ESMO 2018 - Update Axel Grothey West Cancer Center, U Tennessee - PowerPoint PPT Presentation

ESMO 2018 - Update Axel Grothey West Cancer Center, U Tennessee

Disclosures • Consulting activities (honoraria went to the Mayo Foundation or West Cancer Center) • Amgen • Bayer • Pfizer • Roche/Genentech • BMS • Imclone/Eli-Lilly • Boston Biomedicals • ARRAY I WILL include discussion of investigational or off-label use of a product in my presentation.

Notable Presentations • Colorectal Cancer • CheckMate 142 - Phase 2 trial of Nivo/ Ipi as first-line therapy in MSI-H/ MMR-D mCRC Lenz et al • MODUL Cohort 2 - Randomized phase 3 trial of maintenance FP/ Atezo/ Bev vs FP/ BEV in first-line mCRC Grothey et al • TRIBE-2 - Phase 3 trial of first-line FOLFOXIRI/ BEV vs Sequentail FOLFOX/ FOLFIRI + BEV in mCRC Cremolini et al • Non-CRC • TAGS - Phase 3 trial of TAS-102 vs placebo in refractory mCRC Arkenau et al • Phase Ib trial of Atezo/ BEV as first-line therapy in uHCC Pishvaian et al

HIGHLY CONFIDENTIAL Durable Clinical Benefit With Nivolumab Plus Low-Dose Ipilimumab as First-Line Therapy in Microsatellite Instability-High/Mismatch Repair Deficient Metastatic Colorectal Cancer Heinz-Josef Lenz, 1 Eric Van Cutsem, 2 Maria Luisa Limon, 3 Ka Yeung Mark Wong, 4 Alain Hendlisz, 5 Massimo Aglietta, 6 Pilar García-Alfonso, 7 Bart Neyns, 8 Gabriele Luppi, 9 Dana B. Cardin, 10 Tomislav Dragovich, 11 Usman Shah, 12 Ajlan Atasoy, 13 Roelien Postema, 13 Zachary Boyd, 13 Jean- Marie Ledeine, 13 Michael James Overman, 14 Sara Lonardi 15 1 USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 2 University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; 3 Hospital Universitario Virgen del Rocio, Sevilla, Spain; 4 Westmead Hospital, Sydney, Australia; 5 Institut Jules Bordet, Brussels, Belgium; 6 Candiolo Cancer Institute and University of Torino Medical School, Candiolo, Italy; 7 Hospital Gral Universitario Gregorio Marañon, Madrid, Spain; 8 University Hospital Brussels, Brussels, Belgium; 9 University Hospital of Modena, Modena, Italy; 10 Vanderbilt – Ingram Cancer Center, Nashville, TN, USA; 11 Banner MD Anderson Cancer Center, Gilbert, AZ, USA; 12 Lehigh Valley Hospital, Allentown, PA, USA; 13 Bristol-Myers Squibb, Princeton, NJ, USA; 14 The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 15 Istituto Oncologico Vento IOV-IRCSS, Padova, Italy Presentation number: LBA18_PR

CheckMate-142 CheckMate-142 Study Design • CheckMate-142 is an ongoing, multi-cohort, nonrandomized phase 2 study evaluating the efficacy and safety of nivolumab-based therapies in patients with mCRC (NCT02060188) Previously treated Nivolumab 3 mg/kg Q2W a • Histologically Primary endpoint: confirmed Nivolumab 3 mg/kg + • ORR per investigator metastatic or Previously treated assessment (RECIST v1.1) ipilimumab 1 mg/kg Q3W recurrent CRC (4 doses and then Other key endpoints: nivolumab 3 mg/kg Q2W) a ORR per BICR, DCR b , • • MSI-H/dMMR per DOR, PFS, OS, and safety local laboratory 1L Nivolumab 3 mg/kg Q2W + N=45 ipilimumab 1 mg/kg Q6W a • Median follow-up for the 1L nivolumab plus low-dose ipilimumab cohort was 13.8 months (range, 9–19) c a Until disease progression or discontinuation in patients receiving study therapy beyond progression, discontinuation due to toxicity, withdrawal of consent, or the study end; b Patients with a CR, PR, or SD for ≥12 weeks divided by the number of treated patients; c Time from first dose to data cutoff BICR = blinded independent central review; CR = complete response; CRC = colorectal cancer; DCR = disease control rate; DOR = duration of response; PFS = progression-free survival; PR = partial response; 5 Q2W = once every 2 weeks; Q3W = once every 3 weeks; Q6W = once every 6 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease

CheckMate-142 Response and Disease Control Nivolumab + ipilimumab Nivolumab + ipilimumab Investigator-assessed Investigator-assessed N = 45 N = 45 ORR a , n (%) ORR a , n (%) 27 ( 60 ) 27 ( 60 ) [44.3–74.3] [44.3–74.3] [95% CI] [95% CI] Best overall response, n (%) Best overall response, n (%) 3 ( 7 ) 3 ( 7 ) CR CR 24 (53) 24 (53) PR PR 11 (24) 11 (24) SD SD 6 (13) 6 (13) PD PD 1 (2) 1 (2) Not determined Not determined DCR b , n (%) DCR b , n (%) 38 ( 84 ) 38 ( 84 ) [70.5–93.5] [70.5–93.5] [95% CI] [95% CI] • Responses were observed regardless of tumor PD-L1 expression, BRAF or KRAS mutation status, or diagnosis of Lynch syndrome – The ORR and DCR in patients with a BRAF mutation (n = 17) were 71% and 88%, respectively a Patients with CR or PR divided by the number of treated patients; b Patients with a CR, PR, or SD for ≥12 weeks divided by the number of treated patients 6 CI = confidence interval

CheckMate-142 Best Reduction in Target Lesions 100 75 Best reduction from baseline 50 in target lesion (%) 25 0 –25 –30% * * * * * –50 * * * * * * * * * * * * * –75 * * * * –100 * * * * * Patients a • 84% of patients had a reduction in tumor burden from baseline *Confirmed response per investigator assessment 7 a Evaluable patients per investigator assessment

CheckMate-142 Characterization of Response • Median time to response was 2.6 months (range, 1.2–13.8 months) • Responses were durable: – Median DOR was not reached Responders (n = 27) a – 82% of responders had ongoing responses at data cutoff – 74% of responders have already had responses lasting ≥6 months On treatment – Most responders (96%) were alive at data cutoff Off treatment First response Censored with ongoing response Censored † † Death 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Weeks a Response per investigator assessment 8

CheckMate-142 Progression-Free and Overall Survival Nivolumab + ipilimumab Nivolumab + ipilimumab Nivolumab + ipilimumab Nivolumab + ipilimumab Nivolumab + ipilimumab OS a OS a PFS a PFS a N = 45 N = 45 N = 45 N = 45 Median OS, months (95% CI) Median OS, months (95% CI) NR (NE) NR (NE) Median PFS, months (95% CI) Median PFS, months (95% CI) NR (14.1–NE) NR (14.1–NE) 9-mo rate (95% CI), % 9-mo rate (95% CI), % 89 (74.9–95.1) 89 (74.9–95.1) 9-mo rate (95% CI), % 9-mo rate (95% CI), % 77 (62.0–87.2) 77 (62.0–87.2) 12-mo rate (95% CI), % 12-mo rate (95% CI), % 83 (67.6–91.7) 83 (67.6–91.7) 12-mo rate (95% CI), % 12-mo rate (95% CI), % 77 (62.0–87.2) 77 (62.0–87.2) 100 Progression-free survival (%) 90 90 Overall survival (%) 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 21 Months Months No. at risk 45 37 34 24 15 7 7 45 42 40 38 24 13 1 0 a Per investigator assessment. 9 mo = month; NE = not estimable; NR = not reached

CheckMate-142 Summary and Conclusions • Nivolumab (Q2W) plus low-dose ipilimumab (Q6W) demonstrated robust and durable clinical benefit as a 1L treatment for MSI-H/dMMR mCRC – High ORR (60%, with 7% CR) – Durable responses (median DOR not reached) – High rate of disease control for ≥12 weeks (84%) – Most patients had a reduction in tumor burden from baseline (84%) – Median PFS and OS not reached with a median follow-up of 14 months – 12-month PFS and OS rates were 77% and 83%, respectively • Nivolumab plus low-dose ipilimumab was well-tolerated (grade 3–4 TRAEs, 16%) with a low rate of discontinuation due to TRAEs (7%) • Nivolumab plus low-dose ipilimumab may represent a new 1L treatment option for patients with MSI-H/dMMR mCRC 10

Fluoropyrimidine (FP) and bevacizumab � atezolizumab as first-line treatment for BRAF wt metastatic colorectal cancer: findings from the MODUL trial of biomarker-driven maintenance Grothey A, 1 Tabernero J, 2 Arnold D, 3 de Gramont A, 4 Ducreux M, 5 O’Dwyer PJ, 6 Van Cutsem E, 7 Bosanac I, 8 Srock S, 8 Mancao C, 8 Gilberg F, 8 Winter J, 8 Schmoll H-J 9 1 West Cancer Center, Germantown, TN, USA; 2 Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 3 Asklepios Clinic Altona, Hamburg, Germany; 4 Franco-British Institute, Levallois-Perret, France; 5 Gustave Roussy, Villejuif, Université Paris Saclay, France; 6 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 7 University Hospitals Gasthuisberg, Leuven and KU Leuven, Leuven, Belgium; 8 F. Hoffmann-La Roche Ltd, Basel, Switzerland; 9 Martin-Luther-University, Halle, Germany esmo.org

12 Rationale for combined PD-L1 and VEGF inhibition • In combination, bevacizumab may enhance atezolizumab’s efficacy by reversing VEGF-mediated immunosuppression to promote T-cell infiltration into the tumour Bevacizumab Normalizes the tumour vasculature, Atezolizumab increasing T-cell infiltration 2-6 Activated Promotes T-cell activation by allowing B7.1 co-stimulation 1 T cells Bevacizumab Decreases the activity of Dendritic immunosuppressive cells (MDSCs and Tumour cells Tregs) 2,3,7-10 cells Tumour Atezolizumab antigens Restores anticancer immunity 1 with activity further enhanced through VEGF- mediated immunomodulatory effects Bevacizumab Promotes DC maturation 2,11,12 1. Chen & Mellman 2013; 2. Hegde et al. 2018; 3. Wallin et al. 2016 DC, dendritic cell; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell 4. Goel et al. 2011; 5. Motz et al. 2014; 6. Hodi et al. 2014 7. Gabrilovich & Nagaraj 2009; 8. Roland et al. 2009; 9. Facciabene et al. 2011 10. Voron et al. 2015; 11. Gabrilovich et al. 1996; 12. Oyama et al. 1998