Progression patterns and therapeutic sequencing following immune checkpoint inhibition for hepatocellular carcinoma: An international observational study

Abstract

Background and Aims Different approaches are available after the progression of disease (PD) to immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC), including the continuation of ICI, treatment switching to tyrosine kinase inhibitors (TKIs) and cessation of anticancer therapy. We sought to characterise the relationship between radiological patterns of progression and survival post‐ICI, also appraising treatment strategies. Methods We screened 604 HCC patients treated with ICIs, including only those who experienced PD by data cut‐off. We evaluated post‐progression survival (PPS) according to the treatment strategy at PD and verified its relationship with radiological patterns of progression: intrahepatic growth (IHG), new intrahepatic lesion (NIH), extrahepatic growth (EHG), new extrahepatic lesion (NEH) and new vascular invasion (nVI). Results Of 604 patients, 364 (60.3%) experienced PD during observation. Median PPS was 5.3 months (95% CI: 4.4–6.9; 271 events). At the data cut‐off, 165 patients (45%) received no post‐progression anticancer therapy; 64 patients (17.6%) continued ICI beyond PD. IHG (HR 1.64 [95% CI: 1.21–2.22]; p = .0013) and nVI (HR 2.15 [95% CI: 1.38–3.35]; p = .0007) were associated with shorter PPS. Multivariate models adjusted for progression patterns, treatment line and albumin‐bilirubin grade and Eastern Cooperative Oncology Group performance status at PD confirmed receipt of ICI beyond PD with (HR 0.17, 95% CI: 0.09–0.32; p < .0001) or without subsequent TKI (HR 0.39, 95% CI: 0.26–0.58; p < .0001) as predictors of prolonged PPS versus no anticancer therapy. Conclusions ICI‐TKI sequencing is a consolidated option in advanced HCC. nVI and IHG predict a poorer prognosis. Despite lack of recommendation, the continuation of ICI beyond progression in HCC is adopted clinically: future efforts should appraise which patients benefit from this approach.

The prognostic role of tumour progression and liver function at progression under immunotherapy for hepatocellular carcinoma

“…In the current issue of Liver International, Talbot et al 11 Firstly, and as expected, the median PPS after ICI therapies for patients receiving further-line therapies was significantly longer than those who have not received further lines of treatment (10.3 months vs. 1.9 months, respectively; p < .0001). They also suggest that the receipt of the continuation of ICI after progression then switch to tyrosine kinase inhibitors (TKI), which might be associated with improved prognosis (median PPS of 9.7 months for patients treated in first-line, vs. 1.3 months for no treatment), while continuation ICI without the further switch to TKI trended to be associated with lower PPS than switch to TKI (median PPS of 5.6 vs. 10.9 months, respectively), illustrating that TKI might indeed have activity after ICI and thus continue to play an important role in HCC.…”

“…They also suggest that the receipt of the continuation of ICI after progression then switch to tyrosine kinase inhibitors (TKI), which might be associated with improved prognosis (median PPS of 9.7 months for patients treated in first-line, vs. 1.3 months for no treatment), while continuation ICI without the further switch to TKI trended to be associated with lower PPS than switch to TKI (median PPS of 5.6 vs. 10.9 months, respectively), illustrating that TKI might indeed have activity after ICI and thus continue to play an important role in HCC. Secondly, Talbot et al 11 validate the pattern of progression 12 in the context of ICI-based systemic therapies, confirming that patients with new vascular invasion (nVI) have a poorer prognosis. This is an important point because the lack of pattern of progression in HCC studies could be one of the reasons for the poor surrogacy of radiological endpoints when assessed at both the trial (i.e.…”

“…Of course, Talbot et al 11 analyses have some significant limitations. Importantly, most patients were treated with single-agent anti-PD-1 in second-line or more, which is different from the current standard of care of first-line combination immunotherapy.…”

“…by using individual patient data). 13 Thirdly, Talbot et al 11 draw attention to the evaluation of liver function during the follow-up, in the prognosis of patients with HCC during systemic therapy. The authors find that higher albuminbilirubin (ALBI) grade at progression disease is associated with a poorer prognosis, albeit not statistically significantly so in multivariable analysis while considering the receipt of further treatment.…”

Immunotherapy in hepatocellular carcinoma: how will it reshape treatment sequencing?

“…Yet, while promising also in a real-world scenario, this approach seems much less adopted for unselected patients in a less rigorous setting like that of clinical practice. 88 Immunotherapy rechallenge. Despite maintaining ICIs beyond progression might be considered in specific circumstances, immunotherapy discontinuation is usually advised upon tumor progression and/or after the occurrence of severe AEs in clinical trials, and limited evidence exists regarding the clinical outcomes at treatment resumption.…”