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.

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). 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. 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. 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.

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Déclaration de conflit d'intérêts

Conflict of interest statement 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.