 mg/m 2 Q3W + 5-FU 800 mg/m 2 Q3W or Capecitabine 1000 mg/m 2 BID Q3W Pembrolizumab 200 mg Q3W Tx continued for 24 mos or until PD, intolerable toxicity, or withdrawal of consent; survival follow-up until study end, death, or withdrawal *HER2/neu positive allowed in cohort 1 if prior trastuzumab administered. Primary endpoints: ORR, safety; secondary endpoints: DoR, PFS, OS Exploratory biomarker endpoints: efficacy by MSI, GEP Fuchs CS, et al. ASCO Abstract 4003.

42 KEYNOTE-059 (Cohort 1): Baseline Characteristics Characteristic Fuchs CS, et al. ASCO Abstract All Pts (N = 259) Median age, yrs (range) 62 (24-89) Male, n (%) 198 (76.4) Geographic region, n (%) United States East Asia Other ECOG PS, n (%) 0 1 Primary tumor location, n (%) Gastric GEJ 124 (47.9) 34 (13.1) 101 (39.0) 107 (41.3) 151 (58.3) 125 (48.3) 133 (51.4) Characteristic, n (%) Prior therapies Prior surgery for gastric cancer All Pts (N = 259) 134 (51.7) 75 (29.0) 50 (19.3) 66 (25.5) HER2 positive 63 (24.3) PD-L1 expression Positive* Negative *CPS 1% where CPS is (PD-L1 staining cells/total tumor cells) x (57.1) 109 (42.1)

43 KEYNOTE-059 (Cohort 1): Response Confirmed Response, % (95% CI) All Pts (N = 259) ORR 11.6 ( ) CR 2.3 ( ) PR 9.3 ( ) SD 16.2 ( ) PD 56.0 ( ) DCR* 27.0 ( ) Median follow-up: 5.8 mos (range: mos) *CR + PR + SD 2 mos. Fuchs CS, et al. ASCO Abstract 4003.

44 KEYNOTE-059 (Cohort 1): Safety TRAE Occurring in > 5% of Pts, % All Pts (N = 259) Any Grade Grade 3/4 Fatigue Pruritus Rash Hypothyroidism Decreased appetite Anemia Nausea Diarrhea D/c for TRAEs: abnormal hepatic function, bile duct stenosis, n = 1 each. Grade 5 TRAEs: acute kidney injury, pleural effusion, n = 1 each. irae Occurring in > 1% of Pts, % All Pts (N = 259) Any Grade Grade 3/4 Any Hypothyroidism Hyperthyroidism Colitis Pneumonitis Thyroiditis Infusion reaction Severe skin reaction* Arthralgia *Includes erythema multiforme, jaundice, rash, maculopapular rash. Systemic corticosteroids for iraes: n = 13. Treatment interruption due to iraes: n = 10. Fuchs CS, et al. ASCO Abstract 4003.

45 KEYNOTE-059 (Cohort 1): Response by PD-L1 Expression and Line of Therapy Confirmed Response, % (95% CI) ORR CR PR DCR* *CR + PR + SD 2 mos. Positive (n = 148) 15.5 ( ) 2.0 ( ) 13.5 ( ) 33.1 ( ) PD-L1 Line of Therapy PD-L1 and Third Line of Therapy Negative (n = 109) 6.4 ( ) 2.8 ( ) 3.7 ( ) 19.3 ( ) Third (n = 134) 16.4 ( ) 3.0 ( ) 13.4 ( ) 31.3 ( ) Fourth (n = 125) 6.4 ( ) 1.6 ( ) 4.8 ( ) 22.4 ( ) Positive (n = 75) 22.7 ( ) 2.7 ( ) 20.0 ( ) 38.7 ( ) Negative (n = 58) 8.6 ( ) 3.4 ( ) 5.2 ( ) 22.4 ( ) Fuchs CS, et al. ASCO Abstract 4003.

46 KEYNOTE-059 (Cohort 1): Maximum Change From Baseline in Target Lesion Size Change From BL (%) PD-L1 positive PD-L1 negative PD-L1 expression unknown Pts With Reduction, % All pts* 42.4 PD-L1 positive 47.3 PD-L1 negative 36.3 *Included pts with measurable disease at BL and 1 post-bl assessment (n = 223) Fuchs CS, et al. ASCO Abstract Reproduced with permission.

47 Confirmed Responders (n = 30) KEYNOTE-059 (Cohort 1): Depth and Duration of Response Treatment Exposure and Duration of Response CR PR PD Death Ongoing pembrolizumab treatment Mos Since First Dose Longitudinal Change From BL in Tumor Size Among Responders (n = 30) Outcome All Pts* PD-L1+ PD-L1-24 Treatment discontinued Treatment ongoing Median DoR, mos (95% CI) 8.4 (1.6+ to 17.3+) 16.3 (1.6+ to 17.3+) 6.9 (2.4 to 7.0+) *Included pts with measurable disease at BL and 1 post-bl assessment (n = 30). No PD at last disease assessment. Fuchs CS, et al. ASCO Abstract Reproduced with permission. Change From BL (%) Mos Since Treatment Initiation 24

48 KEYNOTE-059 (Cohort 1): Survival 100 OS All Pts (N = 259) Median OS, mos (95% CI) 5.6 ( ) 100 PFS All Pts (N = 259) Median PFS, mos (95% CI) 2.0 ( ) mo OS rate, % OS (%) PFS (%) Mos Pts at risk, n Mos Pts at risk, n Fuchs CS, et al. ASCO Abstract Reproduced with permission.

49 KEYNOTE-059 (Cohort 1): Exploratory Analyses Confirmed Response, % (95% CI) ORR MSI assessed in 174 pts MSI-high: 4.0% MSI-High (n = 7) 57.1 ( ) Non MSI-High (n = 167) 9.0 ( ) CR 14.3 ( ) 2.4 ( ) PR 42.9 ( ) 6.6 ( ) DCR* 71.4 ( ) 22.2 ( ) *CR + PR + SD 2 mos. 18-Gene T-Cell Inflamed GEP Score Nonresponder Responder 18-gene T-cell inflamed GEP score, assessed in 144 pts, associated with significantly improved response to pembrolizumab (P =.014) Fuchs CS, et al. ASCO Abstract Reproduced with permission.

50 KEYNOTE-059 (Cohort 1): Conclusions In pts with advanced gastric/gej cancer and 2 prior therapies, pembrolizumab well tolerated with promising antitumor activity, durable responses ORR: 11.6%; higher in PD-L1+ vs PD-L1- tumors (15.5% vs 6.4%) and MSI-high vs non MSI-high tumors (57.1% vs 9.0%) Study investigators suggest pembrolizumab as potential therapeutic option for this pt population Pembrolizumab in earlier-line therapy and in chemotherapy combinations under investigation for advanced gastric/gej cancer in ongoing randomized trials Fuchs CS, et al. ASCO Abstract 4003.

51 Thank You