Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

Bernhard Scheiner; Daniel Roessler; Samuel Phen; Mir Lim; Katharina Pomej; Tiziana Pressiani; Antonella Cammarota; Thorben W Fründt; Johann von Felden; Kornelius Schulze; Vera Himmelsbach; Fabian Finkelmeier; Ansgar Deibel; Alexander R Siebenhüner; Kateryna Shmanko; Pompilia Radu; Birgit Schwacha-Eipper; Matthias P Ebert; Andreas Teufel; Angela Djanani; Florian Hucke; Lorenz Balcar; Alexander B Philipp; David Hsiehchen; Marino Venerito; Friedrich Sinner; Michael Trauner; Antonio D'Alessio; Claudia A M Fulgenzi; David J Pinato; Markus Peck-Radosavljevic; Jean-François Dufour; Arndt Weinmann; Andreas E Kremer; Amit G Singal; Enrico N De Toni; Lorenza Rimassa; Matthias Pinter

doi:10.1016/j.jhepr.2022.100620

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

JHEP Rep. 2022 Oct 27;5(1):100620. doi: 10.1016/j.jhepr.2022.100620. eCollection 2023 Jan.

Authors

Bernhard Scheiner^{1

2}, Daniel Roessler³, Samuel Phen⁴, Mir Lim⁴, Katharina Pomej^{1

2}, Tiziana Pressiani⁵, Antonella Cammarota^{5

6}, Thorben W Fründt⁷, Johann von Felden⁷, Kornelius Schulze⁷, Vera Himmelsbach⁸, Fabian Finkelmeier⁸, Ansgar Deibel⁹, Alexander R Siebenhüner^{10

11}, Kateryna Shmanko¹², Pompilia Radu^{13

14}, Birgit Schwacha-Eipper¹⁴, Matthias P Ebert^{15

16

17}, Andreas Teufel^{16

18}, Angela Djanani¹⁹, Florian Hucke²⁰, Lorenz Balcar^{1

2}, Alexander B Philipp³, David Hsiehchen⁴, Marino Venerito²¹, Friedrich Sinner²¹, Michael Trauner¹, Antonio D'Alessio^{6

22}, Claudia A M Fulgenzi^{22

23}, David J Pinato^{22

24}, Markus Peck-Radosavljevic²⁰, Jean-François Dufour¹³, Arndt Weinmann¹², Andreas E Kremer^{9

25}, Amit G Singal⁴, Enrico N De Toni³, Lorenza Rimassa^{5

6}, Matthias Pinter^{1

2}

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
² Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
³ Department of Medicine II, University Hospital, LMU Munich, Munich, 81377, Germany.
⁴ Department of Medicine, UT Southwestern Medical Center, Dallas TX, USA.
⁵ Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy.
⁶ Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele (Milan), Italy.
⁷ 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸ Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany.
⁹ Department of Hepatology and Gastroenterology, University Hospital Zurich and University Zurich, Zurich, Switzerland.
¹⁰ Department of Medical Oncology and Hematology, University Hospital Zurich and University Zurich, Zurich, Switzerland.
¹¹ Department of Medical Oncology and Hematology, Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland.
¹² Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
¹³ Hepatology-Department of Biomedical Research, University of Bern, Bern, Switzerland.
¹⁴ Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland.
¹⁵ Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁶ Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁷ DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
¹⁸ Department of Internal Medicine II, Division of Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁹ Department of Internal Medicine I, Division of Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria.
²⁰ Internal Medicine and Gastroenterology (IMuG), Including Centralized Emergency Service (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria.
²¹ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von Guericke University Hospital, 39120 Magdeburg, Germany.
²² Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
²³ Department of Medical Oncology, University Campus Bio-Medico of Rome, Italy.
²⁴ Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
²⁵ Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

Abstract

Background & aims: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line.

Methods: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events.

Results: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively.

Conclusions: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials.

Impact and implications: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy.

Keywords: BOR, best overall response; CR, complete response; DCR, disease control rate; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; Immune checkpoint blocker; Immunotherapy; Liver cancer; NE, not evaluable; ORR, objective response rate; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease; Systemic therapy; TRAEs, treatment-related adverse events; TTP, time-to-progression.