Abstract #TPS467 MORPHEUS: A Phase Ib/II Study Platform Evaluating the Safety and Clinical Efficacy Poster board #Q6 of –Based Combinations in Gastrointestinal Cancers Jayesh Desai,1 Jeremy Kortmansky,2 Neil Segal,3 Marwan Fakih,4 Do-Youn Oh,5 Kyu-Pyo Kim,6 Osama E. Rahma,7 Andrew H. Ko,8 Hyun Cheol Chung,9 Maria Alsina Maqueda,10 Kun-Huei Yeh,11 Shi Li,12 Nedal Al-Sakaff,13 Jilpa Patel,12 Hila Barak,12 Jun Wang,13 Xiaosong Zhang,12 Conrad Bleul,13 Edward Cha,12 Jeeyun Lee14 1Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; 2Yale School of Medicine, New Haven, CT; 3Memorial Sloan Kettering Cancer Center, New York, NY; 4City of Hope Comprehensive Cancer Center, Duarte, CA; 5Seoul National University Hospital, Seoul, Korea; 6Asan Medical Center, Seoul, Korea; 7Dana-Farber Cancer Institute, Boston, MA; 8University of California San Francisco, San Francisco, CA; 9Yonsei Cancer Center, Seoul, Korea; 10Vall d’Hebron Institute of Oncology, Barcelona, Spain; 11National Taiwan University Hospital and Cancer Center, Taipei, Taiwan; 12Genentech, Inc., South San Francisco, CA; 13F. Hoffmann-La Roche, Ltd, Basel, Switzerland; 14Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

BACKGROUND Table 2. Key Molecules to Be Evaluated in MORPHEUS GI Cancer Studies ENROLLMENT Molecules Target Proposed MOA Classification PDAC GC/GEJ CRC Combination Therapies to Treat Patients With Cancer • Patients will be randomized to one of the CIT combination arms or the standard-of-care control arm PD-L1 inhibitor; reactivation of anti-tumor immune response8 + + + • Effective anti-cancer therapies frequently require combinations of agents • Although significant survival benefits have been observed in response responses in more patients by converting the tumor microenvironment • In the preliminary phase of stage 1, most treatment arms will enroll 15 patients VEGF Angiogenesis inhibitor; recruitment of T cells to the TME and promotion of DC maturation11 + + + to target multiple molecular mechanisms simultaneously to monotherapy with programmed death-ligand 1 (PD-L1)/programmed (TME) from non-inflamed to inflamed1,7 --Depending on the CIT combination partners, some arms will have a safety run-in phase or recruit up to 40 patients 12 death-1 (PD-1) inhibitors,3-6 durable clinical benefit has been observed BL-8040 CXCR4 CXCR4 antagonist; recruitment of T cells to the TME + + NA in the preliminary phase • Cancer immunotherapy (CIT) aims to reactivate the cancer-immunity • The development of multiple combinatorial treatment options is necessary to cycle and enable a patient’s immune system to allow for effective only in subsets of patients Kinase inhibitor; T-cell survival and accumulation, immune recognition of tumor cells and --Treatment arms demonstrating clinical activity will enroll 25 additional patients in the expansion phase provide more-personalized, biomarker-guided treatment plans for patients MEK1/2 13 + + NA 1,2 TME recruitment anti-tumor immune responses • By targeting all immune evasion mechanisms of a patient’s tumor • Countries with clinical sites enrolling patients for the MORPHEUS GI cancer studies are shown in Figure 2 and listed in Table 4 simultaneously, CIT combinations may generate durable anti-tumor Stops or slows the growth of dividing cells; tumor-cell killing results in release of tumor Chemotherapy Cell cycle 14 + + NA and allows recognition by the immune system Figure 2. Countries With Enrollment Sites for the MORPHEUS-PDAC, MORPHEUS-GC/GEJ and MORPHEUS-CRC Studies β-glucan; activation of innate immune system through complement receptors, Fc receptors Imprime PGG PAMP NA NA + THE MORPHEUS PLATFORM and Dectin-115 • • The MORPHEUS platform is designed to identify early signals of clinical New treatment arms can be opened as novel combinations • Here we describe the MORPHEUS studies for patients with CD38 CD38-binding antibody; decrease in Tregs and restoration of CD8+ T-cell function16 NA NA + activity and establish proof-of-concept clinical data that support the become available gastrointestinal (GI) cancers: Linagliptin DPP-4 DPP-4 inhibitor; restores intra-tumoral chemotactic gradient and immune cell recruitment17,18 NA + NA development of combination treatments • Treatment arms that show minimal clinical activity or unacceptable --Pancreatic ductal adenocarcinoma (PDAC) PEGPH20 This comprehensive, adaptive platform consists of multiple, global, toxicity will be closed Hyaluronan Pegylated hyaluronidase; anti-stromal, extracellular matrix/TME modulation19 + + NA • --Gastric or gastroesophageal junction cancer (GC/GEJ) (pegvorhyaluronidase alfa) open-label, randomized, Phase Ib/II trials evaluating novel treatment • Safety and clinical activity data may be evaluated across tumor types and --Colorectal cancer (CRC) Engineered immunoglobulin-cytokine fusion protein; activation of immune effector cells and combinations in patients with different tumor types biomarker-defined populations to identify promising combinations with RO6874281 FAP-IL2v + + NA • Mechanistic, clinical and biomarker knowledge gained in tumor selective promotion of immune responses in the stroma of tumors that overexpress FAP20,21 --In each tumor type–specific MORPHEUS study, multiple CIT combination greater confidence type–specific studies can be applied to refine and improve other CD40 agonist; drives T-cell responses via activation of APCs and stimulates immune- arms will be compared with a single standard-of-care control arm to • Treatments currently being investigated in MORPHEUS platform studies Selicrelumab CD40 + + + MORPHEUS studies as well as future clinical studies mediated responses22,23 minimize the number of patients receiving control treatment (Figure 1) combine the immune atezolizumab (anti–PD-L1)8-10 --The MORPHEUS platform aims to evaluate CIT combinations more with targeted, immunotherapeutic and/or chemotherapeutic agents APC, -presenting cell; DC, dendritic cell; FAP-IL2v, fibroblast activation protein-α–targeted interleukin-2 variant; MOA, mechanism of action; NA, not applicable; PAMP, pathogen-associated molecular pattern; Treg, T regulatory cell; VEGF, vascular endothelial growth factor. efficiently than conventional trial designs

Figure 1. Trial Design of the MORPHEUS Platform Studies Table 3. CIT Combinations Evaluated in MORPHEUS Platform Studies

Screening Stage 1 Stage 2 PDAC GC/GEJ CRC Arma 1L Cohort 2L Cohort 1L Cohort 2L Cohort 3L Cohort Preliminary phase Expansion phase mFOLFOX-6 Nab- + gemcitabine or mFOLFOX-6b + paclitaxel PD / (SOC chemotherapy) Entry CIT combinations: Control nab-paclitaxel + gemcitabine re-entry CIT combinations: Indication biopsy R Experimental arm(s) Table 4. Enrollment Sites for MORPHEUS Studies biopsy Experimental arm(s) SOC chemotherapy + mFOLFOX-6b + atezolizumab + Atezolizumab + Imprime PGG + (stage 1) A Atezolizumab + cobimetinib Atezolizumab + RO6874281 Control (stage 2) atezolizumab + selicrelumab cobimetinib bevacizumab Proposed Countries PDAC GC/GEJ CRC Australia — — + Mandatory serial SOC chemotherapy + biopsy armsa B atezolizumab + selicrelumab + Atezolizumab + PEGPH20 mFOLFOX-6b + atezolizumab Atezolizumab + PEGPH20 Atezolizumab + isatuximab France — — + bevacizumab Germany + + — PD, progressive disease; R, randomization. Republic of Korea + + + Stage 1 SOC chemotherapy + Atezolizumab + selicrelumab + a In the MORPHEUS-GC/GEJ and MORPHEUS-CRC studies, the sponsor may open enrollment in separate mandatory serial biopsy arms with an experimental combination that has demonstrated clinical activity during the preliminary phase of the study for patients who are willing to undergo serial biopsies. The analysis of serial tissue samples will allow for a better C Atezolizumab + BL-8040 — Atezolizumab + BL-8040 understanding of the biological changes occurring during treatment. atezolizumab + bevacizumab bevacizumab Spain + + + SOC chemotherapy + D Atezolizumab + RO6874281 q2w — Atezolizumab + linagliptin — Taiwan — + — atezolizumab + United Kingdom — + + MORPHEUS GI CANCER STUDY DETAILS Atezolizumab + selicrelumab + E — Atezolizumab + RO6874281 q3w — — United States + + + Key Inclusion and Exclusion Criteria Agents Evaluated in MORPHEUS GI Cancer Studies bevacizumab • The following inclusion criteria apply to all MORPHEUS platform studies: • The following exclusion criteria apply to all MORPHEUS platform studies: • The CIT agents and targeted therapies evaluated in MORPHEUS GI F — Atezolizumab + emactuzumab — — — --Age ≥ 18 years --Symptomatic, untreated or actively progressing central nervous cancer studies are listed in Table 2 together with their proposed mechanism FURTHER INFORMATION -- system metastases of action (MOA) c c Measurable disease per Response Evaluation Criteria in Solid Tumors 2A NA Atezolizumab + cobimetinib NA Atezolizumab + RO6874281 NA • MORPHEUS-PDAC: https://clinicaltrials.gov/ct2/show/NCT03193190 (RECIST) version 1.1 (v1.1) --Treatment with investigational therapy ≤ 28 days prior to study • Table 3 lists the standard-of-care control arms and experimental CIT • MORPHEUS-GC/GEJ: https://clinicaltrials.gov/ct2/show/NCT03281369 combination arms evaluated in MORPHEUS-PDAC, MORPHEUS-GC/GEJ --Eastern Cooperative Oncology Group performance status of 0 to 1 treatment initiation Stage 2 2B — Atezolizumab + RO6874281 q3w — — — • MORPHEUS-CRC: https://clinicaltrials.gov/ct2/show/NCT03555149 and 0 to 2 for trial stages 1 and 2, respectively --Systemic treatments ≤ 14 days or 5 half-lives of the drug prior to study and MORPHEUS-CRC --Tumor accessible for biopsy treatment initiation • Patients in stage 1 who experience disease progression per RECIST v1.1, mFOLFOX-6, leucovorin + fluorouracil + oxaliplatin; q2w, every 2 weeks; q3w, every 3 weeks; SOC, standard of care. a Not all experimental arms may be open simultaneously. b Treatment arm currently closed (December 2018). c Patients with disease progression on the control arm have the option to be enrolled in the second-line cohort if they meet the relevant eligibility criteria. • Study-specific key eligibility criteria are listed in Table 1 unacceptable toxicity or loss of clinical benefit as determined by the REFERENCES investigator may be eligible to receive a different treatment combination --Additional study-, stage- and treatment arm–specific inclusion and 1. Chen DS, Mellman I. Immunity. 2013;39:1-10. 10. TECENTRIQ (atezolizumab) [summary of product characteristics]. 19. Infante JR, et al. Br J Cancer. 2018;118:153-161. during stage 2 Welwyn Garden City, UK: Roche Registration Ltd.; 2018. exclusion criteria apply Key Study Objectives and Endpoints 2. Hegde PS, et al. Clin Cancer Res. 2016;22:1865-1874. 20. Liao W, et al. Immunity. 2013;38:13-25. 3. Rittmeyer A, et al. Lancet. 2017;389:255-265. 11. Chen DS, Hurvitz H. Cancer J. 2018;24:193-204. 21. Liu R, et al. Cancer Biol Ther. 2012;13:123-129. Efficacy Additional Endpoints 4. Le DT, et al. N Engl J Med. 2015;372:2509-2520. 12. Feig C, et al. Proc Natl Acad Sci U S A. 2013;110:20212-20217. 22. Bedian V, et al. J Clin Oncol. 2006;24(18 suppl):2539. Table 1. Patient Populations and Study-Specific Key Eligibility Criteria 5. Powles T, et al. Lancet. 2018;391:748-757. 13. Ebert PJ, et al. Immunity. 2016;44:609-621. 23. Gladue RP, et al. J Clin Oncol. 2006;24(18 suppl):2514. • Primary endpoint: investigator-assessed objective response rate per RECIST v1.1 • Efficacy endpoints per alternative criteria: 6. Overman MJ, et al. Lancet Oncol. 2017;18:1182-1191. 14. Zitvogel L, et al. Immunity. 2013;39:74-88. 24. Hodi FS, et al. J Clin Oncol. 2018;36:850-858. PDAC GC/GEJ CRC 15. Ries CH, et al. Cancer Cell. 2014;25:846-859. Secondary endpoints: --Immune-modified RECIST24 7. Kim JM, Chen DS. Ann Oncol. 2016;27:1492-1504. 25. Seymour L, et al. Lancet Oncol. 2017;18:e143-e152. 1L Cohort 2L Cohort 1L Cohort 2L Cohort 3L Cohort • 8. Herbst RS, et al. Nature. 2014;515:563-567. 16. Feng X, et al. Clin Cancer Res. 2017;23:4290-4300. 25 --Investigator-assessed progression-free survival per RECIST v1.1 during stage 1 --Modified RECIST v1.1 for immune-based therapeutics 9. TECENTRIQ (atezolizumab) [package insert]. South San Francisco, 17. Casrouge A, et al. J Clin Invest. 2011;12:308-317. NCT number NCT03193190 NCT03281369 NCT03555149 CA: USA, Inc.; 2018. 18. Barreira da Silva R, et al. Nat Immunol. 2015;16:850-858. --Overall survival (OS) • Pharmacokinetics and immunogenicity Metastatic CRCa without BRAF mutation Patient population Metastatic PDACa Metastatic or locally advanced unresectable adenocarcinoma of the stomach or GEJa or microsatellite instability --Landmark OS (e.g., at 6, 12 and 18 months) • Biomarker analyses to understand the mechanisms of action and immune escape, as well as to identify predictive and surrogate biomarkers • Disease progression during treatment • No prior systemic therapy for the locally • Disease progression during or following • Disease progression during or following --Investigator-assessed duration of response per RECIST v1.1 during stage 1 ACKNOWLEDGMENTS --These analyses may include T-cell localization and activation in the TME using digital Inclusion criteria • No prior systemic therapy with 1L gemcitabine- or advanced or metastatic disease a 1L platinum- or fluoropyrimidine- 2 (but not more) separate lines of --Investigator-assessed disease control rate per RECIST v1.1 The patients and their families pathology, transcriptional profiling for evaluation of tumor immune biology, tumor PD-L1 • 5-FU–based chemotherapy • HER2-negative disease containing chemotherapy regimen treatment for metastatic CRC • The investigators and clinical study sites levels, tumor and plasma hyaluronan levels, microsatellite instability status, Epstein–Barr Safety • Industry partners BioLineRx, Ltd; Biothera Pharmaceuticals, Inc; Halozyme, Inc and S.A. Exclusion criteria • Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, including anti–CTLA-4, anti–PD-L1 and anti–PD-1 therapeutic antibodies virus status, genetic alteration of phosphoinositide 3-kinase/phosphatase and tensin • This study is sponsored by F. Hoffmann-La Roche, Ltd. Copies of this poster obtained through Quick Response (QR) Code are 1L, first line; 2L, second line; 3L, third line; 5-FU, 5-fluorouracil. • Incidence, nature and severity of adverse events (AEs) for personal use only and may not be reproduced without permission homolog pathway genes, blood tumor burden markers, circulating tumor DNA, Medical writing assistance for this poster was provided by Steffen Biechele, PhD, of Health Interactions, Inc, ® a Histologically or cytologically confirmed. • from ASCO and the author of this poster. • Occurrence and severity of study treatment–related AEs anti–β-glucan antibodies and systemic inflammation markers in blood and funded by F. Hoffmann-La Roche, Ltd. Corresponding author’s email address: [email protected]

Gastrointestinal Cancers Symposium (ASCO-GI) – January 17-19, 2019, San Francisco, CA, USA