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Phase Ib Study Results: Subgroup Efficacy Analysis of Atezolizumab + Bevacizumab in Patients With Previously Untreated, Unresectable Hepatocellular Carcinoma.

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Disclosures

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  1. Phase Ib Study Results: Subgroup Efficacy Analysis of Atezolizumab + Bevacizumab in Patients With Previously Untreated, Unresectable Hepatocellular Carcinoma Kyung-Hun Lee,1 Baek-Yeol Ryoo,2 Chih-Hung Hsu,3 Kazushi Numata,4 Stacey Stein,5 Wendy Verret,6 Steve Hack,6 Jessica Spahn,6 Bo Liu,6 Heba Abdullah,6 Aiwu Ruth He,7 Michael S Lee8 1 Seoul National University Hospital, Seoul, South Korea; 2Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 3 National Taiwan University Hospital, Taipei, Taiwan; 4 Yokohama City University Medical Center, Yokohama, Japan; 5 Yale School of Medicine, New Haven, CT, USA; 6 Genentech, Inc., South San Francisco, CA, USA; 7 Georgetown University Medical Center, Washington, DC, USA; 8 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

  2. Disclosures • Advisory board: Bayer, Ono Pharmaceutical, Samsung Bioepis, Roche, Eisai, AstraZeneca • Honoraria: Roche, AstraZeneca • This study is sponsored by F. Hoffmann-La Roche, Ltd

  3. Background • Approximately 80% of patients with HCC present with unresectable cancer,1 usually complicated by underlying liver disease1,2 • VEGFR tyrosine kinase inhibitors are the first-line systemic standard of care for unresectable or metastatic HCC2,3 • Associated with modest survival benefits and considerable toxicities2,3 • Unconfirmed ORRs per RECIST 1.1 were 19% with lenvatinib and 7% with sorafenib3 • Single-agent PD-L1/PD-1 immune checkpoint inhibitors have shown clinical activity against HCC, but not yet superiority over standards of care, in randomised studies4,5 • Many HCC tumors are hypervascularised and overexpress VEGF and PD-L16,7 • The anti-VEGF monoclonal antibody bevacizumab showed modest single-agent activity in HCC8 • In addition to anti-angiogenic activity, bevacizumab’s immunomodulatory effects alter the tumour microenvironment and may boost anti–PD-L1-mediated anti-tumour response9-11 • Dual blockade of PD-L1 and VEGF has shown clinical benefit in other tumour types12-14 1. Lau WY, et al. An Surg. 2001; 2. Villanueva A, et al. NEJM. 2019; 3. Kudo M, et al. Lancet. 2018; 4. Finn RS, et al. JCO. 2019 (abstract 4004); 5. BMS press release. https://www.clinicaltrialsarena.com/news/bms-checkmate-459-trial/. 2019; 6. Morse MA, et al. CCR. 2019; 7. Gao Q, et al. CCR. 2009; 8. Wattenberg MM, et al. Cancer Med. 2019; 9. Motz GT, et al. Nat Med. 2014; 10. Roland CL, et al. Mol Can Ther. 2009; 11. Voron T, et al. J Exp Med. 2015; 12. Reck M, et al. Lancet Respir Med. 2019; 13. Wallin JJ, et al. Nat Commun. 2016; 14. McDermott DF, et al. JCO 2016.

  4. Phase Ib GO30140 Study Design (NCT02715531) • Eligibility Criteria: • Measurable disease per RECIST 1.1 • ECOG PS 0/1 • Adequate haematologic and organ function • No prior systemic therapy • No prior treatment with anti–CTLA-4, anti–PD-1 or anti–PD-L1 antibodies • Arm A:Unresectable HCC (n = 104) • Up to Child-Pugh score B7 • Atezolizumab 1200 mg IV q3w + bevacizumab 15 mg/kg IV q3w Until disease progression, unacceptable toxicity or loss of clinical benefit Survival follow-up Arm B: Gastric cancer Arm C: Pancreatic cancer Arm E: Oesophageal cancer Arm F: Randomized first-line HCC (atezolizumab + bevacizumab vs atezolizumab) At clinical data cutoff (14 June 2019), 104 patients with HCC treated with atezolizumab + bevacizumab in Arm Awere evaluable for safety and efficacy with a median follow-up of 12.4 months HCC mRECIST, HCC modified Response Evaluation Criteria in Solid Tumours; INV, investigator; IRF, independent review facility.

  5. Baseline Demographics and Clinical Characteristics a Includes the United States, Australia, New Zealand, and Japan. Data cutoff: 14 June 2019.Lee MS, et al. Liver Cancer 2019;8:207 (abstract O-034).

  6. Clinical Activity with Atezolizumab + Bevacizumab DCR, CR + PR + SD; NE, not estimable; +, censored. Data cutoff: 14 June 2019.Lee MS, et al. Liver Cancer 2019;8:207 (abstract O-034).

  7. Progression Free Survivaland Overall Survival Summary Data cutoff: 14 June 2019.

  8. Subgroup Analysis: Demographic Characteristics ORR a ORR by IRF RECIST 1.1. b 95% CIs were constructed using Clopper Pearson method.Data cutoff: 14 June 2019.

  9. Subgroup Analysis: HCC Characteristics ORR a ORR by IRF RECIST 1.1. b 95% CIs were constructed using Clopper Pearson method.c Non-viral HCC etiology includes unknown non-hepatitis B and C cause. d Includes patients with bile duct invasion, main portal vein invasion and/or liver occupancy ≥ 50%. Data cutoff: 14 June 2019.

  10. Subgroup Analysis: PD-L1 Status Patients ORR IC, tumour-infiltrating immune cells; TC, tumour cells. a ORR by IRF RECIST 1.1. b 95% CIs were constructed using Clopper Pearson method. c PD-L1 testing was based on IHC SP263;86 patients were evaluable for PD-L1 status. Data cutoff: 14 June 2019.

  11. Baseline Characteristics of Complete Responders a Per IRF-assessed RECIST 1.1.. Data cutoff: 14 June 2019.

  12. Safety Summary: Atezolizumab + Bevacizumab a Grade 5 treatment-related adverse events: abnormal hepatic function, hepatic cirrhosis and pneumonitis. Data cutoff: 14 June 2019.

  13. Adverse Events of Special Interest in ≥ 5% of Patients • Fifteen patients (14%) on the combination atezolizumab + bevacizumab required systemic corticosteroids within 30 days of an atezolizumab AESI • The most common hepatic events requiring systemic corticosteroid within 30 days of AE were increased AST (3%) and ALT (3%) levels • Bevacizumab bleeding AESIs included:- Upper gastrointestinal haemorrhageb Any grade = 3 (3%) Grade 3-4 = 2 (2%)-Oesophageal varices haemorrhage Any grade = 2 (2%) Grade 3-4 = 2 (2%) a Regardless of causality of an individual event. b Includes 1 unrelated Grade 5 event. Data cutoff: 14 June 2019.

  14. Summary • Clinically meaningful and durable objective responses were observed • Confirmed ORR with atezolizumab + bevacizumab was36% per IRF-assessed RECIST 1.1 • 76% of responses per IRF-assessed RECIST 1.1 are ongoing and the median duration ofresponsewas not reached • 12% of patients achieved CR per IRF-assessed RECIST 1.1 • Results were consistent across RECIST assessments • Benefit of atezolizumab + bevacizumab was generally consistent among subgroups analysed • Clinical activity was observed irrespective of PD-L1 status • Combination of atezolizumab + bevacizumab was generally well tolerated and toxicities were manageable • No new safety signals were identified beyond the established single-agent safety profiles • Atezolizumab + bevacizumab may become a promising treatment option for patients with unresectable HCC • This combination is being evaluated further in the IMbrave150 Phase III study (NCT03434379) Data cutoff: 14 June 2019.

  15. Acknowledgements and Study Investigators • The patients and their families and caregivers • Participating study investigators and clinical sites • This study is sponsored by F. Hoffmann-La Roche, Ltd. • Medical writing assistance for this oral presentation was provided by Samantha Santangelo, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd. Y Bang J Bendell Y Chao J Chen H Chung S Davis A Dev E Gane B George R He H Hochstera C Hsu M Ikeda J Lee M Lee A Mahipal G Manji M Morimoto K Numata M Pishvaiana S Qin D Ryan B Ryoo N Sasahira S Stein J Strickler N Tebbutt a Previous investigators.

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