Immune-related adverse events portend better prognosis in ICI-treated hepatocellular carcinoma

Among advanced hepatocellular carcinoma (HCC) patients being treated with immune checkpoint inhibitors (ICIs), the occurrence of multisystem and more severe immune-related adverse events (irAEs) is a favourable signal, being associated with survival advantage, according to a Singapore study.

Patients who did vs did not experience irAEs had superior overall (OS; 16.2 vs 4.6 months) and progression-free survival (PFS; 5.5 vs 1.3 months), as well as greater overall response (ORR; 27.8 percent vs 11.3 percent) and disease-control rates (DCR; 67.0 percent vs 28.2 percent). [Liver Cancer 2022;11:9-21]

Among patients with irAEs, those with grade ≥3 vs grades 1–2 events had longer PFS (median, 8.5 vs 3.6 months) and OS (median, 26.9 vs 14.0 months), as did those with ≥2 vs only a single irAE (median, 20.7 vs 13.9 months).

Multivariable Cox regression analysis confirmed that the presence of grade ≥3 irAEs was associated with significantly prolonged OS at the 6-week landmark (adjusted hazard ratio [aHR], 0.34; p=0.030) and the 12-week landmark (aHR, 0.28; p=0.011). Likewise, having ≥2 irAEs conferred extended OS (aHR, 0.35; p<0.001).

Finally, the use of systemic corticosteroids to manage irAEs had no detrimental effect of the observed survival advantage with ICI-based regimens and was even linked to a trend toward a better OS (median, 20.7 vs 14.3 months; p=0.064) and PFS (median, 9.9 vs 3.4 months) relative to nonuse.

“This adds to the growing body of evidence that has demonstrated the association of irAE and efficacy of programmed cell death protein-1/programmed death ligand-1 inhibitors in patients with nonsmall cell lung cancer, melanoma, urothelial carcinoma, head and neck cancer, and gastrointestinal cancers,” according to investigators. [Clin Lung Cancer 2019;20:201-207; J Cancer Res Clin Oncol 2019;145:511-521; J Clin Oncol 2019;37:2730-2737; Oncologist 2020;25:669-679]

“Mechanistically, patients who experience a higher grade irAE [as well as irAEs at multiple sites] should have a higher T-cell activity and, hence, experience better antitumour outcomes than patients who experience a lower grade irAE,” they pointed out. [Bull Cancer 2018;105:1033-1041]

The current study included 168 patients (median age 69 years, 85.7 percent male) with advanced HCC who received at least one dose of an ICI at the National Cancer Centre Singapore. Most patients had hepatitis B infection (57.7 percent), ECOG 0 (60.7 percent), and Child-Pugh A liver cirrhosis (78.0 percent). ICI was given as monotherapy in the majority of patients (82.7 percent) and in combination in 17.3 percent.

“No studies have described this association [between irAEs and ICI efficacy] among patients receiving combination immunotherapy, and our study suggests that the association is likely to be also present among patients who are receiving combination immunotherapy or immunotherapy in combination with TKI or vascular endothelial growth factor inhibitor,” the investigators noted.

Taken together, the present data indicate that the presence of all-grade irAEs may be a potential prognostic biomarker in patients with aHCC treated with ICI, with more severe irAEs and multisystem involvement correlating with better prognosis, they said. “The prompt use of systemic corticosteroids to treat patients with irAEs is key to ensure the best long-term outcomes for these patients.”

The study was limited by its retrospective nature and the predominance of hepatitis B-associated HCC, which precluded generalization of data to non-hepatitis B-associated HCC.