Early Alpha-Fetoprotein Response Is Associated With Survival in Patients With HBV-Related Hepatocellular Carcinoma Receiving Lenvatinib

Abstract

Background/PurposeLenvatinib is a first-line treatment for unresectable hepatocellular carcinoma (uHCC). We assessed the value of early alpha-fetoprotein (AFP) response for predicting clinical outcomes with lenvatinib treatment in patients with HBV-related uHCC and elevated AFP levels.MethodsThis retrospective analysis included patients with HBV-related uHCC and baseline AFP levels ≥20 ng/ml who received lenvatinib for >1 month between November 2018 and May 2021. Early AFP response was defined as a >20% decrease in AFP serum level from baseline after 4 weeks of lenvatinib treatment. Radiological response (Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival, and overall survival were assessed in AFP responders and non-responders.ResultsOf the 46 patients analyzed, 30 (65.2%) were early AFP responders and 16 (34.8%) were non-responders. Compared to the non-responders, early AFP responders had a significantly higher objective response rate (34.5% vs 6.3%, p=0.0349), disease control rate (82.8% vs 50.0%; p=0.0203) and longer median progression-free survival (13.0 vs 7.0 months; HR, 0.464; 95% CI, 0.222-0.967; p=0.028). A subsequent multivariate analysis confirmed that early AFP response (HR, 0.387; 95% CI, 0.183-0.992; p=0.0154), Eastern Cooperative Oncology Group Performance Status of 0 (HR, 0.890; 95% CI, 0.811-0.976; p=0.0132) and Albumin-Bilirubin grade 1 (HR, 0.457; 95% CI, 0.269-0.963; p=0.0327) were independent prognostic factors for longer progression-free survival.ConclusionAFP is an important prognostic factor and a predictive biomarker for survival benefit with lenvatinib treatment in patients with HBV-related uHCC.

Assessment and Monitoring of Response to Systemic Treatment in Advanced Hepatocellular Carcinoma: Current Insights

“…In retrospective analyses with MKIs, ramucirumab, and ICIs alone or in combinations, the on-treatment decrease of AFP levels repeatedly predicted radiologic tumor response and better survival outcomes, supporting a prospective evaluation of the AFP dynamic changes as a surrogate biomarker of survival. [65][66][67][68][69][70][71][94][95][96][97] Further circulating biomarkers, including MKIs targets, their ligands, and other plasma proteins, mainly with a role in inflammation/HCC pathogenesis were found to be prognostic and sometimes predictive in retrospective analyses of the SHARP, REFLECT, RESORCE, and CELESTIAL trials. 95,[100][101][102] However, they were not evaluated as biomarkers of response, and the non-homogenous significance across different studies and treatment arms, the lack of established cut-offs and uniform protocols for their measurement, and the rather intricate process required for their analysis limit further validation and make their use not yet feasible in clinical practice.…”

“…5 Furthermore, in patients receiving lenvatinib outside the landmark clinical trial, AFP response (defined as ≥40% decrease of AFP levels at week 4 among patients with baseline AFP levels ≥10 ng/mL) was the only significant predictor of objective response and a subsequent retrospective study highlighted the association between early AFP response (defined as >20% decrease in AFP levels from baseline to week 4) and higher ORR, DCR, and PFS in a small cohort of Asian patients with HBV-related unresectable HCC. 66,67 Also with atezolizumab plus bevacizumab, AFP response (defined as ≥75% decrease or ≤10% increase of AFP levels from baseline to week 6) significantly correlated with better PFS per RECIST v1.1 and OS in a post hoc analysis performed on the data from the phase 1b trial and then validated with the phase 3 data. 68 Of note, an association with tumor response was documented, with the majority of CRs/PRs being observed in patients who achieved a ≥75% decrease in AFP levels and the majority of disease control cases being reported in patients who experienced ≤10% increase in AFP levels either per RECIST v1.1 or mRECIST.…”

“…Serial serum AFP measurements during systemic treatments are easily reproducible, and retrospective investigations suggest an association between AFP decline (also known as "AFP response") and improved survival. [64][65][66][67][68][69][70][71] Of note, only patients with ≥10-20 ng/mL baseline AFPnearly 70% of patients with advanced HCC -could be considered, given that a "background noise" due to active viral hepatitis or other causes of hepatic inflammatory damage contributes to AFP elevation, particularly at low levels. Furthermore, there is no consensus yet on the definition of AFP-based response or progression.…”

“…In patients with advanced HCC, the prognostic value of elevated baseline AFP levels and AFP response has been thoroughly investigated for first-line agents (sorafenib, lenvatinib, and atezolizumab plus bevacizumab), 5,[65][66][67][68]94 and further-line therapies (regorafenib, cabozantinib, and ramucirumab). 8,9,[69][70][71]80,95 According to a retrospective analysis, AFP response (defined as a >20% decrease of AFP levels from baseline to week 8) was significantly associated with longer OS (13.3 months versus 8.2 months, p = 0.022) in a group of 85 patients treated with sorafenib, and this survival difference remained significant even when more stringent criteria were applied to define AFP responders (≥50% decrease from baseline levels to week 8).…”

“… 5 Furthermore, in patients receiving lenvatinib outside the landmark clinical trial, AFP response (defined as ≥40% decrease of AFP levels at week 4 among patients with baseline AFP levels ≥10 ng/mL) was the only significant predictor of objective response and a subsequent retrospective study highlighted the association between early AFP response (defined as >20% decrease in AFP levels from baseline to week 4) and higher ORR, DCR, and PFS in a small cohort of Asian patients with HBV-related unresectable HCC. 66 , 67 …”