Therapeutic efficacy of ramucirumab after lenvatinib for post-progression treatment of unresectable hepatocellular carcinoma

Sources of patients

A total of 385 patients with u-HCC were treated with lenvatinib at specific institutions in Japan (Ehime Prefectural Hospital, Ogaki Municipal Hospital, Himeji Red Cross Hospital, Takamatsu Red Cross Hospital, Kagawa University, Osaka Medical School, Nippon Medical School, Ehime University Graduate School of Medicine, Teine Keijinkai Hospital, Saiseikai Niigata Hospital, Kagawa Prefectural Central Hospital, Okayama City Hospital, Asahi General Hospital, Toyama University Hospital, Otakanomori Hospital, Tokushima Prefectural Central Hospital, Matsuyama Red Cross Hospital, and Hamamatsu University School of Medicine) between May 2018 and January 2020. Among them, 28 who received ramucirumab as post-progression treatment and showed therapeutic response were evaluated in a retrospective manner.

Basal hepatic disease related to HCC

HCC due to hepatitis C virus (HCV) was judged when the anti-HCV was positive, whereas HCC due to hepatitis B virus (HBV) was judged when the hepatitis B virus surface antigen (HBsAg) was positive.

Methods for hepatic reserve function and therapeutic-response assessments

Child–Pugh classification [12] and albumin-bilirubin (ALBI) grade were used for assessment of the hepatic reserve function. The ALBI grade was calculated with serum-albumin and total-bilirubin values using the following formula: ALBI score = [log10 bilirubin (µmol/L) × 0.66] + [Albumin (g/L) × −0.085)], with the result defined by the following scores: ≤−2.60, Grade 1; >−2.60 to ≤−1.39, Grade 2; and >−1.39, Grade 3 [13–15]. To perform more detailed evaluations of patients with the middle ALBI grade of 2, we used a revised grading system consisting of four levels that included sub-grading for the middle grade of 2 (2a and 2b) based on an ALBI score of −2.27 as the cut-off, which was previously developed based on the value for indocyanine green retention after 15 min (ICG-R15) of 30% [16, 17].

Local physicians at each participating hospital independently evaluated HCC status using dynamic computed tomography (dy-CT) and/or magnetic resonance imaging (MRI) procedures performed at 4 or 8 weeks after the introduction of post-progression treatment (sorafenib or ramucirumab) based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1 [18], when possible.

HCC diagnosis and treatment

Based on an increasing course of AFP, as well as dy-CT [19], MRI [20, 21], contrast-enhanced ultrasonography with perflubutane (Sonazoid^®, Daiichi Sankyo Co., Ltd, Tokyo, Japan) [22, 23], and/or pathological findings, HCC was diagnosed. We used Barcelona Clinic Liver Cancer (BCLC) stage [24] and tumor node metastasis (TNM) stage, determined as previously reported in a study for the TNM staging of HCC conducted by the Liver Cancer Study Group of Japan (LCSGJ) 6th edition [25] (TNM-LCSGJ), to evaluate tumor progression. Written informed consent for MTA treatment was obtained from all of the patients. The protocol used in the present study was approved by the Institutional Ethics Committee of Ehime Prefectural Central Hospital (IRB No. 30-66).

Ramucirumab treatment and assessment of adverse events

Ramucirumab was given as an intravenous injection at a dose of 8 mg/kg once every 2 weeks. According to the guidelines for the administration of ramucirumab, the dose should be reduced or the treatment should be interrupted when a patient develops any Grade 3 or more severe adverse event (AE) or if any unacceptable Grade 2 drug-related AE occurs. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [26]. The worst grade for each AE during the present observation period was recorded. If a drug-related AE occurred, dose reduction or temporary interruption was maintained until the symptom was resolved to Grade 1 or 2, according to the guidelines provided by the manufacturer.

Statistical analysis

Statistical analyses were performed using the Kaplan–Meier method or a log-rank test. A P-value <0.05 was considered statistically significant. Easy R (EZR), version 1.29 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [27], a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria), was used for all statistical analyses.

Patient characteristics

Among the 385 patients treated with lenvatinib during the study period, 28 who subsequently received ramucirumab as post-progression treatment were analysed. Their median age was 70 years and 23 were male. Six were diagnosed pathologically and the others were using the diagnostic algorithm for HCC [24]. No patient had any known past history of chronic hepatic failure, chronic respiratory diseases, or chronic renal failure. Twenty-one were classified as Child–Pugh A and seven as Child–Pugh B, and the median ALBI score was −2.19. BCLC stage C was noted in 25. All had undergone lenvatinib treatment, with ramucirumab used as second-line treatment in 14, as third-line in 9, and as fourth-line in 5 (Table 1).

Therapeutic efficacy

Among these 28 patients, therapeutic response according to RECIST version 1.1 was obtained in 26. Partial response (PR) was observed in only 1 and stable disease (SD) was noted in 10, whereas progressive disease (PD) was seen in 15, with an objective response rate (ORR) of 3.8% (1/26) and a disease-control rate (DCR) of 42.3% (11/26) (Table 2). Until the end of January 2020, ramucirumab treatment was stopped in 18; the major reasons for discontinuation were PD in 16 and AE (Grade 3) in 2 (gastrointestinal bleeding, ascites). The median time to progression (TTP) was 2 months [95% confidential interval (CI), 1.4–3.2 months] (Figure 1A). There were no significant differences for TTP and DCR between patients who only received lenvatinib and those treated with multiple MTA drugs, including lenvatinib before ramucirumab (1.8 vs 2.1 months, P = 0.789) (38.5% vs 46.1%, P = 1.0). TTP was also not significantly different between Child–Pugh class A and B classification (2.0 vs 2.1 months, P = 0.986). At the end of the study period, more than half of the patients had survived, thus the median survival time after introducing ramucirumab and the initial MTA drug were not reached (Figure 1B and C).

Adverse events

Grade 3 AEs noted in the 28 patients were hepatic coma (n = 1; 3.6%), gastrointestinal bleeding (duodenal ulcer: n = 1; 3.6%), ascites (n = 1; 3.6%), fatigue and appetite loss (n = 1; 3.6%), and fever (n = 1; 3.6%), whereas Grade 1/2 AEs included ascites or pretibial edema (n = 6; 21.4%), fatigue and appetite loss (n = 5; 17.8%), diarrhea (n = 3; 10.7%), and fever (n = 1; 3.6%) (Table 3).

Statement of ethics

The present study protocol was approved by the Institutional Ethics Committee of Ehime Prefectural Central Hospital [IRB No. 30-66]. The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.