Colorectal Cancer: Novel Insights

Colorectal Cancer: Novel Insights Richard Kim M.D. Associate Professor Service Chief of Medical Oncology Department of Gastrointestinal Oncology Moffitt Cancer Center Tampa, FL

Richard Kim, MD Colorectal Cancer: Novel Insights Relevant financial relationships in the past twelve months by presenter or spouse/partner. Grant/Research Support: Bayer, BMS, Taiho Consultant: BMS, Lilly, Bayer Speakers Bureau: Lilly 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. 15 th Annual Miami Cancer Meeting

Learning Objectives Know the current trend for treatment of advanced colorectal cancer Know the current status of personalized medicine in advanced CRC Know the differences between left vs right sided colon cancer

CRC US statistics: Impact of CRC 3 rd highest incidence rate (~135,000/yr) 2 nd highest mortality rate (~49,000/yr) CRC Global statistics: 3 rd highest incidence rate ( ~ 1.2million/yr) 4 th highest mortality rate (~608,000/yr) The burden of disease is clearly evident

A High Number of Agents Is Currently Available for the Treatment of mcrc 5-FU Capecitabine Irinotecan Oxaliplatin Bevacizumab Cetuximab Regorafenib Aflibercept Panitumumab TAS-102 Ramucirumab BSC

Landscape in mcrc Bevacizumab and EGFR mabs competing for firstline patients in KRAS wt CRC Bevacizumab, ramucirumab and Aflibercept competing for second-line patients with each other, and with EGFR mabs in KRAS wt CRC Best sequence of therapies (VEGFi vs EGFRi) still to be established Regorafenib and TAS 102 as salvage therapy option Immunotherapy for pts with MMR deficient/msi-h tumor

Tools for Treatment Selection Age PS Comorbidities Tumor burden Potential for cure? Symptoms? Tumor location Clinical Markers Molecular Markers Histologic grade CEA KRAS NRAS BRAF MSI/MMR Patient characteristics + Tumor characteristics

Questions How can biologics be used to their full potential? Prognostic markers -Biomarker that correlates with clinical outcome regardless of therapy Predictive markers-biomarker that is associated with the likelihood of response to therapy Can a patient population be identified which would benefit most from one specific treatment strategy?

Overview of EGFR and VEGFR Growth Signaling Pathways Tumor Cell Endothelial Cell VEGF EGFR KIT PDGFR-β VEGFR Targeted by cetuximab and panitumumab RAS Pl3K Targeted by bevacizumab ramucirumab and aflibercept* *Aflibercept also targets PIGF RAF BRAF MEK AKT ERK mtor ONCOGENESIS ANGIOGENESIS TUMOR MICROENVIRONMENT G.SM.ON.09.2013.0811 Krasinskas AM. Patholog Res Int. 2011;2011:932932; Sitohy B, et al. Cancer Res 2012;72:1909-1914; Bendardaf R, et al. Anticancer Res. 2008;28:3865-3870; Kitadai Y, et al. Am J Pathol. 2006;169:2054-2065; Jayson GC, et al. J Clin Oncol. 2005;23:973-981.

Biomarkers for anti- VEGF Drugs

Spectrum of ras mutations KRAS EXON 2 EXON 3 EXON 4 12 13 40% 59 61 117 3.3% 5.6% 146 NRAS EXON 2 EXON 3 EXON 4 12 13 3.5% 59 61 117 2.8% 0.9% 146

Updated Analysis of PRIME study KRAS exon 2 codon 12/13 KRAS exon 3 codon 61 KRAS exon 4 codon 117/146 NRAS exon 2 codon 12/13 NRAS exon 3 codon 61 BRAF exon 15 codon 600 40% 4% 6% 3% 4% 8% 17% Oliner et al., ASCO 2013

PRIME Biomarker Analysis: OS in Patients With WT KRAS Exon 2 and WT RAS mcrc Proportion Alive, % Proportion Alive, % WT KRAS Exon 2 WT KRAS Exon 2 FOLFOX4 alone (n=331) 100 Panitumumab FOLFOX4 alone + FOLFOX4 (n=331) (n=325) 100 Panitumumab + FOLFOX4 (n=325) 90 90 HR=0.83 (95% CI, 0.67-1.02) 80 HR=0.83 P=0.072 (95% CI, 0.67-1.02) 80 70 P=0.072 70 60 60 50 50 40 40 30 30 20 20 19.7 23.9 10 mos 19.7 mos 23.9 10 0 mos mos 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time, Months Time, Months FOLFOX4 alone (n=259) 100 Panitumumab FOLFOX4 alone + FOLFOX4 (n=259) (n=253) 100 90 Panitumumab + FOLFOX4 (n=253) 90 80 HR=0.78 (95% CI, 0.62-0.99) 80 HR=0.78 P=0.043 (95% CI, 0.62-0.99) 70 P=0.043 70 60 60 50 50 40 40 30 30 20 20 10 20.2 26.0 10 mos 20.2 mos 26.0 0 mos mos 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time, Months Time, Months Proportion Alive, % Proportion Alive, % WT KRAS/NRAS WT KRAS/NRAS Oliner J, et al. ASCO. 2013 (abstr 3511). Oliner J, et al. ASCO. 2013 (abstr 3511). 15 17

PRIME Biomarker Analysis: OS in Patients With MT RAS or WT KRAS Exon 2/MT Other RAS FOLFOX4 alone (n=276) 100 Panitumumab FOLFOX4 alone + FOLFOX4 (n=276) (n=272) 100 90 Panitumumab + FOLFOX4 (n=272) 90 80 HR=1.25 (95% CI, 1.02-1.55) 80 70 HR=1.25 P=0.034 (95% CI, 1.02-1.55) 70 P=0.034 60 60 50 50 40 40 30 30 20 20 15.6 19.2 10 mos 15.6 mos 19.2 10 0 mos mos 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time, Months Time, Months Proportion Alive, % Proportion Alive, % MT RAS MT RAS FOLFOX4 alone (n=57) 100 Panitumumab FOLFOX4 alone + FOLFOX4 (n=57) (n=51) 100 90 90 80 HR=1.29 (95% CI, 0.79-2.10) 80 HR=1.29 70 P=0.305 (95% CI, 0.79-2.10) 70 P=0.305 60 60 50 50 40 40 30 30 20 20 17.1 18.3 10 mos 17.1 mos 18.3 10 0 mos mos 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 Time, Months Time, Months Proportion Alive, % Proportion Alive, % WT KRAS Exon 2/MT Other RAS WT KRAS Exon 2/MT Other RAS Oliner J, et al. ASCO. 2013 (abstr 3511). Oliner J, et al. ASCO. 2013 (abstr 3511). 16 16

Take home point testing for these additional codons could help screen 20% more patients with mcrc for treatment with EGFR inhibitors This method could help to more accurately select patients who will benefit from EGFR inhibitors. NCCN now recommends testing for all RAS mutations

BRAF Mutations in CRC BRAF is primary effector of KRAS signaling BRAF mutations: Tumor Cell EGF Occur most frequently in exon 15 (V600E) Found in 4%-14% of patients with CRC P P P P Ras Raf Mutually exclusive with KRAS mutations MEK Tumor cell proliferation and survival Erk Yarden. Nat Rev Mol Cell Biol. 2001;2:127; Di Nicolantonio. J Clin Oncol. 2008;26:5705; Artale. J Clin Oncol. 2008;26:4217.

The Prognosis of Patients With BRAF V600E Mutations is Poor Roth AD, et al. J Clin Oncol. 2010;28(3):466-474. Tol J, et al. N Engl J Med. 2009;361(1):98-99.

Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406) Scott Kopetz, 1 Shannon McDonough, 2 Heinz-Josef Lenz, 3 Anthony Magliocco, 4 Chloe Atreya, 5 Luis A. Diaz Jr., 6 Carmen Allegra, 7 Kanwal Raghav, 1 Van Morris, 1 Stephen Wang, 8 Christopher Lieu, 9 Katherine A. Guthrie, 2 Howard S. Hochster 10 1 The University of Texas MD Anderson Cancer Center, Houston, TX; 2 Fred Hutchinson Cancer Research Center, Seattle, WA; 3 USC Norris Comprehensive Cancer Center, Los Angeles, CA; 4 H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 5 University of California, San Francisco, San Francisco, CA; 6 Memorial Sloan Kettering Cancer Center, NewYork, NY; 7 University of Florida, Gainesville, FL; 8 Kaiser Permanente, Sacramento, CA; 9 University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO; 10 Yale Cancer Center, New Haven, CT

Study Design R E G I S T R A T I O N Local BRAF testing No local BRAF testing BRAF V600E Mutation Central Testing Performed R A N D O M I Z A T I O N ARM 1: Cetuximab + Irinotecan ARM 2: Vemurafenib + Cetuximab + Irinotecan Progression Progression Off Study STEP 3: Cross-over to add Vemurafenib Off Study Wild-type (off study) Vemurafenib 960mg PO bid continuous Cetuximab 500mg/m2 IV q2weeks Irinotecan 180mg/m2 IV q2weeks Presented by: Scott Kopetz, MD, PhD

Primary Endpoint: Progression-free survival Presented by:

Conclusions The combination of vemurafenib, cetuximab, and irinotecan (VIC) met its primary endpoint demonstrating improved progression-free survival in patients with BRAF V600E CRC Addition of Vemurafenib to IC showed activity even after progression on IC VIC represents a new treatment for metastatic BRAF V600E colorectal cancer

What is the impact of site of primary tumour?

Primary Tumor Location and Potential Treatments Anti-PD1 Right-sided MSI-H Left-sided Bev + Triplet CT BRAF MT HER2+ HER2-targeted agents KRAS MT KRAS WT AREG/EREG Bufill JA. Ann Intern Med. 1990;113:779-788; Missiaglia E, et al. ASCO 2013. Abstract 3526; Brule SY, et al. ASCO 2013. Abstract 3528; The Cancer Genome Atlas Network. Nature. 2012490:61-70; Bendardaf R, et al. Anticancer Res. 2008;28:3865-3870.

CALGB/SWOG 80405: KRAS wt 1 ST LINE MET / ADVANCED COLORECTAL KRAS wt Codons 12 & 13 N = 1137 FOLFIRI or FOLFOX MD choice Chemo + Cetuximab Chemo OS = + 29.9 Cetuximab mos PFS = 10.4 mos : NO DIFFERENCE Chemo + Bevacizumab Chemo OS + = Bevacizumab 29.0 mos PFS = 10.8 mos PRESENTED AT THE 2014 ASCO ANNUAL MEETING DATA IS THE PROPERTY OF THE AUTHOR

Meta-analysis: Sidedness in MCRC Holch et al, Eur J Cancer, 2017 Favors LEFT Presented by:

Predictive impact bev versus anti-egfrs Chemo+anti-EGFR vs Chemo+Bev FIRE 3 CALGB PEAK RAS wt FOLFIR I+ BEV FOLFI R I+ CET RAS wt CHEMO + BEV CHEMO + CET RAS wt FOLFO X+ BEV FOLFO X+ PAN

FIRE-3 Tejpar et al., JAMA Oncol 2016

Right versus Left: PEAK OS Kaplan-Meier estimate 100 80 60 40 20 Median OS (95% CI), months Pmab + FOLFOX Beva + FOLFOX HR (95% CI) Left 43.4 (31.6 63.0) 32.0 (26.0 47.4) 0.84 (0.22 3.27) Right 17.5 (9.1 30.7) 21.0 (6.0 29.0) 0.45 (0.08 2.49) 1: Pmab + FOLFOX left 2: Beva + FOLFOX left 3: Pmab + FOLFOXright 4: Beva + FOLFOX right 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 No. of subjects: Overall survival (months) 1: 53 51 49 46 44 41 36 33 32 31 25 17 13 6 3 2 0 2: 54 51 48 44 43 40 35 31 26 21 17 13 10 5 3 2 0 3: 22 21 18 13 11 10 8 7 6 5 4 3 2 1 0 4: 14 12 11 11 7 6 4 3 1 0 Censor indicated by vertical bar Boeckx ESMO 2016; Peeters et al. Ann Oncol 2017. Apr 25. Epub ahead of print. Beva, bevacizumab; HR, hazard ratio; OS, overall survival; Pmab, panitumumab

Right versus Left: CALGB80405 study - OS 31% p for interaction0.009 Lenz et al. ESMO Congress 2016.

Minimal difference between bev and cetux in left sided tumors Venook A, ASCO 2017; abstract 3503

Take Home Points Left sided primary colorectal cancers have better prognosis than right sided colon cancers Right sided colorectal cancers do not benefit from anti-egfr therapy but do benefit from bevacizumab Left sided tumors benefit from both bevacizumab and anti- EGFR therapy

MSI-high CRC and Immune Checkpoint Blockade

Background In non selected colorectal cancer patients PD- 1 blockade seems to be ineffective. Average tumor has dozens of somatic mutations. Mismatch repair deficient tumors harbor thousands of mutations Somatic mutations have the potential to generate neo-antigiens which can be recognized by immune system.

Clinical Trial Design: Basket Trial Colorectal Cancer Noncolorectal Cancer Group A Mismatch-repair proficient (n = 25) Group B Mismatch-repair deficient (n = 25) Group C Mismatch-repair deficient (n = 21) Anti PD-1 antibody (Pembrolizumab): 10 mg/kg q 2 week Primary endpoint: Immune-related ORR and the 20-week immune-related PFS rate Mismatch-repair status was assessed in tumors with the use of the MSI Analysis System MSI, Microsatellite Instability Analysis System Le DT, et al. N Engl J Med. 2015;372(26):2509-2520.

Best Radiographic Response % Change from Baseline SLD 100 50 0-50 M M R-proficient CRC M M R -deficient CRC -100

Objective Responses According to RECIST Criteria RECIST, Response EvaluationCriteria in Solid Tumors Le DT, et al. N Engl J Med. 2015;372(26):2509-2520.

Progression-free Survival 100 MMR-deficient (mpfs = not reached) Percent survival 50 MMR-proficient (mpfs = 2.3 mos) 0 0 3 6 9 12 15 18 21 24 27 30 Time

100 Overall Survival MMR-deficient (mos = Not reached) Percent survival 50 MMR-proficient (mos = 5.98 mos) 0 0 3 6 9 12 15 18 21 24 27 30 Time

Nivolumab ± Ipilimumab in Treatment of Patients With Metastatic Colorectal Cancer With and Without High Microsatellite Instability: CheckMate 142 Interim Results Michael Overman, 1 Scott Kopetz, 1 Ray McDermott, 2 Joseph Leach, 3 Sara Lonardi, 4 Heinz-Josef Lenz, 5 Michael Morse, 6 Jayesh Desai, 7 Andrew Hill, 8 Michael Axelson, 9 Rebecca A. Moss, 9 Chen-Sheng Lin, 9 Monica Goldberg, 9 Thierry Andre 10 1 MD Anderson Cancer Center, Houston, TX, USA; 2 St Vincent s University Hospital, Dublin, Ireland; 3 Allina Health System, Minneapolis, MN, USA; 4 Istituto Oncologico Veneto IOV-IRCSS, Padova, Italy; 5 USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 6 Duke University Office of Research Administration, Durham, NC, USA; 7 Royal Melbourne Hospital, Victoria, Australia; 8 Tasman Oncology Research Pty Ltd, Southport, Queensland, Australia; 9 Bristol-Myers Squibb, Princeton, NJ, USA; 10 Hopital Saint Antoine, Paris, France

Phase 2 CheckMate 142 Study Design: MSI-H Cohort mstage 1 Responses a mstage 2 MSI-H Second-line colon MSI-H 7/19 Nivo 3 mg/kg (Q2W) 1 prior treatment for metastatic disease 1 target lesion ECOG PS of 0-1 Nivo 3 mg/kg (Q2W) Responses a cstage 1 Responses a cstage 2 b 3 6/19 Nivo 3 mg/kg + Ipi 1 mg/kg (Q3W x 4 doses) Then Nivo 3 mg/kg (Q2W) 7/19 Nivo 3 mg/kg + Ipi 1 mg/kg (Q3W x 4 doses) Then Nivo 3 mg/kg (Q2W) a In patients with centrally confirmed MSI-H status b Currently enrolling cstage 1 = combination therapy stage 1; cstage 2 = combination therapy stage 2; Ipi = ipilimumab; mstage 1 = monotherapy stage 1; mstage 2 = monotherapy stage 2; Nivo = nivolumab; Q2W = every 2 weeks; Q3W = every 3 weeks 47

Investigator-Assessed Best Overall Response in Patients With MSI-H Receiving Nivolumab Monotherapy ORR, n (%) (95% exact CI) Nivolumab 3 mg/kg (n = 47) a 12 (25.5) (15.4, 38.1) 100 75 50 Nivolumab 3 mg/kg Off treatment Nivolumab treatment ongoing 1 st occurrence of new lesion CR or PR % change truncated to 100 Complete response 0 Partial response 12 (25.5) Stable disease 14 (29.8) Progressive disease 17 (36.2) Change From Baseline (%) 25 0-25 -50 Unable to determine 4 (8.5) Median time to response, mo (range) Median duration of response, mo (range) 2.12 (1.3 13.6) NE (0.0 b 15.2 b ) -75-100 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Weeks Horizontal reference line indicates 30% reduction 48

Response and Disease Control ORR, n (%) 95% CI dmmr/msi-h per Local Laboratory (N = 74) Investigato r 23 (31.1) 20.8, 42.9 BICR 20 (27.0) 17.4, 38.6 dmmr/msi-h per Central Laboratory (n = 53) Investigato r 19 (35.8) 23.1, 50.2 BICR 17 (32.1) 19.9, 46.3 Best overall response, n (%) CR PR SD PD Unable to determine 0 23 (31.1) 29 (39.2) 18 (24.3) 4 (5.4) 2 (2.7) 18 (24.3) 28 (37.8) 20 (27.0) 6 (11.1) 0 19 (35.8) 21 (39.6) 10 (18.9) 3 (5.7) 1 (1.9) 16 (30.2) 21 (39.6) 12 (22.6) 3 (5.7) Disease control for 12 weeks, n (%) a 51 (68.9) 46 (62.2) 39 (73.6) 37 (69.8) BICR, blinded independent central review. a Patients with CR, PR, or SD for 12 weeks. Presented by: Dr Michael J. Overman

Overall Survival 100 90 80 Median OS [95% CI], months 12-month OS rate [95% CI], % NR [17.1, NE] 73.8 [59.8, 83.5] Probability of Survival (%) a 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 Months No. at risk 74 64 54 24 21 21 14 10 3 0 NR, not reached. a Patients evaluated as dmmr/msi-h by local laboratory. Presented by: Dr Michael J. Overman

Reduction in Target Lesion Size Regardless of PD-L1 Expression Tumor PD-L1 Expression Abundance of PD-L1 Expressing Tumor- Associated Immune Cells Investigator-Assessed Best Change in Target Lesion Size (%) 1% < 1% + Confirmed CR/PR Investigator-Assessed Best Change in Target Lesion Size (%) Rare Intermediate Numerous + Confirmed CR/PR ORR, n/n (%) Investigato r BICR ORR, n/n (%) Investigato r BICR Tumor PD-L1 expression 1% < 1% 7/20 (35.0) 6/21 (28.6) 11/45 13/45 (28.9) (24.4) Abundance of PD-L1 expressing immune cells Rare Intermediate Numerous 5/23 (21.7) 5/20 (25.0) 9/23 (39.1) 4/22 (18.2) 4/20 (20.0) 10/23 (43.5) Presented by: Dr Michael J. Overman

Patients Study Design Stage 1 Stage 2 Histologica lly confirmed metastatic/ recurrent CRC dmmr/msi-h per local laboratory 1 prior line of therapy MONOTH ERA PY ARM COMBINA TIO N ARM NIVO 3 mg/kg Q2W NIVO 3 mg/kg + IPI 1 mg/kgq3w (4 doses and then NIVO 3 mg/kgq2w) If 7/19 confirmed responders, continue enrollment Primary endpoint: ORR per investigator assessment (RECIST v1.1) If 7/19 confirmed responders, continue enrollment NIVO 3 mg/kg Q2W n = 74 NIVO 3 mg/kg + IPI 1 mg/kgq3w (4 doses and then NIVO 3 mg/kgq2w) n = 84 Other key endpoints: ORR per blinded independent central review (BICR), PFS, OS, and safety Current analysis included all patients (n = 84) who received their first dose 6 months prior to the data cut-off - Median (range) time from first dose to data cut-off: 8.6 (6.3-19.4) months ORR, overall response; OS, overall survival; PFS, progression-free survival Andre T, et al. J Clin Oncol. 2017;35(suppl): Abstract 3531.

Investigator-Assessed Best Overall Response in Patients With MSI-H Receiving Nivolumab + Ipilimumab Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg (n = 27) a Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg ORR, n (%) (95% exact CI) 11 (41.3) (18.6, 50.9) 100 75 Off treatment Nivolumab + ipilimumab treatment ongoing Complete response 1 50 1 st occurrence of new lesion CR or PR Partial response 10(37) Stable disease 14 (51.9) Progressive disease 2(7 ) Unable to determine 0 Change From Baseline (%) 25 0-25 -50 Median time to response, mo (range) 2.73 (1.2 6.9) -75 Median duration of response, mo (range) NE (NE NE) -100 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 a Patients with 12 weeks of follow-up b Includes censored observations CR = complete response; NE = not estimable; PR = partial response Weeks Horizontal reference line indicates 30% reduction 53

Event, n (%) Treatment-Related Adverse Events in 15% of Patients With MSI-H Nivolumab 3 mg/kg (n = 70) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg (n = 30) Any grade Grade 3 4 Any grade Grade 3 4 Any event 41 (58.6) a 10 (14.3) 25 (83.3) 8 (26.7) Fatigue 13 (18.6) 1 (1.4) 6 (20.0) 0 Diarrhea 10 (14.3) 1 (1.4) 13 (43.3) 0 Pruritus 8 (11.4) 0 5 (16.7) 1 (3.3) Nausea 5 (7.1) 0 6 (20.0) 0 Pyrexia 3 (4.3) 0 7 (23.3) 0 Any event leading to discontinuation a One Grade 5 event of sudden death 4 (5.7) 2 (2.9) 4 (13.3) 4 (13.3) 57

Question?? Can we convert non-immunogenic tumor into immunogenic tumor?

PD-L1 and MEK Inhibition: A Rational Combination MEK inhibition alone can result in intratumoral T-cell accumulation and MHC I upregulation, and synergizes with an anti-pdl1 agent to promote durable tumor regression 1 CD8 + T cell per tumor cell Class I MHC P = 0.0024 Tumor volume (mm 3 ) Control Anti-PDL1 MEKi (38963) MEKi + anti-pdl1 ND MEKi ND MEKi Day To examine the possible benefits of MEK inhibition with an anti-pdl1 agent, we evaluated cobimetinib + atezolizumab in patients with advanced solid tumors MHC, major histocompatibility complex; ND, no drug (vehicle alone). CT26 (KRASmt) CRC models. 1. Ebert et al. Immunity 2016. Bendell J, et al. Cobimetinib and atezolizumab in CRC. ASCO 2016 59

Cobimetinib + Atezolizumab in CRC: Phase Ib Dose Escalation and Cohort Expansion Study a Cobimetinib was administered on 21 days on/7 days off dosing schedule. Atezo, atezolizumab; cobi, cobimetinib; DLT, drug limited toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; KRASmt, KRAS mutant; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer Bendell J, et al. J Clin Oncol. 2016;34(suppl): Abstract 3502.

Efficacy: Change Maximum SLD Reduction From Baseline, % 50 40 20 0-20 -40-60 -80 PD PD TC 3 PD PD PD PD in Tumor Burden PD PD PD PD PD SD SD SD PD SD SD PR T C0 PR PR T C0 TC N A PR T C0 PD-L1 IC status NA IC0 IC1 IC2 IC3 4 patients had partial responses (confirmed per RECIST v1.1) MSI status of CRC patients was examined by NGS-based scoring: 3 of 4 responders were mismatch-repair proficient (not MSI-H); 1 responder had unknown MSI status and was not evaluable Tumor volume reduction was not associated with PD-L1 status: TC3 (n = 1; PD), TC0 (n = 18), NA (n = 4) PD-L1 IHC status on tumor cells (TC) and tumor-infiltrating immune cells (IC) defined as: TC3 = TC 50% PD-L1+ cells; IC3 = IC 10% PD-L1+ cells; TC2 = TC 5% and < 50% PD-L1+ cells; IC2 = IC 5% and < 10% PD-L1+ cells; TC1 = TC 1% and < 5% PD-L1+ cells; IC1 = IC 1% and < 5% PD-L1+ cells; TC0 = TC < 1% PD-L1+ cells; IC0 = IC < 1% PD-L1+ cells. NA, not available; NGS, next generation sequencing. Efficacy-evaluable patients. 2 patients missing or unevaluable are not included. Data cut-off February 12, 2016. Bendell J, et al. Cobimetinib and atezolizumab in CRC. ASCO 2016 61

Efficacy: Change in Tumor Burden Over Time Change in Sum of Longest Diameters from Baseline, % PD SD PR/CR a Discontinued atezolizumab New lesion Median duration of response was not reached (range: 5.4 to 11.1+ mo) Responses are ongoing in 2 of 4 responding patients Time on Study (mo) a Confirmed per RECIST v1.1. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. Efficacy-evaluable patients. 2 patients missing or unevaluable are not included. Data cut-off February 12, 2016. Bendell J, et al. Cobimetinib and atezolizumab in CRC. ASCO 2016 62

Phase Ib Dose Escalation and Cohort Expansion Study (NCT01988896) Presented By Johanna Bendell at 2018 Gastrointestinal Cancers Symposium

Duration of Response Presented By Johanna Bendell at 2018 Gastrointestinal Cancers Symposium

Progression-Free Survival and Overall Survival Presented By Johanna Bendell at 2018 Gastrointestinal Cancers Symposium

COTEZO IMblaze-370: Phase 3 Trial Atezolizumab With and Without Cobimetinib vs Regorafenib Atezolizumab + cobimetinib 840 mg IV days 1, 15 + 60 mg days 1-21 Eligibility Criteria: mcrc 2 prior therapies Progression on or within 3 months of prior therapy ECOG PS 0-1 N = 360 2:1:1 R Atezolizumab 1200 mg IV on day 1 28 day cycle Treatment until: Disease progression, unacceptable toxicity, or death Regorafenib 160 mg per d Days 1-21; 28 day cycle Outcomes Primary endpoint: OS Secondary endpoint: PFS, ORR, DOR, QoL, safety 1, https://clinicaltrials.gov/ct2/show/nct02788279

Summary VEGF and EGFR mabs competing for first-line patients in RAS wt CRC For anti-egfr treatment, all RAS tests are required Primary tumor location is related to effect of cetuximab Bevacizumab, Ramucirumab and Aflibercept competing for second-line patients with each other, and with EGFR mabs in KRAS wt CRC

Summary Best sequence of therapies (VEGFi vs EGFRi) still to be established Regorafenib and TAS 102 as salvage therapy option Checkpoint inhibitors are highly active in select molecular subsets Rationale combination maybe able to covert cold tumor to hot tumor

Thank you! GI oncology questions Richard.kim@moffitt.org