Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice

David J Pinato; Thomas U Marron; Pallavi Shruti Mishra-Kalyani; Yutao Gong; Guo Wei; David Szafron; Elad Sharon; Anwaar Saeed; Tomi Jun; Sirish Dharmapuri; Abdul R Naqash; Thoetchai Peeraphatdit; Anuhya Gampa; Yinghong Wang; Uqba Khan; Mahvish Muzaffar; Musharraf Navaid; Chieh J Lee; Pei-Chang Lee; Anushi Bulumulle; Bo Yu; Sonal Paul; Neil Nimkar; Dominik Bettinger; Hannah Hildebrand; Yehia I Abugabal; Tiziana Pressiani; Nicola Personeni; Antonio D'Alessio; Ahmed O Kaseb; Yi-Hsiang Huang; Celina Ang; Julie Schneider; Anjana Pillai; Lorenza Rimassa; Kirsten B Goldberg; Richard Pazdur; Marc Theoret; Steven Lemery; 'Lola Fashoyin-Aje; Alessio Cortellini; Lorraine Pelosof

doi:10.1016/j.ejca.2021.08.020

Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice

Eur J Cancer. 2021 Nov:157:140-152. doi: 10.1016/j.ejca.2021.08.020. Epub 2021 Sep 8.

Authors

David J Pinato¹, Thomas U Marron², Pallavi Shruti Mishra-Kalyani³, Yutao Gong⁴, Guo Wei⁴, David Szafron⁵, Elad Sharon⁶, Anwaar Saeed⁷, Tomi Jun², Sirish Dharmapuri², Abdul R Naqash⁸, Thoetchai Peeraphatdit⁹, Anuhya Gampa⁹, Yinghong Wang¹⁰, Uqba Khan¹¹, Mahvish Muzaffar¹², Musharraf Navaid¹², Chieh J Lee¹³, Pei-Chang Lee¹³, Anushi Bulumulle¹², Bo Yu¹⁴, Sonal Paul¹⁵, Neil Nimkar¹⁵, Dominik Bettinger¹⁶, Hannah Hildebrand⁷, Yehia I Abugabal¹⁷, Tiziana Pressiani¹⁸, Nicola Personeni¹⁸, Antonio D'Alessio¹⁹, Ahmed O Kaseb¹⁷, Yi-Hsiang Huang²⁰, Celina Ang², Julie Schneider⁴, Anjana Pillai⁹, Lorenza Rimassa²¹, Kirsten B Goldberg⁴, Richard Pazdur⁴, Marc Theoret⁴, Steven Lemery⁴, 'Lola Fashoyin-Aje⁴, Alessio Cortellini²², Lorraine Pelosof²³

Affiliations

¹ Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W120HS, UK. Electronic address: [email protected].
² Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA.
³ Office of Biostatistics, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA.
⁴ Office of Oncologic Diseases, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA.
⁵ Dept of Internal Medicine, Baylor College of Medicine, Houston, TX, USA.
⁶ Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.
⁷ Division of Medical Oncology, Department of Medicine, Kansas University Cancer Center, Westwood, KS, USA.
⁸ Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
⁹ Section of Gastroenterology, Hepatology & Nutrition, The University of Chicago Medicine, 5841 S. Maryland Ave., Chicago, IL, 60637, USA.
¹⁰ Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Division of Hematology and Oncology, Weill Cornell Medicine/New York Presbyterian Hospital, 1305 York Avenue, Room Y1247, New York, NY, 10021, USA.
¹² Division of Hematology/Oncology, East Carolina University, 600 Moye Boulevard, Greenville, NC, 27834, USA.
¹³ Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁴ Lincoln Medical Center, 234 East 149th Street, Bronx, NY, USA.
¹⁵ New York Presbyterian Brooklyn Methodist Hospital, 506 6th St, Brooklyn, NY, USA.
¹⁶ Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany.
¹⁷ Dept of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁸ Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele, 20090, Italy.
¹⁹ Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W120HS, UK; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele, 20090, Italy.
²⁰ Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
²¹ Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele, 20090, Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Milan, Rozzano, 20089, Italy.
²² Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W120HS, UK; Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, L'Aquila, 67100, Italy. Electronic address: [email protected].
²³ Office of Oncologic Diseases, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA. Electronic address: [email protected].

PMID: 34508996
DOI: 10.1016/j.ejca.2021.08.020

Abstract

Purpose: The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC).

Patients and methods: We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association.

Results: In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25-0.75) and PFS (HR 0.48; 95% CI: 0.31-0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46-0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32-0.95) in the multi-institutional dataset.

Conclusion: Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.

Keywords: HCC; Immune-related adverse events; Immunotherapy; Response; Survival; Toxicity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / mortality
Clinical Trials as Topic
Female
Humans
Immune Checkpoint Inhibitors / adverse effects*
Liver Neoplasms / drug therapy*
Liver Neoplasms / mortality
Male
Middle Aged
Young Adult

Substances

Immune Checkpoint Inhibitors

Grants and funding

PS3416/WT_/Wellcome Trust/United Kingdom