TY - JOUR
T1 - Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer
T2 - Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice
AU - Pinato, David J.
AU - Marron, Thomas U.
AU - Mishra-Kalyani, Pallavi Shruti
AU - Gong, Yutao
AU - Wei, Guo
AU - Szafron, David
AU - Sharon, Elad
AU - Saeed, Anwaar
AU - Jun, Tomi
AU - Dharmapuri, Sirish
AU - Naqash, Abdul R.
AU - Peeraphatdit, Thoetchai
AU - Gampa, Anuhya
AU - Wang, Yinghong
AU - Khan, Uqba
AU - Muzaffar, Mahvish
AU - Navaid, Musharraf
AU - Lee, Chieh J.
AU - Lee, Pei Chang
AU - Bulumulle, Anushi
AU - Yu, Bo
AU - Paul, Sonal
AU - Nimkar, Neil
AU - Bettinger, Dominik
AU - Hildebrand, Hannah
AU - Abugabal, Yehia I.
AU - Pressiani, Tiziana
AU - Personeni, Nicola
AU - D'Alessio, Antonio
AU - Kaseb, Ahmed O.
AU - Huang, Yi Hsiang
AU - Ang, Celina
AU - Schneider, Julie
AU - Pillai, Anjana
AU - Rimassa, Lorenza
AU - Goldberg, Kirsten B.
AU - Pazdur, Richard
AU - Theoret, Marc
AU - Lemery, Steven
AU - Fashoyin-Aje, ‘Lola
AU - Cortellini, Alessio
AU - Pelosof, Lorraine
N1 - Funding Information:
DB is supported by the Berta-Ottenstein Programme, Faculty of Medicine, University of Freiburg .
Funding Information:
DJP is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416).DB is supported by the Berta-Ottenstein Programme, Faculty of Medicine, University of Freiburg.DJP received lecture fees from ViiV Healthcare, Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, AstraZeneca; received research funding (to institution) from MSD, BMS. DB has received lecture and speaker fees from Bayer Healthcare and the Falk Foundation Germany. DB has received lecture and speaker fees from Bayer Healthcare, the Falk Foundation Germany and consulting fees from Boston Scientific. LR received lectures fees from AbbVie, Amgen, Eisai, Gilead, Ipsen, Lilly, Roche, Sanofi; advisory board/consulting fees from Amgen, ArQule, Basilea, Bayer, Celgene, Eisai, Exelixis, Hengrui, Incyte, Ipsen, Lilly, MSD, Roche, Sanofi; travel expenses from Ipsen; received research funding (to institution) from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Incyte, Ipsen, Lilly, MSD. NP received lecture fees from AbbVie and Gilead; travel expenses from ArQule. YHH has received advisory board/consulting fees for BMS, MSD, Bayer Healthcare, IPSEN, EISAI, Gilead and Lilly. AS received research funding (to institution) from AstraZeneca, Exelixis, BMS and Clovis; advisory board/consulting fees from BMS, AstraZeneca, and Exelixis. AC received speakers? fee from AstraZeneca, MSD, Novartis and Eisai and advisory board fees from MSD, AstraZeneca, BMS and Roche. All other authors declare no competing interests.The authors would like to acknowledge the infrastructure support provided by Imperial Experimental Cancer Medicine Centre, Cancer Research UK Imperial Centre, the Imperial College BRC and the Imperial College Healthcare NHS Trust Tissue Bank.
Funding Information:
DJP is supported by grant funding from the Wellcome Trust Strategic Fund ( PS3416 ).
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
KW - HCC
KW - Immune-related adverse events
KW - Immunotherapy
KW - Response
KW - Survival
KW - Toxicity
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U2 - 10.1016/j.ejca.2021.08.020
DO - 10.1016/j.ejca.2021.08.020
M3 - Article
C2 - 34508996
AN - SCOPUS:85114471862
SN - 0959-8049
VL - 157
SP - 140
EP - 152
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -