The combination of camrelizumab plus apatinib demonstrated a high objective response rate (ORR) and disease-control rate (DCR), as well as durable responses and long survival as treatment of patients with advanced hepatocellular carcinoma (HCC), according to the results from the phase 2 RESCUE clinical trial (NCT03463876).
In addition, the trial demonstrated a manageable safety profile with the combination.
In advanced HCC, the efficacy of immune checkpoint inhibition monotherapy is limited, but the combination of these agents with an anti-angiogenic agent has emerged as a potential novel treatment strategy. The phase 1 study was launched in October 2016 to evaluate this combination of camrelizumab, a high-affinity, humanized IgG4-k PD-1 monoclonal antibody, and apatinib, the selective VEGFR-2 tyrosine kinase inhibitor, and demonstrated promising antitumor activity with an acceptable safety profile in patients with advanced HCC.
The non-randomized, open-label, multicenter RESCUE study enrolled patients with advanced HCC who were either treatment-naïve or refractory/intolerant to first-line targeted therapy in order to assess both the efficacy and safety of the combination in both the first- and second-line settings. The study was conducted across 25 centers in China. Camrelizumab was administered intravenously at either 200 mg for bodyweight ≥50 kg or 3 mg/kg for bodyweight <50 kg for 20 to 60 min every 2 weeks. Apatinib was administered orally at 250 mg/day in 4-week cycle.
The primary end point was ORR by an Independent Review Committee (IRC) per RECIST v1.1, and the secondary end points included investigator-assessed ORR per RECIST, ORR by IRC per mRECIST, DCR, duration of response (DOR), progression-free survival (PFS), probability of overall survival (OS) at 9, 12, and 18 months, and safety. Seventy patients in the frontline setting and 120 in the second-line setting were enrolled to RESCUE between March 13, 2018 and January 3, 2019 and received study treatment.
The ORR by IRC per RECIST v1.1 was 34% in the first-line cohort (95% CI, 23-47) and 23% in the second-line cohort (95% CI, 15-31), and the DCR rate was 77% (95% CI, 66-86) and 76% (95% CI, 67-83), respectively. In the first-line cohort, complete responses (CRs) were observed in 1 patient (1%), partial responses (PRs) in 23 (33%), stable disease (SD) in 30 (43%), and progressive disease (PD) in 13 (19%). In the second-line cohort, 2 (2%) achieved a CR, 25 (21%) achieved a PR, 64 (53%) had SD, and 26 (22%) had PD.
The median DOR was 14.8 months in the first-line cohort (95% CI, 5.5-not reached [NR]) and was NR in the second-line cohort. The median PFS in the first-line cohort was 5.7 months (95% CI, 5.4-7.4) and 5.5 months (95% CI, 3.7-5.6) in the second-line cohort. The median time to recurrence was 1.9 months (range, 1.8-3.7) for both arms.
The best response, according to mRECIST, was a CR in both the first-line (n = 6; 9%) and the second-line cohorts (n = 2; 2%). PRs were observed in 26 patients (37%) from the first-line arm and 28 (23%) in the second-line arm. SD was achieved by 23 (33%) in the first line and 61 (51%) in the second line, and PD was observed in 12 (17%) and 26 (22%), respectively. The ORR was 46% (95% CI, 34-58) in the first-line cohort and 25% (95% CI, 18-34) in the second-line cohort.
According to mRECIST, the median DOR was NR in either arm, and the median PFS was 6.4 months (95% CI, 4.8-9.2) in the first-line cohort and 5.5 (95% CI, 3/7-7.3) in the second-line cohort. The median time to recurrence was 1.9 months (range, 1.8-2.5) and 1.8 months (95% CI, 1.8-3.5), respectively.
The median OS was 20.3 months in the first-line cohort (95% CI, 15.0-NR) and NR in the second-line cohort (95% CI, 17.3-NR).
In terms of safety, grade 3 or higher treatment-related adverse events (TRAEs) occurred in 147 (77/4%) of patients overall, and serious TRAEs occurred in 55 patients (28.9%). Only 2 (1.1%) treatment-related deaths were recorded in the RESCUE study.
The most common grade 3 or higher TRAEs included hypertension in 65 patients (34.2%), gamma-glutamyl transferase increase in 22 (11.6%), neutropenia in 21 (11.1%), aspartate aminotransferase increase in 20 (10.5%), hyperbilirubinemia in 20 (10.5%), thrombocytopenia in 19 (10.0%), and hand-foot syndrome in 17 (8.9%). The most common TRAE of any grade was hypertension, which occurred in 138 patients (72.6%).
To be included in this study, patients had to have a histologically confirmed diagnosis of unresectable or metastatic advanced HCC who were either treatment-naïve or had progressed on or became intolerant to frontline targeted therapy. Patients had to have BCLC stage B or C and an ECOG performance status of 0 or 1.
The baseline characteristics demonstrated the median age of patients was 53 years (range, 44-60) in the first-line cohort and 52 years (range, 43-58) in the second-line cohort. The majority of patients were male, which included 63 (90.0%) in the first-line cohort and 106 (88.3%) in the second-line cohort, and the ECOG performance status was mostly 0, in 46 patients (65.7%) and 68 patients (56.7%), respectively. Additionally, 62 patients (88.6%) in the first-line cohort and 106 (88.3%) in the second-line cohort had HBV infection.
The BCLC stage was primarily C, which was observed in 58 patients (82.9%) and 98 (81.7%) in the first- and second-line arms, and 48 (68.6%), and 91 (75.8%) had extrahepatic metastases, respectively. The majority of patients in the first- and second-line settings had received prior surgery (67.1% v. 83.3%), while others received radiotherapy (17.1% v. 26.7%), interventional therapy (62.9% v. 77.5%), and local ablation (30.0% v. 35.8%).
Based on the findings from this study, the authors concluded that the combination of camrelizumab and apatinib may represent a novel therapeutic option for both patients with advanced HCC in the first- and second-line settings of treatment.
Xu J, Gu S, Zhang Y, et al. Camrelizumab © in combination with apatinib (a) in patients with advanced hepatocellular carcinoma (rescue): an open-label, multi-center, phase 2 trial. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 983P.