Immunotherapies in management of HCC

Overview on recent advances in immune therapies for management of liver cancer

1. Immunotherapies for Hepatocellular Carcinoma Ahmed Mohamed Elmoughazy Assistant lecturer, Experimental and clinical internal medicine, Medical research institute, Alexandria University

2. Introduction

3. Most HCC in Occurs in the Setting of Cirrhosis Alcoholic liver disease Hepatitis B viral infection Nonalcoholic steatohepatitis Hepatitis C viral infection HCC Cirrhosis Chronic hepatitis Normal liver Chronic inflammation Ramakrishna. Liver Cancer. 2013;2:367.

4. Liver Cancer Incidence and Mortality are Increasing SEER Database. 10 8 6 4 2 1975 1980 1985 1990 1995 2000 2005 2010 2017 Year Rate Per 100,000 Persons Rate of New Cases Death Rate

5. Introduction

6. Introduction

7. Introduction

8. Introduction

9. Introduction

10. Rationale

11. TIME An immunosuppressive tumor‐immune microenvironment (TIME) is characterized by an abundance of Regulatory T cells (Treg) Immunosuppressive myeloid cells such as tumor‐associated macrophages (TAMs) or myeloid‐derived suppressor cells (MDSCs).

12. Immunosuppressive lymphocytes Regulatory T cells (Tregs) have an essential role in maintenance of self‐tolerance and regulation of immune responses under physiologic conditions as well as in disease states including cancer. Circulating Tregs are increased in patients with HCC and correlate with tumor progression and decreased patient survival TGF‐β and VEGF promote abundance and differentiation of Tregs. Accordingly, blockade of either VEGF or TGF‐β restrains tumor growth.

13. Immunosuppressive myeloid cells Tumor‐associated macrophages (TAMs) with high levels of CD163 called M2‐like, and abundance of M2‐like macrophages in patients with HCC is associated with increased tumor nodules and venous infiltration.

14. Immunosuppressive myeloid cells

15. Immunosuppressive myeloid cells

16. Natural killer cell Natural killer cell (NK) dysfunction also occurs in HCC and correlates with patient survival. Accumulation of CD11b − CD27 − NK cells, an immature and inactive phenotype with poor cytolytic activity, is associated with HCC progression NK cell function can also be dampened by immunosuppressive cells such as MDSCs and Tregs, as well as immunosuppressive cytokines including IL‐10 and TGF-β.

17. CD8+ T lymphocytes

18. CD8+ T lymphocytes

19. Cancer Medicine, Volume: 11, Issue: 3, Pages: 571-591, First published: 24 December 2021, DOI: (10.1002/cam4.4468) C himeric antigen receptor (CAR) T‐cells

20. Immune checkpoint inhibitors

21. PD-1 predominantly acts as a “brake” on more peripherally located immune cells (e.g. tumor-infiltrating lymphocytes and other immune cells) in response to PD-L1 and PD-L2 which were mainly expressed by tumor cells and antigen-presentation cells; CTLA-4 predominantly acts as a “brake” on more centrally located immune cells (e.g. lymph node) in response to T cell receptor engagement and CD28 co-stimulation. Monoclonal antibodies targeting PD-1/PD-L1 or CTLA-4 relieve the brakes on the suppressed T cells and unleash their anti-tumor immunity against cancer cells.

22. Cancer Medicine, Volume: 11, Issue: 3, Pages: 571-591, First published: 24 December 2021, DOI: (10.1002/cam4.4468)

23. Nivolumab Nivolumab was the first anti-PD-1 mAb to demonstrate significant clinical activity in advanced HCC. In a phase I/II clinical trial ( CheckMate 040), nivolumab demonstrated 20% objective response rate (ORR) and a durable duration of response (median 9.9 months). In the subgroup of sorafenib-experienced patients, ORR was 14% and the median survival was 15.1 months. Regorafenib was the only approved agent after failure of sorafenib at that time and the remarkable clinical activity of nivolumab filled the large unmet need. Nivolumab thus became the first anti-PD-1 mAb to be granted accelerated approval from the US FDA for patients who failed sorafenib.

24. Combination therapy: nivolumab plus ipilimumab Ipilimumab is CTLA-4 inhibitor. The objective response rate was 31% (vs 14% nivolumab alone). The best outcomes were seen with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every three weeks, followed by maintenance nivolumab. The median OS was 22.2 months (versus 12.5 and 12.7 months in the other two groups)

25. Combination therapy: nivolumab plus ipilimumab Immune-mediated adverse events were also more common in this cohort with median time to onset was 1.3 months Based on this study, combination nivolumab plus ipilimumab was approved in March 2020 for treatment of HCC in patients previously treated with sorafenib

26. CheckMate 459: Nivolumab vs Sorafenib as First-line Therapy for Advanced HCC Predefined threshold of statistical significance for OS with nivolumab not met, although nivolumab demonstrated clinical benefit ORR: nivolumab, 15%; sorafenib, 7% 3 6 9 12 15 18 21 24 27 30 33 36 39 Mos PFS (%) 20 40 60 80 100 Nivolumab Sorafenib 3 6 9 12 15 18 21 24 27 30 33 36 39 20 40 60 80 100 Mos OS (%) Nivolumab Sorafenib Slide credit: clinicaloptions.com Yau. ESMO 2019. Abstr LBA38_PR. Median OS, Mos (95% CI) Nivolumab Sorafenib 16.4 (13.9-18.4) 14.7 (11.9-17.2) HR: 0.85 (95% CI: 0.72-1.02 ; P = .0752 ) Median PFS, Mos (95% CI) Nivolumab Sorafenib 3.7 (3.1-3.9) 3.8 (3.7-4.5) HR: 0.93 (95% CI: 0.79-1.10) Open-label, randomized phase III trial of nivolumab vs sorafenib for pts with advanced HCC (Child-Pugh class A) and no prior systemic therapy for HCC (N = 743)

27. CheckMate 459

28. Pembrolizumab

29. Pembrolizumab

30. Pembrolizumab

31. Anti-angiogenic combinations

32. IMbrave150: Atezolizumab + Bevacizumab vs Sorafenib for First-line Treatment of HCC 1. Finn. NEJM. 2020;382:1894. 2. Lee. Lancet Oncol. 2020;21:808. Slide credit: clinicaloptions.com Treatment until Progressive disease (PD) or intolerable toxicity Multicenter, randomized, open-label phase III trial [1] GO30140: randomized phase Ib study showed potential benefit of atezolizumab + bevacizumab for patients with advanced HCC (ORR 36%) [2] Patients with locally advanced or metastatic and/or unresectable HCC with no previous systemic therapy, Child-Pugh A, and ECOG PS ≤ 1* (N = 501) Atezolizumab 1200 mg Q3W + Bevacizumab 15 mg/kg Q3W (n = 336) Sorafenib 400 mg BD (n = 165) Coprimary endpoints: OS and PFS *Trial included subgroups of high-risk patients excluded from other contemporary phase III trials: ~ 40% had macrovascular invasion; specifically included patients with 50% hepatic involvement or main portal vein invasion or invasion of the portal vein branch contralateral to the primarily involved lobe.

33. 20 40 60 80 100 IMbrave150: Updated OS and PFS Median follow-up: 15.6 mos. Slide credit: clinicaloptions.com Finn. NEJM. 2020;382:1894. Finn. ASCO GI 2021. Abstr 267. Primary analysis OS/PFS HR: 0.58/0.59 (median f/u 8.6 mos ) Median OS, mos (95% CI) Atezo + Bev (n = 336) 19.2 (17.0-23.7) Sorafenib (n = 165) 13.4 (11.4-16.9) Stratified HR (95% CI) 0.66 (0.52-0.85) P = .0009 OS (%) 2 4 6 8 10 12 Mos 6-mo OS 85% 14 16 18 20 22 24 26 28 29 72% 12-mo OS 67% 56% 18-mo OS 52% 40% 20 40 60 80 100 PFS (%) Mos 6-mo PFS 55% 2 4 6 8 10 12 14 16 18 20 22 24 26 27 38% 12-mo PFS 35% 21% 18-mo PFS 24% 12% Median PFS, mos (95% CI) Atezo + Bev (n = 336) 6.9 (5.7-8.6) Sorafenib (n = 165) 4.3 (4.0-5.6) Stratified HR (95% CI) 0.65 (0.53-0.81) P = .0001

34. IMbrave150: Safety EGD within 6 mos of initiating treatment required to evaluate for varices; varices of any size according to local standards of care Upper GI bleeding rate in atezo + bev vs sorafenib groups: 7% vs 4.5%; this was consistent with historical data in other studies of bevacizumab in HCC Cheng. ESMO Asia 2019. Abstr LBA3. Finn. NEJM. 2020;382:1894. Slide credit: clinicaloptions.com ≥ 10% frequency in either arm and > 5% difference between arms. 60 50 40 30 20 10 10 20 30 40 50 60 Diarrhea PPE Decreased appetite Hypertension Abdominal pain Alopecia Asthenia Pyrexia ALT increased Proteinuria Infusion-related reaction All-grade AEs Grade 3/4 AEs Atezo + Bev Sorafenib Patient-reported QoL also improved with atezo + bev vs sorafenib (median TTD: 11.2 vs 3.6 mos )

35. Key Warnings and Precautions for First-Line Atezolizumab/Bevacizumab Atezolizumab [1] History of organ transplant History of autoimmune disease Immune-mediated pneumonitis, hepatitis, colitis, endocrinopathies Bevacizumab [2] GI perforations Surgery in last 28 days; incompletely healed wound Recent hemoptysis or major bleed (variceal bleeding) Fistula Uncontrolled hypertension > 2 g proteinuria Congestive heart failure Slide credit: clinicaloptions.com 1. Atezolizumab PI. 2. Bevacizumab PI.

36. Durvalumab ± tremelimumab HIMALAYA trial is a multicentre phase III trial exploring the safety and efficacy of Durvalumab (a PD-L1 inhibitor) ± Tremelimumab (a CTLA-4 inhibitor) VS Sorafenib in patients with advanced HCC who have not received prior systemic therapy and are also not eligible for locoregional therapy

37. Durvalumab ± tremelimumab

38. Durvalumab ± tremelimumab Largely based on these results, the US FDA has approved the combination of tremelimumab plus durvalumab for patients with unresectable HCC in October 2022.

39. FDA-Approved Systemic Therapy for Advanced HCC 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Sorafenib First Line Lenvatinib Atezolizumab + bevacizumab Second Line and Beyond Nivolumab + ipilimumab* Pembrolizumab* Regorafenib Cabozantinib Ramucirumab *Accelerated approval.

40. Cancer Medicine, Volume: 11, Issue: 3, Pages: 571-591, First published: 24 December 2021, DOI: (10.1002/cam4.4468)

41. Systemic Therapy for HCC in 2021 Based on RCTs Based on non-randomized trials Slide credit: clinicaloptions.com Regorafenib Cabozantinib Pembrolizumab Ramucirumab Nivolumab + ipilimumab Lenvatinib Sorafenib Atezo + bev Nivolumab

42. Combination therapy Combination immune checkpoint inhibitor (ICI) strategies reported or in ongoing phase III clinical trials are presented. CTLA4, cytotoxic T lymphocyte-associated antigen 4; VEGF, vascular endothelial growth factor.

43. Current clinicals trials on systemic immunotherapy in advanced HCC Copyright © 2023 American Association for the Study of Liver Diseases - Wolters Kluwer Health, Inc. All rights reserved. 53

44. Copyright © 2023 American Association for the Study of Liver Diseases - Wolters Kluwer Health, Inc. All rights reserved. 54 Strategies integrating ICI based on HCC stage currently under investigation.

45. Immune-Related AEs Seen With Immune Checkpoint Inhibitors Uveitis Orbital inflammation Pneumonitis Hypothyroidism Hepatitis Rash and vitiligo Pancreatitis Autoimmune diabetes Adrenal insufficiency Enterocolitis Arthralgia Dry mouth Hypophysitis Slide credit: clinicaloptions.com Minchot. Eur J Cancer. 2016;54:139.

46. irAE IMbrave150 reported: hepatitis (43.2%), rash (19.5%, hypothyroidism (10.9%), hyperthyroidism (4.6%), pancreatitis (2.7%), and diabetes mellitus (2.4%), They were predominantly grade 1–2. Only 12% of these patients required systemic corticosteroid.

47. General Guidelines for Management of irAEs Grade 1: asymptomatic to mild symptoms Observation Supportive care Continue ICI therapy Grade 2: moderate symptoms Local or noninvasive intervention indicated Withhold ICI, consider redose if toxicity resolves to grade ≤1 Consider corticosteroids May be able to continue treatment Grade 3: medically significant but not immediately life-threatening Stop ICI immediately Hospitalization indicated High-dose steroids indicated Slow steroid taper over ≥1 mo once toxicity resolves to grade ≤1 Grade 4: life-threatening consequences Urgent intervention Permanently discontinue ICI therapy Atezolizumab adverse reaction management brochure. Nivolumab adverse reaction management guide. Pembrolizumab adverse reaction management guide. Slide credit: clinicaloptions.com Consult promptly with relevant specialists for affected organ systems Dose reduction of ICI is NOT a recommended strategy

48. irAE Atezolizumab-bevacizumab combination does not seem to increase the risk of irAE requiring steroid as compared to single agent ICI (e.g., 8.2% of patients in the pembrolizumab group received steroid in KEYNOTE240 study). However, up to 20% of patients receiving tremelimumab-durvalumab in HIMALAYA study required high dose steroid.

49. irAE : Management In general, the management of irAEs is based on three pillars. First, close monitoring >>>>>weekly clinical controls up to hospitalization depending on the severity of events. Second, temporary interruption or permanent discontinuation of ICI therapy depending on the type and severity of irAEs may be necessary. In general, permanent discontinuation of ICI therapy should be considered for irAEs of grade ≥ 3 Third, administration of glucocorticoids for irAEs of grade ≥ 2 may be indicated (0.5 up to 2 mg/kg/day prednisone PO or IV depending on the type and severity of irAEs ).

50. irAE : hepatitis The diagnosis and management of immune‐related hepatitis in patients with HCC undergoing ICI therapy is particularly challenging. Importantly, up to 20% of placebo‐treated patients present with any grade AST elevation. Before diagnosing immune‐related hepatitis, intrahepatic tumor progression, HBV, and/or HCV flares or newly acquired viral hepatitis, CMV (cytomegalovirus) reactivation, hepatotoxic drug side effects, cholestasis, and ascites should be excluded. In addition, a liver biopsy should be considered before steroid administration.

51. irAE : Pneumonitis Pneumonitis represents a potential life‐threating irAE . Exclusion of infectious etiologies and hepatopulmonary syndrome must be done. For grade 2, steroids should be initiated, and tapering should be performed over 4–6 weeks. Infliximab or mycophenolate mofetil may be used after glucocorticoid failure.

52. CCO Online Interactive Decision Support Tool: NCCN Guidelines® for Management of irAEs

53. Major immunotherapeutic approaches for HCC.

54. Take Home Messages Atezolizumab + bevacizumab now the standard systemic therapy regimen for metastatic HCC EGD mandatory within 6-12 months of therapy initiation For patients with advanced HCC and Child-Pugh B liver function, data with selected agents showing safety, efficacy ( eg , nivolumab, sorafenib) Multiple systemic therapy options available for second-line treatment and beyond (immune checkpoint inhibitors and targeted agents) Knowledge of key irAEs and management strategies essential to optimal use of immune checkpoint inhibitors

55. Suggestions for Further reading 1.Sangro B, Sarobe P, Hervás -Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021 Aug;18(8):525–43. 2.Foerster F, Gairing SJ, Ilyas SI, Galle PR. Emerging immunotherapy for HCC: A guide for hepatologists. Hepatology. 2022 Jun;75(6):1604. 3.Liu TH, Shen YC, Cheng AL. Immune checkpoint inhibitors for hepatocellular carcinoma – A game changer in treatment landscape. Journal of the Formosan Medical Association. 2022 Aug 1;121(8):1371–83. 4.Liu JKH, Irvine AF, Jones RL, Samson A. Immunotherapies for hepatocellular carcinoma. Cancer Medicine. 2022;11(3):571–91. 5.Xie Y, Xiang Y, Sheng J, Zhang D, Yao X, Yang Y, et al. Immunotherapy for Hepatocellular Carcinoma: Current Advances and Future Expectations. Journal of Immunology Research. 2018 Mar 26;2018:e8740976.