The anti-PD-1 inhibitor camrelizumab showed antitumor activity in pretreated Chinese patients with advanced hepatocellular carcinoma and displayed manageable toxicities, according to a recent paper in Lancet Oncology.
The anti-PD-1 inhibitor camrelizumab (AiRuiKa, SHR-1210) showed antitumor activity in pretreated Chinese patients with advanced hepatocellular carcinoma (HCC) and displayed manageable toxicities, according to a recent paper inLancet Oncology.
Nearly 15% of patients displayed an objective response (n = 32 of 217; 14.7%; 95% Confidence Interval [CI], 10.3 20.2). The overall survival (OS) probability at 6 months was 74.4% (95% CI, 68.0 – 79.7).
Slightly less than one-fourth of patients (n = 47, 22%) experienced grade 3 or 4 treatment-related adverse events (AEs). The most common of these were increased aspartate aminotransferase (n = 10, 5%) and decreased neutrophil count (n = 7, 3%). The most common treatment-related AEs of any grade were reactive cutaneous capillary endothelial proliferation (RCCEP) in 145 of 217 patients (67%). Additionally, 55 patients (25%) developed increased aspartate aminotransferase, while similar numbers of patients developed increased alanine aminotransferase (n = 51, 24%), and proteinuria (n = 50, 23%).
The investigators judged that 2 deaths were potentially treatment-related (1 each due to liver dysfunction and multiple organ failure).
“In China, regorafenib is the only approved second-line therapy for advanced hepatocellular carcinoma. Considering the high malignancy and heterogeneity of disease and scarce treatment options for Chinese patients, there is a great unmet need to develop novel drugs for advanced hepatocellular carcinoma,” wrote the authors, led by Shukui Qin, MD, PhD, Cancer Center of Jinling Hospital, Nanjing, China. “This study showed that camrelizumab showed antitumour activity and could be a second-line and beyond treatment option for advanced hepatocellular carcinoma patients, even for a population with a high proportion of patients with HBV [hepatitis B virus] infection.”
Patients were eligible for this phase II randomized open-label trial if they had advanced HCC and had progressed on or were intolerant of previous systemic treatment. Other eligibility requirements included having at least one measurable lesion, Child-Pugh scores of 7 or less, an ECOG performance score of 0 or 1, and adequate organ function.
Exclusion factors included previous anti-PD-1 or anti-PD-L1 immunotherapy for HCC, cholangiocarcinoma or fibrolamellar and mixed hepatocellular subtypes. Other active malignancies, symptomatic ascites, and gastrointestinal bleeding in the past 6 months were also exclusionary.
Patients were randomized 1:1 to receive camrelizumab 3 mg/kg intravenously either every 2 weeks or every 3 weeks. Patients in the 2-week group received their infusions over 30 minutes on day 1, day 15, and day 29 of each 6-week cycle. Patients in the 3-week group on received treatment on day 1 and day 22 of each cycle. Dose modifications were not allowed, although treatment interruptions were permitted. On-study imaging began at week 8 and continued every 6 weeks up through 12 months. After a year, imaging continued at 12-week intervals until treatment discontinuation.
The study’s primary endpoints were objective response as assessed by blinded independent central review and 6-month OS. Secondary endpoints were the proportion of patients with disease control, duration of response, time to progression, progression-free survival (PFS), OS and safety. The authors also conducted a prespecified exploratory analysis to assess PD-L1 expression as a potential biomarker for camrelizumab treatment.
Investigators enrolled 220 patients, 111 in the 2-week group and 109 in the 3-week group. Of these, 217 patients received at least one treatment dose. Nearly 80% of patients (n = 171, 79%) had an ECOG performance score of 1 and slightly more than half (n = 111, 51%) had an AFP concentration of 400 ng/mL or greater. More than 80% of patients had extrahepatic metastases (n = 177, 82%) or had HBV infection (n = 181, 83%). Nearly half the patients (n = 49, 23%) had received 2 or more previous systemic treatments.
At the November 2018 data cutoff, the median follow-up was 12.5 months (Interquartile Range [IQR] 5.715.5), and 37 patients (17%) were still receiving the treatment. The median duration of exposure to camrelizumab was 4.6 months (IQR 2.1–9.7). Disease progression was the main reason for treatment discontinuation; 87 patients (40%) received subsequent therapy.
Approximately half of the patients in each group had died as of data cutoff, including 55 of 109 (50%) in the 2-week group and 60 of 108 (56%) in the 3-week group. Approximately 80% of all patients experienced a PFS survival event, including 89 (82%) in the 2-week group and 86 (80%) in the 3-week group.
Qin et al noted that camrelizumab had a safety profile similar to other PD-1 immune checkpoint inhibitors, except for the occurrence of RCCEP. “RCCEP occurred on the skin (mainly on the face and trunk), and a few instances were complicated by reactive capillary endothelial proliferation in oral and nasal mucosa and palpebral conjunctiva, but not in the respiratory tract and gastrointestinal mucosa,” they wrote. “RCCEPs were mild or moderate, clinically controllable, and self-limiting. Consistent with the findings in solid tumors, in most patients in this study, RCCEP was reported in the early treatment cycles.”
Regarding their exploratory endpoint, Qin et al noted that PD-L1 expression data were available for 30 patients. Among 11 patients with expression of PD-L1 of 1% or higher, 4 patients (36%) achieved an objective response. Among 19 patients with PD-L1 of less than 1%, only 2 patients (11%) achieve an objective response. The authors wrote that the proportion of PFS events was 9 of 11 patients (82%) and 16 of 19 patients (84%), respectively.
Looking ahead, Qin et al plan to report in a future article their comprehensive investigation of RCCEP in advanced HCC. They hope to include the occurrence features and clinicopathological characteristics, as well as predictive value by landmark analysis.
Qin et al also plan to look beyond monotherapy in future work. “In addition to monotherapy with PD-1 inhibitors, additional treatment strategies such as combination with targeted therapy or chemotherapy are needed to further improve treatment outcomes,” they wrote.
Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial.Lancet Oncol. 2020;21:57180. Published online February 26, 2020.https://doi.org/10.1016/S1470-2045(20)30011-5