Bristol-Myers Squibb, Braine-l Alleud, Belgium; 12 MD Anderson Cancer Center, Houston, TX, USA

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1 3531 Combination of nivolumab (NIVO) + ipilimumab (IPI) in the treatment of patients (pts) with deficient DNA mismatch repair (dmmr)/high microsatellite instability (MSI-H) metastatic colorectal cancer (mcrc): CheckMate 142 Study Thierry Andre, 1 Sara Lonardi, 2 Ka Yeung Mark Wong, 3 Michael Morse, 4 Ray McDermott, 5 Andrew Hill, 6 Alain Hendlisz, 7 Heinz-Josef Lenz, 8 Joseph Leach, 9 Rebecca A. Moss, 10 Z. Alexander Cao, 10 Jean-Marie Ledeine, 11 Scott Kopetz, 12 Michael Overman 12 1 Hopital Saint Antoine, Paris, France; 2 Istituto Oncologico Veneto IOV-IRCSS, Padova, Italy; 3 The University of Sydney, Sydney Medical School, Sydney, Australia; 4 Duke University Office of Research Administration, Durham, NC, USA; 5 St Vincent s University Hospital, Dublin, Ireland; 6 Tasman Oncology Research Pty Ltd, Southport, Queensland, Australia; 7 Institut Jules Bordet, Brussels, Belgium; 8 University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 9 Allina Health System, Minneapolis, MN, USA; 10 Bristol-Myers Squibb, Princeton, NJ, USA; 11 Bristol-Myers Squibb, Braine-l Alleud, Belgium; 12 MD Anderson Cancer Center, Houston, TX, USA

2 Background Patients with DNA mismatch repair deficient/microsatellite instability high (dmmr/msi H) metastatic colorectal cancer (mcrc) [ 5% of patients] are less likely to benefit from conventional chemotherapy than patients with proficient MMR (pmmr) mcrc 1-3 dmmr/msi H CRC is associated with a high mutational burden and is particularly susceptible to immune checkpoint inhibitor blockade 4,5 The combination of nivolumab (NIVO), an anti PD 1 mab, and ipilimumab (IPI), an anti-ctla 4 mab, has demonstrated efficacy and manageable safety profile in multiple solid tumors 6-8 CheckMate 142 is a multi cohort phase 2 study investigating the efficacy and safety of NIVO ± IPI in patients with dmmr/msi-h mcrc. NIVO monotherapy demonstrated durable responses, sustained disease control, and 12-month OS rate of 74% 9

3 Best Reduction From Baseline in Target Lesion (%) Investigator Assessed Response with NIVO Monotherapy (n = 74) 9 ORR: 31% 62% of patients had a reduction in tumor burden from baseline Median TTR: 2.8 months Median DOR: not reached; 83% (19/23) responses ongoing Confirmed CR or PR per investigator % Change truncated at NIVO ± IPI has demonstrated encouraging efficacy and manageable safety and in patients with dmmr/msi-h mcrc. 10 Here we report the results from the NIVO + IPI cohort of CheckMate 142 in all patients (n = 84) who had received their first dose 6 months prior to the data cut off (Jan 2017)

4 Study Design Figure 1. Study Design 9,10 Patients Stage 1 Stage 2 Histologically confirmed metastatic/ recurrent CRC dmmr/msi-h per local laboratory 1 prior line of therapy MONOTHERAPY ARM COMBINATION ARM NIVO 3 mg/kg Q2W NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses and then NIVO 3 mg/kg Q2W) If 7/19 confirmed responders, continue enrollment If 7/19 confirmed responders, continue enrollment NIVO 3 mg/kg Q2W NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses and then NIVO 3 mg/kg Q2W) Primary endpoint: ORR per investigator assessment (RECIST v1.1) Other key endpoints: ORR per blinded independent central review (BICR), PFS, OS and safety Tumor imaging assessments were performed every 6 weeks for 24 weeks and every 12 weeks thereafter until disease progression or discontinuation Treatment beyond progression was permitted if the patient was determined by the investigator to be benefiting from and tolerating study therapy

5 Results Table 1. Baseline Patient Demographics and Disease Characteristics Age Median (range), years < 65 years, n (%) dmmr/msi-h (N = 84) 57 (21-81) 61 (73) Male, n (%) 48 (57) Race, n (%) White Black Asian Other ECOG performance status, n (%) 0 1 Disease stage at initial diagnosis, n (%) I II III IV 77 (92) 2 (2) 3 (4) 2 (2) 31 (37) 53 (63) 9 (11) 33 (39) 42 (50)

6 Table 1. Baseline Patient Demographics and Disease Characteristics (cont) Clinical history of Lynch syndrome, n (%) Yes No Unknown Mutation status, n (%) BRAF/KRAS wild type BRAF mutated KRAS mutated Tumor PD-L1 expression quantifiable at baseline, n (%) 1% < 1% Prior lines of therapy, n (%) dmmr/msi-h (N = 84) 27 (32) 25 (30) 32 (38) 22 (26) 21 (25) 30 (36) 16 (24) 50 (76) 1 (1) 17 (20) 31 (37) 23 (27) 12 (14) Prior radiotherapy, n (%) 17 (20)

7 Results Median (range) time from first dose to data cut-off: 8.4 ( ) months Table 2. Patient Disposition and Exposure dmmr/msi-h (N = 84) Number of doses received, mean (SD) 14.4 (10.8) Continuing treatment, n (%) 51 (61) Discontinued treatment, n (%) 33 (39) Reasons for discontinuing treatment, n (%) Disease progression Treatment-related adverse event Death a Adverse event unrelated to study drug Lost to follow up Patient decision Not reported/other 15 (18) 11 (13) 1 (1) 1 (1) 1 (1) 1 (1) 3 (4) SD, standard deviation. a Patient died prior to assessment due to disease progression.

8 Efficacy Investigator-assessed response was achieved in 55% of patients and the disease control rate was 79% (Table 3) Table 3. Summary of Response and Disease Control with NIVO + IPI ORR, n (%) [95% CI] Best overall response, n (%) CR PR SD PD Not determined/reported Disease control for 12 weeks, a n (%) [95% CI] dmmr/msi-h (N = 84) 46 (55) [43.5, 65.7] 2 (2) 44 (52) 26 (31) 9 (11) 3 (4) 66 (79) [68.3, 86.8] Median TTR, months (range) 2.8 ( ) Median DOR, months, [95% CI] NR [NE, NE] DOR, duration of response; NE, not estimable; NR, not reached; TTR, time to response. a Defined as patients with complete response, partial response, or stable disease for 12 weeks..

9 Best Reduction From Baseline in Target Lesion (%) Efficacy 80% of patients had a reduction in tumor burden from baseline (Figure 2) Figure 2. Best Reduction in Target Lesion Size with NIVO + IPI Confirmed CR or PR per investigator -100

10 Change in target lesion from baseline, (%) Efficacy Characterization of response with NIVO + IPI is demonstrated in Figure 3; 85% (39/46) of responses were ongoing at the time of the data cut-off Figure 3. Change in Tumor Burden Over Time with NIVO + IPI Time since start of treatment (week) On treatment CR or PR 1 st occurrence of new lesion

11 Probability of Progression- Free Survival Median time from first dose to death or last known alive date: 8.7 months (range, 0.1 to 20.1) The 9 month rates of PFS and OS were 77% and 88%, respectively (Figure 4) Medians for PFS and OS had not yet been reached Figure 4. PFS (A) and OS (B) per Investigator Assessment with NIVO + IPI A PFS rate (95% CI), % 6 months 77 (66.5, 85.1) 9 months 77 (66.5, 85.1) Median PFS (95% CI), months NR (11.5, NE) No. at Risk Time (months) NE = not estimable; NR = not reached.

12 Probability of Overall Survival B OS rate (95% CI), % 6 months 89 (80.2, 94.2) 9 months 88 (78.1, 93.1) Median OS (95% CI), months NR (NE, NE) No. at Risk Time (months) NE = not estimable; NR = not reached.

13 Safety AEs were manageable, with Grade 3/4 TRAEs reported in 29% of patients (Table 4) No treatment-related deaths were reported Table 4. Summary of TRAEs with NIVO + IPI dmmr/msi-h (N = 84) Patients, n (%) Any Grade Grade 3 or 4 Any TRAE 57 (68) 24 (29) Serious TRAEs 15 (18) 14 (17) Discontinuation due to TRAEs a 11 (13) 8 (9) TRAEs reported in 10% of patients Diarrhea 20 (24) 1 (1) Fatigue 14 (17) 1 (1) Aspartate aminotransferase increase 14 (17) 8 (9) Pyrexia 13 (16) 0 Pruritus 13 (16) 2 (2) Alanine aminotransferase increase 12 (14) 7 (8) Nausea 12 (14) 0 Hyperthyroidism 11 (13) 0 Hypothyroidism 11 (13) 0 a All events (ALT level increase, autoimmune hepatitis, colitis, dyspnea, necrotizing myositis, pneumonitis, immune sarcoidosis, transaminase increase, thrombocytopenia) occurred in one patient each with the exception of acute kidney injury, which was reported in 2 patients.

14 Author s Conclusions NIVO + IPI provided durable responses, sustained disease control, and encouraging survival data in pretreated patients with dmmr/msi-h mcrc ORR of 55%, with 79% of patients achieving disease control for 12 weeks 85% of responses ongoing with median DOR not yet reached 88% of patients alive at 9 months NIVO + IPI demonstrated a manageable safety profile; 29% of patients had grade 3/4 TRAEs This trial is ongoing and patients will continue to be followed for survival

15 References 1. Koopman M, et al. Br J Cancer. 2009;100: Venderbosch S, et al. Clin Cancer Res. 2014; 20: Goldstein J et al. Ann Oncol. 2014;25: Giannakis M et al. Cell Reports. 2016;15: Llosa NJ et al. Cancer Discov. 2015;5: Wolchok JD et al. N Engl J Med. 2013;369: Postow MA et al. N Engl J Med. 2015;372: Antonia SJ et al. Lancet Oncol. 2016;17: Overman M et al. J Clin Oncol. 2017;35:(suppl 4S;abstract 519). 10. Overman M et al. Ann Oncol. 2016;27(6): (abstract 479P).

16 Acknowledgments The patients and families that made this trial possible The investigators that participated in this trial Bristol-Myers Squibb, Inc. (Princeton, NJ) and Ono Pharmaceutical Co., Ltd. (Osaka, Japan) The study was supported by Bristol-Myers Squibb, Inc. All authors contributed to and approved the presentation; medical writing and editorial assistance was provided by Kathy Covino, PhD of Chrysalis Medical Communications, Inc., funded by Bristol-Myers Squibb, Inc. ClinicalTrials.gov identifier NCT

Nivolumab in Patients With DNA Mismatch Repair Deficient/Microsatellite Instability High Metastatic Colorectal Cancer: Update From CheckMate 142

Nivolumab in Patients With DNA Mismatch Repair Deficient/Microsatellite Instability High Metastatic Colorectal Cancer: Update From CheckMate 142 Abstract #519 Overman MJ, Lonardi S, Leone F, McDermott