Phase Ib Study Results: Subgroup Efficacy Analysis of Atezolizumab + - - PowerPoint PPT Presentation

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Phase Ib Study Results: Subgroup Efficacy Analysis of Atezolizumab + - - PowerPoint PPT Presentation

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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

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

13th Annual Conference

20 ► 22 September 2019 Chicago, USA

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; 2 Asan 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

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

Disclosures

  • Advisory board: Bayer, Ono Pharmaceutical, Samsung

Bioepis, Roche, Eisai, AstraZeneca

  • Honoraria: Roche, AstraZeneca
  • This study is sponsored by F. Hoffmann-La Roche, Ltd

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

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
  • r 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.

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

Phase Ib GO30140 Study Design (NCT02715531)

HCC mRECIST, HCC modified Response Evaluation Criteria in Solid Tumours; INV, investigator; IRF, independent review facility.

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At clinical data cutoff (14 June 2019), 104 patients with HCC treated with atezolizumab + bevacizumab in Arm A were evaluable for safety and efficacy with a median follow-up of 12.4 months

Until disease progression, unacceptable toxicity or loss of clinical benefit Eligibility Criteria:

  • Measurable disease per RECIST 1.1
  • ECOG PS 0/1
  • Adequate haematologic and
  • rgan 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 Arm B: Gastric cancer Arm C: Pancreatic cancer Arm E: Oesophageal cancer Arm F: Randomized first-line HCC (atezolizumab + bevacizumab vs atezolizumab) Primary endpoints (Arm A)

  • IRF-assessed ORR per RECIST 1.1, safety

Key secondary endpoints (Arm A)

  • DOR and PFS per IRF RECIST 1.1
  • ORR, DOR and PFS per IRF HCC mRECIST
  • ORR, DOR and PFS per INV-assessed RECIST 1.1
  • OS

Survival follow-up

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

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).

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Characteristic Arm A: Atezolizumab + bevacizumab N = 104 Median age (range), years 62 (23-82) Sex, male, n (%) 84 (81) Region, n (%) Asia (excluding Japan) 59 (57) Rest of worlda 45 (43) ECOG PS 1, n (%) 52 (50) Child-Pugh class, n (%) A5 | A6 | B7 77 (74) | 21 (20) | 6 (6) Aetiology of HCC, n (%) HBV | HCV | Non-viral 51 (49) | 31 (30) | 22 (21) AFP ≥ 400 ng/mL, n (%) 37 (36) EHS, n (%) 74 (71) MVI, n (%) 55 (53) EHS and/or MVI, n (%) 91 (88) Prior TACE, n (%) 56 (54) Prior radiotherapy, n (%) 20 (19)

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

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).

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Arm A: Atezolizumab + Bevacizumab (N = 104)

IRF RECIST 1.1 IRF HCC mRECIST INV RECIST 1.1 Confirmed ORR, n (%) (95% CI) 37 (36) (26 – 46) 41 (39) (30 – 50) 34 (33) (24 – 43) CR, n (%) 12 (12) 16 (15) 3 (3) PR , n (%) 25 (24) 25 (24) 31 (30) DCR, n (%) 74 (71) 74 (71) 78 (75) Ongoing response, n (%) n = 37 28 (76) n = 41 28 (68) n = 34 24 (71) Median DOR, mo (95% CI) NE (11.8 – NE) NE (11.8 – NE) NE (11.7– NE) DOR range, mo 1.6+ to 31.0+ 1.6+ to 31.0+ 3.5 to 31.0+ ≥ 9 mo, n (%) 20 (54) 25 (61) 21 (62) ≥ 12 mo, n (%) 11 (30) 11 (27) 12 (35)

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

Progression Free Survival and Overall Survival Summary

Arm A: Atezolizumab + Bevacizumab (N = 104) Progression Free Survival

IRF RECIST 1.1 IRF HCC mRECIST INV RECIST 1.1

  • No. of events (%)

69 (66) 69 (66) 75 (72) Median PFS (95% CI), mo 7.3 (5.4 – 9.9) 7.3 (5.4 – 9.9) 7.4 (5.6 – 10.7) 6-month PFS rate (%) 54 55 56 12-month PFS rate (%) 35 35 38

Overall Survival

  • No. of deaths (%)

47 (45) Median OS (95% CI), mo 17.1 (13.8 – NE) 6-month OS rate (%) 82 12-month OS rate (%) 63

Data cutoff: 14 June 2019.

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

Subgroup Analysis: Demographic Characteristics

a ORR by IRF RECIST 1.1. b 95% CIs were constructed using Clopper Pearson method.

Data cutoff: 14 June 2019.

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Patients, n Responders, n ORR,a % 95% CIb All 104 37 36 26–46 Age < 65 years 67 25 37 26–50 ≥ 65 years 37 12 32 18–50 Sex Male 84 30 36 26–47 Female 20 7 35 15–59 Region Asia (excluding Japan) 59 19 32 21–46 Rest of world 45 18 40 26–56 ECOG PS 52 23 44 31–59 1 52 14 27 16–41

0% 20% 40% 60% 80% 100% ORR

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

Subgroup Analysis: HCC Characteristics

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.

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Patients Responders ORR,a % 95% CIb All 104 37 36 26–46 HCC etiology Hepatitis B 51 17 33 21–48 Hepatitis C 31 16 52 33–70 Non-viralc 22 4 18 5–40 AFP level < 400 ng/ml 60 23 38 26–52 ≥ 400 ng/ml 37 13 35 20–53 Extra-hepatic spread Yes 74 21 28 19–40 No 30 16 53 34–72 Macrovascular invasion Yes 55 16 29 18–43 No 49 21 43 29–58 EHS and/or MVI Yes 91 29 32 23–43 No 13 8 62 32–86 High-risk diseased Yes 26 9 35 17-56 No 78 28 36 25-48

0% 20% 40% 60% 80% 100% ORR

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

Subgroup Analysis: PD-L1 Status

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;

Data cutoff: 14 June 2019. 86 patients were evaluable for PD-L1 status.

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Responders ORR,a % 95% CIb All 104 37 36 26–46 PD-L1 statusc 1% cut-off TC or IC ≥ 1% 61 25 41 29–54 TC and IC < 1% 25 7 28 12–49 5% cut-off TC or IC ≥ 5% 37 17 46 30–63 TC and IC < 5% 49 15 31 18–45 10% cut-off TC or IC ≥ 10% 30 15 50 31–69 TC and IC < 10% 56 17 30 19–44

0% 20% 40% 60% 80% 100%

Patients

ORR

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

Baseline Characteristics of Complete Responders

Characteristic Complete Respondersa (n = 12) Median age (range), years 62 (51-78) Age ≥ 65 years, n (%) 4 (33) Race, n (%) Asian = 8 (67); White = 2 (17); Other = 2 (17) Region, n (%) Asia (excluding Japan) = 7 (58); Rest of World = 5 (42) Baseline ECOG PS 1, n (%) 5 (42) Child-Pugh class, n (%) A5 = 11 (92); A6 = 1 (8) Etiology of HCC, n (%) HBV = 7 (58); HCV = 5 (42) BCLC stage at study entry, n (%) B = 2 (17); C = 10 (83) AFP ≥ 400 ng/mL, n (%) 4 (33) EHS present, n (%) 9 (75) MVI present, n (%) 5 (42) EHS and/or MVI present, n (%) 10 (83) Prior HCC local therapy (ie TACE, RFA or TARE), n (%) 7 (58)

a Per IRF-assessed RECIST 1.1..

Data cutoff: 14 June 2019.

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

Safety Summary: Atezolizumab + Bevacizumab

Arm A: Atezolizumab + Bevacizumab (N = 104) Median treatment duration (range), mo Atezolizumab 8.3 (0 - 34.3) Bevacizumab 8.2 (0 - 34.3) Any-grade AEs, n (%) 100 (96) Treatment related 91 (88) Grade 3-4 AEs, n (%) 55 (53) Treatment related 41 (39) Grade 5 AEs, n (%) 7 (7) Treatment relateda 3 (3) Serious AEs, n (%) 46 (44) Treatment related 25 (24) AE leading to withdrawal, n (%) All treatments 10 (10) Most Common AEs by Preferred Terms (≥ 20% of pts), n (%)

Arm A: Atezolizumab + Bevacizumab (N = 104) Any Grade Grade 3-4

Proteinuria 38 (37) 7 (7) Decreased appetite 36 (35) 1 (1) Fatigue 29 (28) 1 (1) Rash 24 (23) Pyrexia 24 (23) 2 (2) Diarrhea 23 (22) 3 (3) Hypertension 22 (21) 15 (14) Abdominal pain 21 (20) 4 (4) Pruritus 21 (20) Most Common SAEs by Preferred Terms (≥ 3% of pts), n (%) Pyrexia 5 (5) 2 ( 2) Cholangitis 3 (3) 3 ( 3) Upper gastrointestinal haemorrhage 3 (3) 2 ( 2)

a Grade 5 treatment-related adverse events: abnormal hepatic function, hepatic cirrhosis and pneumonitis.

Data cutoff: 14 June 2019.

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

Adverse Events of Special Interest in ≥ 5% of Patients

a Regardless of causality of an individual event. b Includes 1 unrelated Grade 5 event.

Data cutoff: 14 June 2019.

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Most common AESIsa

Preferred Terms, n (%)

Safety-Evaluable Population (N = 104)

Any Grade Grade 3-4 Atezolizumab AESI Rash 24 (23) AST increased 16 (15) 5 (5) Blood bilirubin increased 14 (14) 6 (6) ALT increased 12 (12) 3 (3) Hypothyroidism 9 ( 9) Ascites 7 ( 7) 3 (3) Infusion-related reaction 5 (5) Bevacizumab AESI Proteinuria 38 (37) 7 (7) Hypertension 22 (21) 15 (14) Epistaxis 13 (13)

  • 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%)

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

Summary

  • Clinically meaningful and durable objective responses were observed

– Confirmed ORR with atezolizumab + bevacizumab was 36% per IRF-assessed RECIST 1.1 – 76% of responses per IRF-assessed RECIST 1.1 are ongoing and the median duration of response was not reached – 12% of patients (including 7 with HBV) achieved CR per IRF-assessed RECIST 1.1 – Results were consistent across RECIST assessments

  • Benefit of atezolizumab + bevacizumab was generally consistent among

subgroups analysed

– Patients with HCV and those without MVI and EHS had numerically higher ORRs – 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.

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13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

https://bit.ly/2ZCXqHc Lee KH. Atezo + Bev in HCC

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,
  • f Health Interactions and funded by F. Hoffmann-La Roche, Ltd.

a Previous investigators.

15 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