Comparative effectiveness of sorafenib, lenvatinib, and nivolumab as first-line systemic therapy for patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis treated at VA Medical Centers.

Abstract

4102 Background: Up to 90% of cases of hepatocellular carcinoma (HCC) in the U.S. occur in patients with cirrhosis. As prognosis in patients with decompensated cirrhosis may be more related to liver function than tumor stage, patients with Child-Pugh (CP) class B and C cirrhosis are often excluded from randomized trials despite representing up to 30% of patients treated with systemic therapy in clinical practice. While prospective data such as the GIDEON registry and CHECKMATE-040 have demonstrated safety of sorafenib and nivolumab in CP B cirrhosis, studies of comparative effectiveness of sorafenib, lenvatinib, and nivolumab are lacking. Methods: We performed a retrospective cohort study of patients with HCC and CP B cirrhosis at U.S. Veterans Affairs Medical Centers who initiated first systemic therapy with sorafenib, lenvatinib, or nivolumab between 9/22/2017 and 2/13/2021. Overall survival (OS) by first systemic therapy was assessed with Kaplan Meier analysis and Cox proportional hazards modeling with pre-specified candidate covariates and a backward elimination approach for variable selection. Missing data were imputed by multiple imputation with chained equations. Results: Among 401 CP B patients undergoing first systemic therapy, 98% were male, 29% had macrovascular invasion (MVI), 35% had extrahepatic spread (EHS), 57%/29%/13% had CP score 7/8/9, 5% had hepatic encephalopathy, 37% had ascites, 63%/2%/36% had HCV/HBV/non-viral cirrhosis, 63% had prior embolization or ablation, and 35% had ECOG performance status of > = 2. Of these patients, 320 received sorafenib, 33 received lenvatinib, and 48 received nivolumab. In univariate analysis, median OS was 4.8 months (95% CI 3.8 – 6.0; 1 year OS 21.8%) in the sorafenib cohort, 6.9 months (95% CI 4.4 – 8.4 months; 1 year OS 27.8%) in the lenvatinib cohort, and 7.7 months (95% CI 3.9 – 9.1 months; 1 year OS 31.7%) in the nivolumab cohort. Covariates with at least one category significantly associated with survival that were retained in the multivariate model included CP score, MELD-Na, BMI, log(AFP), time from diagnosis to systemic treatment, ECOG performance status, Cirrhosis Comorbidity index, and VA complexity level (all p < 0.05); MVI, EHS, and age were retained in the model as pre-specified despite lack of statistical significance. Compared with sorafenib, nivolumab was associated with significantly lower hazard of death (adjusted HR 0.63; 95% CI 0.43 – 0.91; p = 0.015) while hazard of death for lenvatinib treatment was not significantly different (adjusted HR 0.83; 95% CI 0.54 – 1.28, p = 0.41). Conclusions: Among patients with HCC and CP class B cirrhosis undergoing first systemic therapy, nivolumab was associated with significantly lower hazard of death compared to sorafenib after adjusting for important covariates.

Outcome of patients with HCC and liver dysfunction under immunotherapy: a systematic review and meta-analysis

“…Thereafter, 21 articles were excluded and 15 studies were finally included for meta-analysis (1 clinical trial and 14 observational studies), [13,[23][24][25][26][27][28][29][30][31][32][33][34][35][36] 4 of these being abstracts. [25][26][27][28] Between reviewer agreement for the inclusion process was 0.75 (95% CI, 0.70-0.80), as assessed by the kappa coefficient. There was disagreement with respect to 4 studies and it was resolved by a third reviewer (M.R.…”

“…[32][33][34] In total, 639 (27.7%) patients were classified as Child-Pugh B and 34 (1.5%) as Child-Pugh C. [27,29,31,33,35] Three of the studies included only Child-Pugh B patients [13,26,30] and 1 study included Child-Pugh B and C patients only. [27] Patients Child-Pugh B and C patients The treatment line was described in 319 patients (47.1%), [13,23,[26][27][28]30,36] of which 212 patients (66.5%) were in the first line, 93 (29.2%) in the second line, and 14 (4.9%) in the third line. Only 3 of the 15 studies [13,28,30] reported the BCLC stage in Child-Pugh B or C patients but in none of these studies was the OS analyzed according to the BCLC stage.…”

“…After initial screening, 186 articles not relevant for the study were excluded and 36 potential study reports were assessed for eligibility at the full-text level. Thereafter, 21 articles were excluded and 15 studies were finally included for meta-analysis (1 clinical trial and 14 observational studies),13,23–36 4 of these being abstracts 25–28…”

“…[20][21][22] Regardless the lack of any evidence, it has been widely hypothesized that immunotherapy could potentially have a less pronounced impact on liver function and could be safer for HCC patients with liver dysfunction, resulting in improved survival. However, until now only 1 single-arm clinical trial with nivolumab in first-line or after sorafenib [12] has evaluated this population and some immunotherapy-based regimes [23][24][25][26][27][28][29][30][31][32][33][34][35][36] have assessed this special population and in real-life studies reported heterogeneous results.…”

Real-world treatment patterns, clinical outcomes, and health care resource utilization in advanced unresectable hepatocellular carcinoma

“…It is unclear if this is due to those patients having overall better general fitness or if the treatment was effective in this patient population. Given that clinical trials and provincial drug reimbursement criteria are typically restricted to Child-Pugh A patients, real-world studies of effectiveness of emerging therapies for Child-Pugh B patients, particularly Child-Pugh score B7, should be conducted to determine if clinical outcomes could be improved for those patients and this is currently being explored by several groups (24,25). Finally, we observed that patients with HCV, the most common etiologic risk factor in this study, had better survival than patients with an unknown etiology.…”